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Revista Mexicana de

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

Órgano Oficial de Difusión de la AMN

AcademiaMexicana deNeurología, A.C.

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

International editorial comitee

National editorial comitee

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

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

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

Héctor Gerardo Hernández RodríguezMaestro Alejandro GarcíaRebeca BarrosoDesign Cortex

Statistical AdvisorStyle corrector

TranslatorDesign

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

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

Contenidos ContentsEDITORIAL• Carta Editorial por el Dr. Ildefonso

Rodríguez Leyva

CONTRIBUCIONES ORIGINALES• Enfermedad de Fabry. Reporte de doce casos• Predictores Clínicos, Psicoafectivos y

Neuropsicológicos en la Respuesta al Tratamiento Profiláctico de la Cefalea Crónica Diaria

• Reserva cognitiva y factores asociados en una muestra de adultos mayores indígenas

• Cambios del dolor neuropático en dos pacientes con síndrome de salida torácica debido a costilla cervical accesoria

• Validación de la versión en español de la Aberrant Behavior Checklist-Community en pacientes autistas mexicanos.

REVISIONES • Modelo de reserva cognitiva: orígenes,

principales factores de desarrollo y aplicabilidad clínica

• Investigación sobre Cuidados Paliativos en México. Revisión Sistemática Exploratoria

• Epilepsia del lóbulo temporal por displasia tipo IIIa. ¿Qué sabemos de esta entidad?

REPORTES DE CASO• Síndrome de Susac (vasculopatía

retinococleocerebral): reporte de un caso

EDITORIAL• Editorial letter by Dr. Ildefonso

Rodríguez Leyva

ORIGINAL CONTRIBUTIONS• Fabry disease. Report of twelve cases• Clinical, Psychoaffective and

Neuropsychological Predictors in Response to Prophylactic Treatment of Chronic Daily Headache

• Cognitive reserve in indigenous• Changes of neuropathic pain in two patients

with thoracic outlet syndrome due to accessory cervical rib

• Validation of the spanish version of the Aberrant Behavior Checklist in Mexican autistic patients.

REVIEWS• Cognitive Reserve Model: Its Origins,

Main Developmental Factors and Clinical Applicability.

• Research on Palliative Care in Mexico. Scoping review

• Temporal lobe epilepsia caused by dysplasia type IIIa

CASE REPORTS• Susac’s Syndrome (retinocochleocerebral

vasculopathy): a case report

Revista Mexicana de Neurociencia march-april 19,2 (2018): 1-3

Editorial2

REVISTA MEXICANA DE NEUROCIENCIA MARCH 2018

Dear readers,

We are a year away from having accepted the challenge of continuing to lead the Mexican Journal of Neuroscience on a good path, after the great work done by Drs. Carlos Cantú Brito and Erwin Chiquete Anaya, as Editor-in-Chief and as co-editor respectively, we have been learning about the complexity of this work and we are working with the support of experts and the entire neurological community of the country in order to achieve indexation and a best positioning of the journal, that we hope will be proud of the Neurology of Mexico.

One of the important points in this achievement is to have a journal published in both Spanish and English, with the highest quality standards and that is why an expert translator is supporting us; however, the feasibility of continuing with this process is complicated because of the high cost involved. Faced with this situation, the Board Members have raised the possibility of asking those who favor us with their work to cover the average cost of the translation into English of their article, in the effort to keep this new work scheme viable.

Although the commercial opening of our publication seems bound to support it, we maintain the commitment to avoid influencing the articles that are published to our readers and of course, due to the possible appearance of commercial pharmaceutical houses in the next publications, we do not want to give preference to brands, pharmaceutical products or diagnostic support in an unethical way and our final objective is to favor the neurological knowledge of our readers for the benefit of their patients.

The country is in a new electoral process, in which it is desirable that justice, welfare, health and especially education are sought for all of society, our community participates actively, as we are part of those who have the privilege of having received a professional education that has allowed us to live with wealth that not all the population has, that is why our social commitment becomes more important and the need to transform society

Editorial

Revista Mexicana de Neurociencia march-april 19,2 (2018): 1-3

Editorial 3

in an honest and responsible way also corresponds to us, because if the words move, the example drags.

A similar process is to be lived within the Mexican Academy of Neurology and each one of its members will surely participate actively supporting the one who considers their ideas related. Whoever may end as a winner of this process, our work must maintain a line of transparency so clear that it can be shown with numbers and results to satisfy each one of us who are part of this community, which has managed to increase knowledge of each one of its members, for example by increasing the number of publications to which we have access in our library portal to which each active member has his or her individual and exclusive access.

As you can see, we are in a time of changes, therefore these great challenges could be solved more easily and adequately, in order to have a better Mexican Neuroscience Magazine, also a prosperous Mexican Academy of Neurology and above all a fairer, healthier, more responsible and honest country.

Ildefonso Rodríguez-Leyva Editor-in-Chief

Revista Mexicana de Neurociencia march-april, 2018; 19(2):4-14

Original contributionFabry disease

4

Fabry disease. Report of twelve cases

Enfermedad de Fabry. Reporte de doce casos

Original contribution

Sofía Lucila Rodríguez-Rivera,1 Martín Arturo Silva-Ramírez,1

María Castro-Tarín,1 Flora López-Cebada.1

1Department of Pediatric Neurology, La Raza National Medical Center. Mexico City, Mexico.

Abstract

Introduction: Fabry disease is one of the lysosomal storage diseases caused by deficiency of the enzyme alpha galactosidase acid. In childhood and adolescence, paroxysmal pain and acroparesthesias are characteristic.

Objective: Report clinical characteristics, pain scale, level of IQ and quality of life in children with Fabry disease.

Methods: The most frequent neurological manifestations were determined by clinical history and neurological examination of children with Fabry Disease receiving enzyme replacement therapy at the HG CMN La Raza, from January to May 2016. Brief Pain Inventory,4 quality of life SF366 survey and Wechsler’s scale of intelligence for children reviewed (WISC-R) Verbal Scale5 were applied.

Results: We included 12 patients. Female gender (67%). Onset of neurological manifestations: male 6.25 years old and female 9.12 years old. Autonomic and sensitive neuropathy were the most frequent neurological manifestations. Nine patients presented neuropathic pain (75%), with pain improvement after treatment as reported by the parents in the clinical record. We found 3 patients with borderline IQ and 3 patients with IQ below normal, arithmetic most affected. Seven patients presented quality of life level of 51-60, with greater affectation in social function and body pain, a situation that has improved with the use of enzymatic therapy according to what was referred by the relatives.

Conclusions: Enzyme replacement therapy produces improvement in pain scale, cognitive level and quality of life in children treated at IMSS, which is similar to that reported in international literature.

KeywordsFabry disease, enzyme replacement therapy, scales.



5

Corresponding Author: Dra. Sofía Lucila Rodríguez-Rivera.Departamento de Neurología Pediátrica, Centro Médico Nacional La Raza; Calzada Vallejo S/N,Col. La Raza, Delegación Azcapotzalco. Ciudad de México; México. Código Postal: 02990Tel.: (871) 1 74-85-15.E-mail: [email protected]

Resumen

Introducción: La enfermedad de Fabry es una de las enfermedades de depósito lisosomal producida por la deficiencia de la enzima alfa galactosidasa ácida. En la infancia y la adolescencia son características las crisis de dolor paroxístico y acroparestesias.

Objetivo: Reportar características clínicas, escala de dolor, nivel de coeficiente intelectual y calidad de vida en niños con enfermedad de Fabry.

Métodos: Se determinaron las manifestaciones neurológicas más frecuentes mediante historia clínica y exploración neurológica de niños portadores de Enfermedad de Fabry que reciben terapia de reemplazo enzimática en el HG CMN La Raza, de enero a mayo 2016. Se aplicaron encuestas de escala de dolor Brief Pain Inventory4 y calidad de vida SF366, y para el nivel cognitivo se utilizó escala de inteligencia de Wechsler para niños revisada (WISC-R) Escala Verbal.5

Resultados: Se incluyeron 12 pacientes con predominio del género femenino (67%). Edad de inicio de manifestaciones neurológicas: masculinos 6.25 años y femeninos 9.12 años. Las manifestaciones neurológicas más frecuentes fueron neuropatía autonómica y sensitiva. Nueve pacientes presentaron dolor neuropático (75%), con mejoría del dolor después de tratamiento según lo informado por los padres en la historia clínica. Se encontraron 3 pacientes con coeficiente intelectual limítrofe y 3 pacientes con coeficiente intelectual debajo de lo normal; el área más afectada fue aritmética. Siete pacientes presentaron nivel de calidad de vida de 51-60, con mayor afectación en función social y dolor corporal, situación que ha mejorado con el uso de terapia enzimática de acuerdo a lo referido por los familiares.

Conclusiones: La terapia de reemplazo enzimática produce mejoría en la escala de dolor, nivel cognitivo y calidad de vida en niños atendidos en el IMSS, lo cual es similar a lo reportado en la literatura internacional.

Palabras claveEnfermedad de Fabry, terapia reemplazo enzimática, escalas.



6

Introduction

Methods

Results

Fabry disease is one of the lysosomal storage disorders, caused by a deficiency of the α-galactosidase A enzyme.1 There are therapeutic alternatives available for the control of this disease, one of which is enzyme replacement therapy. It is known internationally that this therapy allows to reduce the amount of glycolipids stored in the tissues, modifies neuropathic pain, decreases frequency and intensity of acral pain episodes, stabilizes renal function, and reduces excess cardiac mass, as well as it improves the quality of life and the symptomatology at the digestive level.2 In Mexico, reports exist only of adult patients treated with enzyme therapy.3 Information about children is still scarce, and we consider it pertinent to communicate the series of cases of children with Fabry disease that receive enzymatic therapy at the Mexican Social Security Institute. Therefore, we performed a cross-sectional study in which we described clinical characteristics, pain scale, level of IQ, and quality of life in children with Fabry disease who received enzyme replacement therapy.

A descriptive and cross-sectional study was conducted. The study included 12 children with Fabry disease receiving enzymatic therapy in La Raza General Hospital at the National Medical Center in Mexico City, in the period from January to May 2016. Patients who agreed to participate underwent the usual physical examination in an external consult. In two subsequent appointments, the Brief Pain Inventory4 was applied to assess pain at its average and maximum expression, rating it as mild (0-3), moderate (4-7), or severe (8-10). The Wechsler Intelligence Scale for Children—Revised (WISC-R) Verbal Scale5 was applied to evaluate the cognitive level under the supervision of a collaborating neuropsychologist. Scale scores are determined as very superior (130 or more), superior (129-120), above average (119-100), average (109-90), below average (89-80), borderline (79-

A total of 12 patients diagnosed with Fabry disease were admitted to our study during the period from January to May 2016.

The patients’ age range was 7 to 16 years, with an average of 12.33 years, 3.39 SD, and a median of 13.5 years. Females predominated with eight patients (67%), males were four patients (33%). Regarding time with neurological manifestations, the children presented a range of 1-12 years, with an average of 4.1 years, 3.29 SD, and a median of 4 years. The range of enzyme replacement therapy was from 3 months to 4 years, with a mean of 2.12 years, 1.12 SD, a mode of 1, and a median of 1.65. (Table 1)

The most frequent clinical manifestations were autonomic and sensory neuropathy in ten patients with Fabry disease.

The paraclinical manifestations found:A. In skull MRI, the most common were cortical subcortical atrophy (3 patients), thalamic hyperintensities (2 patients), corpus callosum dysgenesis (1 patient), and normality (6 patients).

70), mildly impaired (60-50), moderately impaired (49-35), severely impaired (34-20), and profoundly impaired (less than 20). The Short Form Health Survey (SF36)6 was applied. Standardized in 1996 and validated by J. Alonso et al., it allows measuring health-related quality of life across eight domains: physical function, physical role, body pain, general health, vitality, social function, emotional role, and mental health. The items were applied to a scale ranging from 0 to 100, where 0 is the worst result and 100 is the best.

The database was captured in Excel. Average, median, and mode descriptive statistics were performed, as well as the standard deviation of the variables that required it.



7

Table 1. Demographic data of patients with Fabry disease.

B. In the EEG the alterations presented included bioelectrical dysfunction (3 patients), paroxysmal pattern, spikes and polyspikes (3 patients), and normality (6 patients). (Figure 1)

In the pain scale,4 three patients were found to have mild intensity, eight had moderate, and one severe. (Figure 2)

Regarding the cognitive level scale,5 three patients with borderline IQ were identified, three patients with IQ below average, three patients with average IQ, one patient with IQ above average, and two patients with very superior IQ. (Figure 3)

Demographic data

1

2

3

4

5

6

7

8

9

10

11

12

Current age, years

15

16

16

7

13

15

15

10

7

14

11

9

Sex,M1/F2

M

F

M

F

M

F

F

F

F

F

F

M

Age of onset of NM3, years

10

15

4

3

4

11

11

8

6

10

9

7

Time withNM3, years

5

1

12

4

9

4

4

2

1

4

2

2

Time withERT4, years

3

3

2.5

2

4

2

1.3

1

1

0.25

0.25

1

In the scale of quality of life6 in patients with Fabry disease, seven patients showed a 51-60 level, with greater affectation in the areas of social function and body pain. (Figure 4)

In the three scales it was possible to identify that the longer they had treatment, the better the improvement in their pain scores, cognitive level, and quality of life; however, it was not possible to know what the baseline was prior to the enzyme therapy because all the children admitted to the study had already been diagnosed and treated with enzymatic therapy when they arrived at our office.

1 Male2 Female3 Neurologic Manifestations4 Enzyme Replacement Therapy



8

Figure 1. Neurologic and paraclinical manifestations in patients with Fabry disease (A and B). EEG, Electroencephalography; CNMR, Cardiac Nuclear Magnetic Resonance.

Hearing lossTrophic changes

Lower motor neuronsUpper motor neurons

EpilepsyPsycomotor retardationAutonomic neuropathy

Sensory neuropathy

PATIENTS

A.N

EUR

OLO

GIC

MA

NIF

ESTA

TIO

NS

0 2 4 6 8 10 12

Paroxysmal EEG

EEG with bioelectrical dysfunction

CNMR cortical subcortical atrophy

CNMR dysgenesis of the corpus callosum

CNMR thalamic hyperintensities

PATIENTS

B.

PAR

AC

LIN

ICA

L

0 0.5 1 1.5 2 2.5 3 3.5

3

3

3

2

1



9

PATI

ENTS

A.

3

8

8

MILD MODERATENEUROPATHIC PAIN SCALE

SEVERE

9

8

7

6

5

4

3

2

1

0

TIM

E W

ITH

ER

T1

B.

1.8 1.85

1

MILD MODERATENEUROPATHIC PAIN SCALE

SEVERE

21.81.61.41.2

10.80.60.40.2

0

Figure 2. Pain scale in relation to time with enzyme replacement therapy in patients with Fabry disease (A and B).

1Enzyme Replacement Therapy, years.



10

Figure 3. Cognitive level scale in relation to time with enzyme replacement therapy in patients with Fabry disease (A and B).

1Enzyme Replacement Therapy, years.

4321

0

COGNITIVE LEVEL

COGNITIVE LEVEL



11

87654321

0

QUALITY OF LIFE



12

Twelve patients with Fabry disease were included during the period from January to May 2016.

Regarding demographic data, there was a predominance of the female gender with 67% of the cases. In the past it was believed that the disease only affected men and that women were asymptomatic carriers; however, it has been observed that females can also manifest signs and symptoms and they can be as severe as the males’.7

The boys presented onset of neurological manifestations in the range of 4-10 years of age, with an average of 6.25 years and a median of 5.5 years. The girls presented onset of neurological manifestations in the range of 3-15 years of age, with an average of 9.12 years and a median of 9.5 years. This coincides with the world literature reports of age of onset in males at 6-10 years, and in females at 8.1-14 years.8

Regarding the neurological manifestations in patients with Fabry disease in our study, we observed that the most frequent neurological manifestations were autonomic and sensory neuropathy. This is similar to what was reported by Ries in a 2005 prospective study9 of children with Fabry disease, in which he showed that the predominant clinical manifestation was neuropathic pain. Furthermore, the systematic review of clinical effectiveness and cost-effectiveness according to Connock in 2006,10 allows concluding that the administration of enzymatic therapy produces beneficial effects on pain and the sensorineural function of the patient.

In the pain scale,4 nine patients presented neuropathic pain (75%). The international studies report that neuropathic pain is the most relevant clinical finding in the patient with Fabry disease and constitutes an important cause of disability, absenteeism in the adult population, and hospitalization in the pediatric age.11 In our study, the pain decreased in the scale with the use of long-term therapy according to what was reported by

Discussion

the relatives of the patients, which coincides with the reports by Eng and by Schiffmann in 2001,12-15 and Jin-Ho in 2008,15 who suggested that the administration of enzymatic treatment in patients with Fabry disease produced reduction in pain and improvement in the quality of life of the patients.

At the cognitive level,5 six patients were identified with a deficit (50%) with greater affectation in arithmetic, presenting improvement in IQ level with long-term treatment. The North American working group of Beguscu et al.16 in a quasi-experimental study in 2015, found that with enzyme therapy they observed improvement of working memory and of attention in patients in whom cognitive deficit and alteration of executive functions were documented, which correlates with the findings in our study.

In the quality of life scale,6 seven patients who presented a level of 51-60 with greater affectation in the areas of social function and body pain, showed more improvement the longer they had therapy. A German follow-up study by Hoffmann, et al. in 2005,17 reported that patients with Fabry disease show a deterioration in the quality of life compared to the healthy population, that replacement therapy improves the quality of life scale after one year, and that the improvement becomes more effective after two years. They also report that neuropathic pain is the parameter that most affects the level of quality of life, which coincides with the findings of our study.

Since Fabry’s disease is a progressive, early-onset disease, it is a priority to initiate treatment early to avoid situations of irreversible damage.

Early diagnosis, although a challenge, is the key to a good prognosis in Fabry disease since it is a serious, progressive condition that deteriorates the quality of life, leads to an early death, and it’s almost always diagnosed when the affectation is very advanced, and the organic and tissue damage is irreversible.



13

Conclusions

This study observed that enzyme replacement therapy produces improvement of the pain scale, the cognitive level, and the quality of life in patients with Fabry disease who received this treatment in a group of Mexican children in the La Raza General Hospital, which is similar to what is reported in the international literature.18,19

Currently, in Mexico, enzyme replacement therapy is available. Though it is costly, its advantages are decisive in improving the patient’s quality of life because it modifies the course of the disease and significantly decreases Gb3 concentrations in the early stages. Finally, we consider that other prospective studies that follow up children with Fabry disease are necessary.

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

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



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1. Laney DA, Fernhoff PM, Diagnosis of Fabry disease via Analysis of Family History. J Genet Counsel 2008; 17; 79-83.

2. Hughes DA, Ramaswan U, Elliot P, Deegan P, et al. Guidelines for the Diagnosis and Management of Anderson-Fabry Disease, 2005.

3. Soto M Adrian, Díaz R Baruch, De los Ríos Diana, García Ramos Guillermo. Enfermedad de Fabry: Evento vascular cerebral en un joven y su abordaje diagnóstico. Rev Mex Neuroci. 2010; 11 (5): 359-362.

4. Cleeland CS. Pain assessment: the advantages of using pain scales in lysosomal storage diseases. Acta Paediatr Suppl. 2002; 439:43-7.

5. Elaborado a partir de Kaufman, A. S. (1979). Intelligent Testing with the WISC-R. Nueva York: Wiley; y Kaufman, A. S. (1994). Intelligent Testing with the WISC-III. Nueva York: Wiley.

6. Oliveira FL, Alegra T, Dornelles A, et al. Quality of life of Brazilian patients with Gaucher disease and Fabry disease. JIMD Rep. 2013; 7: 31-7.

7. Desnick RJ, Brady RO. Fabry disease in childhood. J Pediatr. 2004;144:S20-S26.8. Laney DA, Fernhoff PM. Diagnosis of Fabry Disease via Analysis of Family History. J Genet Counsel.

2008;17:79-83.9. Ries M, Gupta S, Moore DF, et al. Fabry Disease. Pediatrics 2005;115: e344–e355 URL: www.

pediatrics.org/cgi/doi/10.1542/peds.2004-1678.10. Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, Moore D. A systematic review

of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1. Health Technology Assessment. 2006; 10:1-130.

11. MacDermot J, MacDermot JD. Neuropathic pain in Anderson-Fabry disease: pathology and therapeutic options. Eur J Pharmacol. 2001;429:121–125.

12. Schiffmann R, Martin R, Reimschisel T, et al. Four-Year Prospective Clinical Trial of Agalsidase Alfa in Children with Fabry Disease. J Pediatr. 2010;156: 832-837.

13. Clarke JTR. Narrative Review: Fabry Disease. Ann Intern Med. 2007: 146 425-433.14. Herrero-Calvo JA. Enfermedad de Fabry: una forma de enfermedad renal crónica diagnosticable y

tratable. Nefrología. 2008;1:13-19.15. Eng CM, Fletcher J, Wilcox WR, et al. Fabry disease: Baseline medical characteristics of a cohort of

1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007;30:184–192.16. Nicolle Bugescu, Andrea Alioto, et.al. The Neurocognitive Impact of Fabry Disease on Pediatric

Patients, American Journal of Medical Genetics, 2015, 204-210.17. B Hoffmann, A Garcia de Lorenzo, Effects of enzyme replacement therapy on pain and health related

quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey). American Journal of Medical Genetics, 2015, 247-252.

18. Wraith JE, Tylki-Szimanska A, Guffon N, et al. Safety and Efficacy of Enzyme Replacement Therapy with Agalsidase Beta: An International, Open-label Study in Pediatric Patients with Fabry Disease. J Pediatr. 2008;152: 563-70.

19. Ramaswami U, Whybra C, Parini R, Pintos-Morell G, Mehta A, Sunder-Plassmann G, Widmer U, Beck M; FOS European Investigators. Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey. Acta Paediatr. 2006; 95:86-92.

References


Original contributionPredictors of Response to Prophylactic Treatment of Chronic Daily Headache

15

Clinical, Affective, and Neuropsychological Predictors of Response to Prophylactic Treatment of Chronic Daily Headache

Predictores Clínicos, Psicoafectivos y Neuropsicológicos en la Respuesta al Tratamiento Profiláctico de la Cefalea Crónica Diaria


Alan Azael Plascencia-Morán,1 Teresita Villaseñor Cabrera,1,2,3 Raúl Amavisca Espinosa,4 Miriam E Jiménez-Maldonado,2,3 Genoveva Rizo-Curiel,5 José Luis Ruiz-Sandoval.3,4

1Master’s Degree in Neuropsychology, University Center for Health Science (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico.2Neuropsychology Service at the “Fray Antonio Alcalde” Civil Hospital of Guadalajara. Guadalajara, Jalisco, Mexico.3Institute of Translational Neuroscience, Department of Neuroscience, University Center for Health Science (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico.4Neurology Service at the “Fray Antonio Alcalde” Civil Hospital of Guadalajara. Guadalajara, Jalisco, Mexico.5Department of Public Health, University Center for Health Science (CUCS), University of Guadalajara, Guadalajara, Jalisco, Mexico.

Abstract

Background: Daily chronic headache (CCD) represents a syndromic spectrum of diagnostic and therapeutic complexity affecting 3 to 5% of the general population.

Objective: To identify clinical, psychoaffective and neuropsychological predictors of good or poor response to the prophylactic pharmacological treatment of CCD.

Methods: Patients with CCD in previous prophylactic pharmacological treatment with age between 20 and 60 years were included. Several psycho-affective tests evaluated the level of anxiety, perception of illness, stress and depression; while neuropsychological domains evaluated attention, work memory, fluency and verbal memory. Good response to treatment was defined as a reduction of ≥ 50% in pain frequency.

Results: Forty patients with CCD (24 with chronic migraine and 16 with chronic tension-type headache) were included; 36 were women and 4 men with an average age of 40 years. Twenty patients were good responders (50%). A less frequency of headache (15 to 25 days per month) and the perception of treatment efficacy were associated with a good response (p = 0.053 and p = 0.008 respectively). There was significant tendency or association for better performance in work memory tests - inverse digits (p = 0.076), scalar digits score (p = 0.072), semantic verbal fluency (p = 0.001) - and the fifth item of the Perri test for verbal memory and learning (p = 0.021) among responders.

Conclusions: In this preliminary study, we identified a better overall and particular performance in some cognitive domains among patients with CCD and favorable response to established prophylactic treatment.

KeywordsHeadache, Chronic daily headache, Chronic tension-type headache, Chronic migraine, Prophylactic.



16

ResumenAntecedentes: La cefalea crónica diaria (CCD) representa un espectro sindromático de complejidad diagnóstica y terapéutica que afecta de 3 a 5% de la población general.

Objetivos: Identificar predictores clínicos, psicoafectivos y neuropsicológicos de buena o mala respuesta al tratamiento farmacológico profiláctico de la CCD.

Métodos: Fueron considerados los pacientes con CCD en tratamiento farmacológico profiláctico previo con edad entre 20 a 60 años. Varias pruebas psicoafectivas evaluaron el nivel de ansiedad, percepción de la enfermedad, estrés y depresión, en tanto que los dominios neuropsicológicos evaluaron atención, memoria de trabajo, fluencia y memoria verbal. La buena respuesta al tratamiento se definió por una reducción ≥ al 50% en la frecuencia del dolor.

Resultados: Cuarenta pacientes con CCD (24 con migraña crónica y 16 con cefalea crónica tipo tensional) fueron incluídos; 36 fueron mujeres y 4 hombres con edad promedio de 40 años. Veinte pacientes fueron buenos respondedores (50%). Una menor frecuencia de cefalea (15 a 25 días por mes) y la percepción de eficacia del tratamiento se asociaron a buena respuesta (p=0.053 y p=0.008 respectivamente). Hubo tendencia o asociación significativa para un mejor desempeño en pruebas de memoria de trabajo - dígitos inversos (p=0.076), puntuación escalar de dígitos (p=0.072), fluencia verbal semántica (p=0.001) - y ensayo 5 de la prueba de Perri para memoria verbal y aprendizaje (p=0.021) entre los respondedores.

Conclusiones: En este estudio preliminar, identificamos un mejor desempeño de manera global y particular en algunos dominios cognitivos entre los pacientes con CCD y respuesta favorable al tratamiento profiláctico establecido.

Palabras claveCefalea, Cefalea crónica diaria, Cefalea crónica tipo tensional, Migraña crónica, Profiláctico.

Corresponding author: Dr. José Luis Ruiz-Sandoval. Servicio de Neurología, Hospital Civil de Guadalajara “Fray Antonio Alcalde”, Hospital 278, Guadalajara Jalisco México. Código Postal 44280.Teléfono: 52 (33) 3614-7748, Ext 44437Fax: 52 (33) 3641-8666, 52 (33) 3641-8666e-mail: [email protected]



17

Introduction

Patients and methods

It is estimated that 90% of the world population will suffer from headache at some point in their life, usually episodically or transiently; however, when a headache occurs more than 15 days a month for a period greater than or equal to three months, then the International Headache Society denominates it Chronic Daily Headache (CDH).1 In the last 15 years, epidemiological studies indicate that CDH affects 3% to 5% of the general population.2,3 CDH is a syndromic spectrum that includes four main entities: transformed migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua,3 all of which can be complicated by medication overuse (medication overuse headache).4,5 CDH represents a diagnostic and therapeutic challenge due to the existence of various conditions such as anxiety, depression, sleep disorders, obesity, and medication overuse, among others, which are assumed to originate and perpetuate it.

In this study, we intend to identify possible predictors of good and bad prognosis in patients with CDH with respect to the established prophylactic pharmacological treatment. Our hypothesis is that there are sociodemographic and clinical variables, as well as affective and cognitive variables that predict a good or poor response to therapeutic efforts not previously identified in the literature.

Patients aged 20-60 years at the headache clinic of the Guadalajara Civil Hospital “Fray Antonio Alcalde” diagnosed with CDH and undergoing prophylactic pharmacological treatment were considered for this comparative cross-sectional descriptive study. Patients with secondary headache, presence of some other type of chronic pain in the context of recurrent diseases, other neurological diagnoses, major psychiatric disorder, sequelae of moderate-severe traumatic brain injury, and rheumatological or terminal oncological diseases were excluded.

CDH patients treated with non-pharmacological therapies were also excluded.

The sample was divided into patients with good and poor response to the established pharmacological prophylactic treatment. It was considered a “good response” when a reduction ≥ 50% in the frequency of headache was achieved.6 Sociodemographic variables included age, sex, education, marital status, occupation, and body mass index. Regarding the characteristics of the CDH, we took into consideration the type of prophylactic treatment established, medication overuse, as well as the frequency of headache (15-25 or 26-30 days per month).

Medication overuse was considered to be: 1) consumption of at least 10 days a month during three months of ergots, triptans, opioids, or analgesics in combination, and 2) consumption at least 15 days a month during three months of simple analgesics: non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol. This information and the type of CDH was obtained from the expert neurologist at the headache clinic.1

The affective aspects evaluated the level of stress (Perceived Stress Scale, PSS),7 of depression (Beck Depression Inventory, BDI),8 and of anxiety (State-Trait Anxiety Inventory, STAI).9 In addition, the Brief Illness Perception Questionnaire, B-IPQ, measured the patient’s perception of the illness (consequence, duration, control, treatment efficacy, severity of symptoms, concern, understanding, and emotional impact).10

The neuropsychological assessment evaluated the following domains: attention (digit retention test of the Wechsler Adult Intelligence Scale, WAIS-III),11 working memory (test of retention of succession of numbers and letters in order or reverse of the WAIS-III),11 verbal memory (Perri Test of verbal and memory learning, Spanish version),12 phonological verbal fluency (PMR test), and verbal semantic fluency (animal test).13 (Figure 1)



18

Data analysis ResultsThe information was analyzed through descriptive and deviation statistics, frequencies, and percentages, for sociodemographic variables. The Pearson X2 test was used for the comparison of qualitative nominal variable frequencies between two groups. In the chi-squared test, the Fisher correction was used when the frequency of a score was 1° of freedom in the probability index. Student’s t-test was used to compare the continuous quantitative variables of normal distribution between two groups. All p values for comparisons were calculated for two tails and were considered significant when p



19

to treatment and neither did the comorbidities of overweight or obesity, nor the history of hypertension, diabetes, or insomnia. (Table 2)

Regarding the characteristics of the headache, there were no differences according to the time of evolution (less than, equal to, or more than 5), type of headache (TM or CTTH), medication overuse (or lack thereof), or prophylactic therapy (mono or poly). Only patients with a frequency of headache of 15-25 days showed a tendency for better response when compared to patients with a frequency of 26-30 days (p=0.053). Regarding the affective aspects analyzed, neither anxiety state, anxiety trait, depression, nor stress influenced as prognostic elements. Regarding perception of the disease, only the conviction of the efficacy of the treatment was associated with good response (p=0.008). (Table 3)

The analysis of neuropsychological performance was applied in its entirety to only 35 patients. In all the applied tests, a better performance was generally obtained—appreciatively—among the patients classified as good responders. However, in some evaluations there was a tendency or a significant association towards a better performance in working memory tests such as the reverse digits (p=0.076), the scalar digit score (p=0.072), the verbal semantic fluency (p=0.001), and test 5 of the Perri test for verbal memory and learning (p=0.021). (Table 4)

Discussion

Chronic daily headache is the third cause of primary headache in the world after episodic tension headache and migraine. It is one of the main reasons to consult a neurologist or neurological clinics specialized in headache.14 Some risk factors associated with CDH include age over 40 years, female sex, low socioeconomic status, single marital status, increasing frequency of headache, analgesic overuse, obesity, snoring, and sleep problems, plus injuries in skull and neck, other types of chronic pain, and adverse

events such as divorce, loss of employment, etc.3

The optimal treatment of CDH requires the following: a. discontinue the current analgesic regimen (very important); b. consider non-pharmacological interventions; c. initiate prophylactic treatment with the objective of reducing frequency and intensity; d. establish a rotation plan for abortive headache drugs. It is also recommended to keep a log indicating the frequency and intensity of the headache, the number of abortive medications required, work absences, and consults at the ER.15,16 However, despite all these measures, CDH is often refractory and the reasons for this resistance are uncertain.16

This study compared the CDH patients who had a good vs a poor response to the prophylactic pharmacological treatment established months before their inclusion to the study. As in other reports, CDH predominated in 90% of females.2,17

Comorbidities such as overweight and obesity were congruent with the prevalence already known for this nutritional disorder in our country.18 The subjective complaint of insomnia was reported in one-third of the patients.

Transformed migraine was the most frequent subtype of CDH in 60% of the cases, a finding similar to that reported in other scenarios and it predominated in the younger population.3

Medication overuse was reported in one-fifth of patients, a figure lower than in other CDH studies where it had been reported in up to 70% of cases.19

Access and costs of medications can explain this finding in our country, although this should be confirmed in future studies. Regarding medication overuse, there was no difference between TM patients and CTTH patients.

In our study, the majority of patients (68%) presented with CDH of five or more years of evolution, and 60% with a headache frequency between 26 and 30 days of the month. Both data highlight that the population included in our study is seriously affected by this condition. It also suggests that in first level medicine or with a specialty other than neurology, there is a subdiagnosis of this type of headache, and it is even highly probable that



20

Age

Sex

Marital status

Schooling

Medication overuseBMI

20-39 years40-60 yearsFemaleMaleSingleMarriedBasic educationSecondary educationYesNoNormalOverweight/obesity

f12

28

36

4

21

19

23

17

8

32

10

30

f11

13

22

2

15

9

14

10

4

20

7

17

f1

15

14

2

6

10

9

7

4

12

3

13

%30

70

90

10

52.5

47.5

57.5

42.5

20

80

25

75

%45.83

54.16

91.66

8.33

62.5

37.5

58.33

41.66

16.66

83.33

29.16

70.83

%6.25

93.75

87.5

12.5

37.5

62.5

56.25

43.75

25

75

18.75

81.25

0.012*

1*

0.121

0.896

0.690*

0.456

Totaln=40

Transformedmigraine

n=24

Chronictension-type

headachen=16

Chi-squaredTM vs CTTH

(p value)

Table 1. Frequencies of sociodemographic aspects (n=40).

many of the medical indications are the cause of CDH, as well as its subsequent refractoriness.

In relation to the prophylactic pharmacological therapy of CDH, we observed a higher frequency in the use of combination drugs (amitriptyline-topiramate, amitriptyline-gabapentin, and other combinations) than in the use of monotherapy. Although dual prophylactic therapies are not strictly prohibited, they are less recommended due to the sum of the side effects.20

Studies that attempt to identify associations or predictors of good or bad prognosis in relation to the acute or prophylactic pharmacological treatment of primary headaches are scarce and often contradictory.21 Although it is not always considered that psychiatric comorbidity influences the response to treatment, anxiety, depression, and stress are relevant to drug resistance and the chronification of any type of headache.22,23 Anxiety

and stress are triggers of headache; likewise, subjects suffering from headache are more anxious than those who do not suffer from any type of pain.24,25 Intense anxiety can increase the severity of pain,26 and in contrast, the decrease in anxiety has been related to a decrease in headache.25,27 Anxiety in patients with headache is also associated with greater disability, poor quality of life, and increased expenses related to health care.15,19

Regarding the predictors of pharmacological response in CDH, Lu et al. in a cohort of 108 participants found a poor response in 35% of the cases after a 2-year follow-up.5 When analyzing the results, five predictors of poor prognosis were identified: 1) age ≥40 years, 2) late onset of CDH (≥32 years), 3) duration ≥6 years of CDH before starting treatment, 4) medication overuse, and 5) headache frequency of 30 days a month. In our study, sex, subtype of CDH, and the presence or absence of psychiatric comorbidities were



21

PredictorsSociodemographic:Age

Sex

Marital status

Schooling

Pathological personal historyInsomnia

Body Mass Index

Years of evolution

Number of days of crisis before prophylactic txTypes of CDH

Medication overuse

Prophylactic treatmentProper administration of txAbortive medication

40 years

Female

Male

Single

Married

Basic education

Secondary education

Denied

DM or HT

No

Yes

Normal

Overweight or obesity



22

Table 3. List of probable predictors of response - psychological factors and perception of the disease (n=40).

PredictorsPsychological factors:Anxiety state

Anxiety trait

Depression

Stress

Perception of the disease by total score in the test

Consequences: affects lifeDuration (term)

Disease control

Tx efficiency

Severe symptoms

Concern

Understanding

Affects emotionally

No

Yes

No

Yes

No

Yes

No

Yes

Benign percep-

tion ≤40

Threatening

perception >40

No

Yes

Short

Long

Great amount

of control

No control

Yes

No

Few

Many

Little

Much

No

Yes

No

Yes

Good response (n=20) f (%)

13 (65%)

7 (35%)

11 (55%)

9 (45%)

11 (55%)

9 (45%)

9 (45%)

11 (55%)

10 (50%)

10 (50%)

8 (40%)

12 (60%)

11 (55%)

9 (45%)

12 (60%)

8 (40%)

20 (100%)

0

5 (25%)

15 (75%)

8 (40%)

12 (60%)

15 (65%)

5 (25%)

10 (50%)

10 (50%)

Poor response (n=20) f (%)

11 (55%)

9 (45%)

7 (35%)

13 (65%)

10 (50%)

10 (50%)

12 (60%)

8 (40%)

6 (30%)

14 (70%)

7 (35%)

13 (65%)

8 (40%)

12 (60%)

9 (45%)

11 (55%)

13 (65%)

7 (35%)

3 (15%)

17 (85%)

6 (30%)

14 (70%)

14 (70%)

6 (30%)

7 (35%)

13 (65%)

Odds ratio(Confidence interval)

1.519 (0.425 – 5.426)

2.27 (0.636 – 8.106)

1 (0.290 – 3.454)

0.545 (0.155 – 1.914)

2.333 (0.638 – 8.538)

1.238 (0.343 – 4.464)

1.833 (0.522 – 6.434)

1.833 (0.522 – 6.434)

---------

1.889 (0.385 – 9.271)

1.556 (0.420 – 5.763)

1.286 (0.319 – 5.175)

1.857 (0.522 – 6.612)

Chi-squared(p value)

1

0.204

1

0.342

0.197

0.744

0.342

0.342

0.008*

0.695*

0.507

0.723

0.337

B-IPQ Perception of the disease:

Analysis of items contained in the test:



23

Direct digits

Reverse digits

Scalar score digits

Succession of numbers

and letters

Phonemic verbal

fluency P

Phonemic verbal

fluency M

Phonemic verbal

fluency R

Semantic verbal

fluency animals

Test 1

Test 2

Test 3

Test 4

Test 5

Interference

Immediate recall

Immediate recall

categories

Delayed recall

Delayed recall

categories

Recognition

Buenos respondedores

(n=18)M ± DE

6.83 ± 1.339

4.5 ± 1.249

6.22 ± 1.478

5.83 ± 1.823

11.39 ± 3.958

8.94 ± 3.589

7.89 ± 3.179

18.89 ± 4.143

5.17 ± 1.689

7.61 ± 2.062

8.72 ± 2.947

10.50 ± 2.383

11.67 ± 1.749

4 ± 1.328

10.06 ± 2.645

10.78 ± 1.734

10.44 ± 2.995

10.67 ± 1.879

15 ± 1.715

Malos respondedores

(n=17)M ± DE

6.53 ± 1.625

3.65 ± 1.498

5.35 ± 1.272

4.59 ± 2.917

10.29 ± 3.670

7.53 ± 3.970

7.94 ± 3.381

14.47 ± 2.918

4.59 ± 1.228

7.06 ± 2.249

8.59 ± 2.063

9.24 ± 2.251

9.71 ± 2.823

4.12 ± 1.364

9.29 ± 1.829

10.71 ± 2.544

10.47 ± 2.478

10.94 ± 2.968

15 ± 1

Odds Ratio(95% IC)

-------

-------

4.571 (0.456-45.857)

2.143 (0.338-13.588)

.560 (0.147-2.140)

1.200 (0.287-5.021)

.686 (0.149- 3.148)

4.364 (0.740- 25.744)

-----

-----

-----

1.400 (0.354-5.542)

5.625 (1.178 - 26.854)

-----

2.925 (0.719-11.907)

-----

-----

-----

-----

t0.605

1.834

1.860

1.524

0.847

1.107

- 0.047

3.628

1.153

0.758

0.155

1.612

2.453

- 0.258

0.985

0.097

- 0.028

- 0.325

0

Valor de p

0.549

0.076

0.072

0.137

0.403

0.276

0.963

0.001

0.257

0.454

0.878

0.116

0.021

0.798

0.332

0.923

0.978

0.748

1

Perri verbal memory test

Table 4. Attention, working memory, verbal fluency, and verbal memory in patients with CDH responding and not responding to prophylactic treatment (n=35).



24

not significant predictors for pharmacological response.5

An Austrian study with 55 patients categorized the response to prophylactic treatment based on the frequency of headache, intensity, and overuse of abortive analgesics. They identified no predictors of good or poor response although a tendency was observed for a lower intensity of headache in TM patients and patients who were of a younger age at the time of onset.30

Scher et al. (2003) conducted a longitudinal investigation in the US to detect predictive factors of both the onset and remission of CDH.31

The authors reported that individuals with an education lower than baccalaureate, Caucasian, and previously married, had an increased risk of suffering from CDH and a low probability of remission. The onset of CDH was also associated with a higher frequency of baseline headache and obesity.

In the retrospective study conducted at the Michigan Headache & Neurological Institute, 267 patients with CDH refractory to treatment were analyzed. The authors report that pain improvement could not be related to sociodemographic, comorbid, or anxiety factors. However, a significant difference was found with respect to personality disorders as a predictor of poor short-term response to treatment, with an even worse prognosis for patients who fit into group B personality disorders (borderline, histrionic, narcissistic, and antisocial).32

In our study, we did not find any predicting factor for good or poor response to the established prophylactic pharmacological treatment, whether clinical, affective, or neuropsychological. However, we did identify some statistically significant findings that let us know that our results are reproducible in other studies with similar characteristics. Equally, we emphasize that many of them have already been reported in the literature as conditions associated with good or poor response. They are:

The occurrence of headache of 26-30 days/month show in our study a statistical tendency for poor response (p=0.053, OR, 3.66: CI: 0.958-14.028).

This variable was also predictive of refractoriness to prophylactic treatment in the study.5

In the analysis of B-IPQ on perception of the disease, the patient’s conviction of treatment efficacy was significantly associated with good response (p=0.008). This response can be an epiphenomenon of other aspects related to patient satisfaction with the healthcare system, treatment of health personnel, idiosyncrasy, placebo effect, access to a clinic specialized in headache, etc. However, other closely related aspects of the B-IPQ were not significant, so this result should be interpreted with caution.

Regarding the findings of applied neuropsychological tests, we emphasize that this is one of the main strengths of our work since there is no reference frame in the literature. Briefly, we describe some relevant background.

The association between migraine and cognitive alterations, during attacks or periods between attacks, continues to be a matter of discussion.33

The slowness of mental processing can occur in both the prodromal phase and the aura phase.34

During migraine attacks, sustained attention, reaction time, and visual-spatial processing can be altered.35,36 However, it is difficult to know if these findings may be related to concurrent pain or to the “encephalopathic disease” pathophysiology. Despite this, epidemiological studies have not indicated any type of long-term cognitive impairment in subjects with migraine.34

Tension headache has been related to a lower performance—but still within normal—in intelligence tests. The hypotheses that explain these deficiencies emphasize school absenteeism in childhood or the loss of professional and academic development opportunities in adult life due to the recurrent appearance of headaches that affect their effectiveness in these areas.37

We identified a better performance in the different domains evaluated in patients with a good response to prophylactic pharmacological treatment with appreciation. Likewise, we identified a significant



25

semantic verbal fluency with better performance in the responding patients, as well as in the verbal memory test 5. That is, there is a better performance in working memory and verbal memory.

At this point, a couple of questions arise: do the responding patients perform better because of the lower frequency of headaches? Or, does the better neuropsychological performance in the “good responder” patients influence the evolution and most favorable response to the treatment?

These dilemmas open a possibility for further investigation. Now we could do a cross-type study and re-evaluate non-responders who become responders in the future, once the changes in pharmacological strategies are made, and at the same time, re-evaluate the currently responding patients with future relapses. The current non-responders should perform better, once they achieve an improvement, and current responders would perform poorly in the event of relapse.

Some weaknesses of our work are, of course, the size and homogeneity of the sample, as well as the treatment time and the possible selection

biases. As Rasmussen points out in investigations based on a clinical population, the frequency of comorbidities and psychological disorders may be higher compared to the general population.17 Consequently, it is feasible that the risk factors are different and it is not possible to generalize with respect to prognostic factors. Also, the poor response is common in subjects treated at specialized health services.

Similarly, the few significant differences found in the neuropsychological tests confirm O’Bryant et al.’s affirmation that studies on the consequences of migraine and tension-type headache on cognitive processes are far from conclusive because they all report inconsistent results.38

The main studies that have tried to determine predictors of good and poor response to pharmacological treatment of CDH are longitudinal and have a considerably larger population. Also, some of them take their sample from the general population and not from the clinical population. All of the above calls for the development of a longitudinal study, with a larger sample and with periodic evaluations.



26

Conclusions

Aknowledgments

In conclusion, in this preliminary study, we identified a better overall and particular performance in some cognitive domains among patients with CDH and favorable response to established prophylactic treatment.

The present work was developed on the thesis of the student Alan Azael Plascencia-Morán in congruence with the Master in Neuropsychology of the generation 2015-2017, attached to the Department of Neurosciences of the University Center of Health Sciences (CUCS), University of Guadalajara. Program with PNP-C recognition (National Graduate Quality Program) / CONACyT.

Conflict of interestThe authors deny a conflict of economic interest or another type of conflict of interest..

FinancingNone



27

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Original contributionCognitive reserve in indigenous

29

Cognitive reserve and associated factors in a sample of indigenous older adults

Cognitive reserve in indigenous


Yenny Vicky Paredes-Arturo,1 Stefany Revelo–Villota,2 Daniel Camilo Aguirre–Acevedo .1,3

1Human and Social Development Group. Psychology Program; Faculty of Humanities and Social Sciences; Mariana University; San Juan de Pasto, Nariño, Colombia. 2Psychology Program; Faculty of Humanities and Social Sciences; Mariana University; San Juan de Pasto, Nariño, Colombia.3Neuroscience Group of Antioquia, Institute of Medical Research; University of Antioquia; Medellín, Antioquia, Colombia.

Abstract

Objective: To describe cognitive reserve and factors associated among older Indigenous from Camëntsá Biyá community of Sibundoy valley, Putumayo (Colombia).

Methods: Cross-sectional study in 67 older indigenous participants aged 60 years and over. Cognitive reserve was described according to demographic characteristics and comorbidity. We explore relation between cognitive reserve and demographic and comorbidity variables and its correlation with Minimental and Fototest.

Results: Female sex (p = 0.002), low educational level (p



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Resumen

Objetivo: Describir la reserva cognitiva y los factores asociados en una muestra de adultos mayores indígenas pertenecientes a la comunidad Camëntsá Biyá, del valle de Sibundoy, Putumayo (Colombia).

Métodos: Estudio corte transversal, en 67 indígenas de 60 años o más. Se evalúo la reserva cognitiva según características demográficas y la comorbilidad y su correlación con el Minimental y el Fototest.

Resultados: Sexo femenino (p=0.002), bajo nivel educativo (p



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Introduction MethodsThe cognitive reserve is conceptualized as a hypothetical construct emerging from the field of dementia, proposed as a mediating factor between a brain pathology and its differential clinical manifestations.1 It is constituted as a complex theoretical reference with no direct measurements for its valuation process, which makes it challenging to develop rigorous investigations that might clarify its characteristics, effects, and possible causal relationships.2 This construct can only be measured indirectly by proxy indicators, that is, indirect variables that are conceived as representative of the original construct.3 Therefore, one of the main limitations in the study of this subject is the absence of a detailed operational definition of this construct.

Consequently, different measurements are used for its quantification.4 For research, in particular, variables such as sociodemographic characteristics, medical history, cognitive level, and emotional state were considered;5 however, of all of them, education is consistently and systematically the most used variable,6 repeatedly analyzed and related through indices of activity or cognitive performance. Culture is also considered a significant factor that intervenes in the development and potentialization of the cognitive reserve7 concerning rural contexts. The literature mentions that the indigenous cultural environment can have a significant and differential influence in the structuring of this construct.8

Thus, when studying cognitive reserve in indigenous senior citizens, a common factor must be considered which is related to the deficiencies present in all sectors, especially those related to the social, educational, and health components. Hence, the two categories of an indigenous ethnic group and the older adult are multiplying factors that together lead to a greater degree of vulnerability in this segment of the population. Therefore, the main objective of this project is to describe the cognitive reserve and the associated factors in a sample of older adults from the Camëntsá Biyá community of the Sibundoy Valley in Putumayo, Colombia.

A descriptive, cross-sectional study was conducted to analyze the effect of demographic factors, medical conditions, emotional state, and cognitive performance with respect to the level of cognitive reserve in elderly adults of the Camëntsá Biyá indigenous community from the Sibundoy Valley in Putumayo, Colombia. The population is of approximately 5,000, of which 300 are elderly. The research included adults of both sexes, 60 years of age or older, belonging to the indigenous community who voluntarily accepted to participate in the study and signed the informed consent. Candidates with visual or auditory impairments or any medical condition that prevented the application of the protocol were excluded. The type of sampling was intentional, not probabilistic, from a database containing information corresponding to this ethnic group.

The evaluation was conducted in the health center of the municipality of Sibundoy Putumayo, during the weekends from March to May 2017. This process was carried out by health professionals in the areas of nursing and psychology. The collected information included age in years, gender, affiliation to the General System of Social Security in Health (SGSS), level of studies, marital status, number of children, whether they receive an economic subsidy, employment status, economic dependence, monthly income, and whether they have a caregiver and what their relationship is to them.

We evaluated history of infectious, chronic, respiratory, and musculoskeletal diseases from self-reports with the following instruction in the questionnaire: “I will list a series of diseases below. Which of them have you suffered or do you currently have?” Among them, the presence of high blood pressure, cerebrovascular disease (CVD), diabetes, obesity, chronic obstructive pulmonary disease (COPD), pneumonia, osteoporosis, arthritis, cataracts, fractures, cancer, and dementia were evaluated. These data were compiled from a structured questionnaire applied by students of nursing and ninth semester of psychology.



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The demographic factors and medical history were evaluated according to a pre-designed questionnaire, applied to the participant or a family member or responsible caregiver. This format was validated at the investigation of multidimensional factors in older adults of the city of San Juan de Pasto.9 Finally, the instrument was piloted including the screening scales.

The Mini-Mental State Examination was used, adapted, and validated in Colombia for the cognitive evaluation.10 The maximum total score is 30 and the main parameters of normality are age and schooling. In daily practice, a score of 23-21 suggests mild dementia, 20-11 means moderate, and less than 10 is severe dementia. This instrument was chosen because it is widely used and has a lower level of complexity with respect to the assessment of global cognitive performance. The images test, or Fototest,11 was applied to evaluate cognitive processes at the memory (visual), language (denomination and verbal fluency), and executive functions levels. Its advantage is its ability to be applied to illiterate subjects. It consists of six items and has an open score in a range of 45 points or more.

Depressive symptomatology was determined using the Yesavage12 Geriatric Depression Scale, which has three categories corresponding to the total score from the sum of 15 items: from 0 to 5 normal, 6 to 10 moderate depression, and from 11 to 15 severe depression. This instrument was chosen for its applicability in the elderly population. Finally, the level of cognitive reserve was assessed by applying the Cognitive Reserve Index questionnaire (CRIq).13 It consists of eight items measuring aspects such as schooling, the completion of training courses, job occupation, musical training, parents’ schooling, and language proficiency. It also inquires about the approximate frequency with which cognitively stimulating activities have been realized throughout life, such as reading and practicing intellectual games like crossword puzzles and chess. To obtain the total CRIq score, the results of each item are added with a maximum of 25 points—higher scores indicate a greater cognitive reserve.

Ethical ConsiderationsIn accordance with the Mariana University’s Manual of Bioethics (Agreement 040 of 2012) and the Ministry of National Health’s resolution 008430 of 1993, this study was determined to be a minimal risk investigation. Its purpose is eminently scientific with no therapeutic intent. At the beginning of the evaluation process, participants were informed about the procedures and objective of the study, the risks, benefits, and confidentiality of the results, as well as of their freedom to withdraw or refuse to participate at any time during the evaluation. This research was endorsed by the Bioethics Committee of the Mariana University.

Statistical AnalysisThe demographic characteristics were taken from the absolute frequency and the percentage. The scores on the CRIq, the Mini-Mental, the Fototest, and the Yesavage were defined using the median and interquartile range (Percentile75-Percentile25). The cognitive reserve score was described and compared using the Chi-Squared test or the Mann-Whitney U test according to demographic characteristics and the presence or absence of medical history (arterial hypertension, dyslipidemia, diabetes mellitus, obesity, heart disease, CVD, COPD, arthritis, consumption of alcoholic beverages, and consumption of psychoactive substances). The Spearman correlation coefficient (rho) was calculated for the analysis of the correlation between the CRIq, the Mini–Mental, the Fototest, and the Yesavage scores—statistical significance level α=0.05. All analyses were performed in IBM SPSS version 23.

ResultsThe demographic characteristics are presented in Table 1. The majority of the participants were female (73%), 43.3% were married, 43.28% were widowed, almost half reached a primary level, 35% were illiterate, and the majority were economically dependent on their family (56.7%). A statistical association was found between cognitive reserve score and sex (p=0.002) as well as schooling (p



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Table 1. Demographic characteristics and average result in the score of the cognitive reserve scale in older adults of the Camëntsá Biyá indigenous community of the Municipality of Sibundoy-Putumayo.

SexFemale

Male

Age, years60 – 72

72 a 88

Marital statusMarried

Widowed

Single / divorced /

partnered

SchoolingCannot read/write

Learned to read and

write

Primary

Type of affiliationBeneficiary

Subsidized

Financially dependent on familyYes

No

Frecuency

49

18

34

33

29

29

9

6

24

37

10

57

38

29

Z=3.1; p=0.002

Z=0.9; p=0.386

X2=5.5; p= 0.065

X2=15.7;

p



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Tabla 2. Result in the cognitive reserve scale according to presence or absence of medical history.

SD: Standard Deviation; IR: Interquartile range; Z: Z statistic with asymptotic approximation of the Mann-Whitney U test.

History, n (%)Arterial hypertension,

n=23 (34.3)

Dyslipidemia, n=5

(7.5)

Diabetes mellitus,

n=12 (17.9)

Obesity, n=3 (4.5)

CVD, n=6 (7.5)

COPD, n=9 (13.4)

Arthritis, n=33 (49.3)

Consumption of

alcoholic beverages,

n=9 (13.4)

Consumption of

psychoactive

substances (including

Yagé), n=47 (70.1)

Z=0.9; p=0.386

Z=0.02; p=0.991

Z=0.5; p=0.592

-

Z=1.6; p=0.115

Z=2.2; p=0.025

Z=0.01; p=0.955

Z=1.4: p=0.153

Z=1.2; p=0.216

Mean8.4

8.3

8.3

8.3

8.4

8.6

8.4

10.3

9.3

SD8.5

3.1

3.1

3.1

3.0

3.1

3.4

4.5

3.9

Median8,0

8,0

8,0

8,0

8,0

8,0

8,0

9,0

8,0

IR4,5

3,3

3,0

3,1

3,0

3,3

3,5

4,5

3,9

Ausente

Mean7.9

8.2

8.0

7.3

6.2

6.4

8.2

7.9

7.8

SD2.3

1.9

3.1

1.5

3.8

2.4

2.6

2.8

2.5

Median7,0

8,0

7,0

7,0

6,0

7,0

8,0

8,0

8,0

IR2,0

3,5

4,5

-

6,5

3,0

3,5

4,0

4,0

Presente Estadístico; valor p

more than men, regardless of the ethnic group to which they belong—a situation that does not differ in the age group evaluated.14 Regarding schooling, the greater percentage of the population has a primary basic education, though there are some subjects in the category of illiterate. This is explained by factors such as difficulty in accessing the educational system, inadequate infrastructure, schooling processes not in accordance with ethnic characteristics, and cultural patterns, among others. Similarly, the level of schooling evidenced is corroborated by the SABE Colombia study (2015) where, on average, the older adult population reached five years of schooling, corresponding to the primary school level.15

Regarding marital status in the evaluated sample, the data show a significant percentage of older adults in the categories of married and widowed.

The participants report that the prevalence of widowhood is due to the armed conflict of the period which had mostly male casualties. Relating it to the sociodemographic diagnosis of indigenous older adults,16 it is observed that 64.6% of them are coupled or married. Out of the six ethnolinguistic groups evaluated, more than 50% of these subjects live in this condition. This is a protective factor, making evident the primary support network—the perception of support and protection in matters related to emotional and economic stability improves with a partner.

In function with the demographic factors, an association of the education variable was determined in the project with the CRIq (p



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the presence of depressive symptomatology.25 Finally, in terms of mental health, the previous argument is more relevant if the relationship between cognitive reserve and emotional component is considered.

Likewise, the existing relationship between the CRIq level and cognitive performance has also been referenced.26 Particularly in the study, this association was determined from the application of the Mini-Mental (rho=0.572; p



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Conclusion

The level of cognitive reserve is related to sociodemographic factors according to gender and educational level. It is determined there is also an association with obstructive pulmonary disease, depressive symptomatology, and the general cognitive state.

Conflicts of interestThe authors declare there is no conflict present regarding the production of the manuscript.

FundingThere was no particular funding source for this scientific report.



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