Revista Mexicana de

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

VOLUME 23 - NUMBER 4 / July-August 2022 – ISSN: 2604-6180

www.revmexneurociencia.com

Editorial
New era of the Revista Mexicana de Neurociencia 117
Antonio Arauz and Luis Dávila-Maldonado

Original articles
Pitfalls and caveats in the diagnostic pathway of people with Parkinson’s disease 119
Amin Cervantes-Arriaga, Cynthia Sarabia-Tapia, Oscar Esquivel-Zapata, Susana López-Alamillo,
Etienne Reséndiz-Henriquez, Teresa Corona, and Mayela Rodríguez-Violante
Cognitive impairment in people with COVID-19 with mild-moderate symptoms in Ecuador 126
Alejandro Checa, Eliana Navas, Verónica Valencia, and Jessica Alcívar
Clinical and environmental risks factors associated with Parkinson’s disease in Yucatan 130
Luis E. Parra Medina, Manuel J. Gurubel-Maldonado, Gloria Arankowsky-Sandoval, José L. Góngora-Alfaro,
Roberto Leal-Ortega, and Jorge E. Salazar-Ceballos
Somatodyspraxia: A novel term proposition as a primary factor of apraxia and its applicability in the PAINT
Neuropsychological Rehabilitation Model for brain injury 137
Adriana Castillo-Sánchez-Lara and Christopher Ruben-Castillo

Review articles
Stroke and atrial fibrillation: An update 149
Nicole Beaton Sur and Jose G. Romano
Neurological complications of interatrial blocks and Bayes’ syndrome 157
Juan M. Farina, Andrés F. Miranda-Arboleda, Pablo A. Lomini, and Adrián Baranchuk

PERMANYER
www.permanyer.com
Revista Mexicana de Neurociencia

EDITORIAL

New era of the Revista Mexicana de Neurociencia

Antonio Arauz1 and Luis Dávila-Maldonado2
1Editor-in-Chief, 2Presidente de la Academia Mexicana de Neurología, Mexico City, Mexico

The Revista Mexicana de Neurociencia emerged as
an informative bulletin of the Mexican Academy of Neu-
rology. In 1999, its first issue appeared as Revista
Mexicana de Neurociencia with Dr. Lilia Núñez-Orozco
as Editor-in-Chief and who directed it until Volume 11,
Number 1, published in January-February 2010. Key
events during this period were the incorporation of the
journal by the International Federation of Neurological
Journals, the reservation of its title, the ISSN number
that made it a formal periodical publication and the in-
clusion in the EBSCO, IMBIOMED, Lilacs, and Artemisa
index.
In 2010, Dr. Carlos Cantú-Brito assumed the editorial
leadership of the journal and during that period, the jour-
nal was renewed and achieved the CONACYT journal
index. In 2017, Dr. Idelfonso Rodríguez Leyva is appoint-
ed Editor-in-Chief and during this period, the Mexican
Academy of Neurology decides to give our journal a new
impetus, incorporating it into the Permanyer publishing
house, changing its content to English, incorporating
electronic submissions and manuscript processing, all
with the purpose of achieving indexation.
Over the past 23  years, Revista Mexicana de Neu-
rociencia growth has been tremendous and is in a
position to continue climbing new goals and objectives
as the official journal of the Mexican Academy of Neu-
rology. As incoming Editor-in-Chief, I will build on a
strong foundation. However, our most important chal-
lenge continues to be convincing the community dedi-
cated to neurological sciences of the importance of
contributing to the journal, mainly with original research.
Convince them of the need and advantages of having a
strengthened journal, with the best quality standards and
indexed. What cannot be achieved without the support of
all members of the Mexican Academy of Neurology and
the neuroscience research community.
In the next years, Revista Mexicana de Neurociencia
must be influential and must attract the articles that
address basic and clinical research that advances our
understanding of neurological diseases. The new edi-
torial board will work to simplify the submission of man-
uscripts, expedite the editorial decision-making pro-
cess, and continue improving all editorial processes
that will not only help us make editorial decisions but
also help authors improve their manuscripts. We have
changed the editorial body, modifying the editorial
structure and including pediatric neurologists, neurolo-
gist, neurosurgeons, basic neuroscience researchers,
neuropsychiatrists, endovascular therapy, and col-
leagues with biostatistical training. The number of edi-
tors increased and the editorial masthead now includes
14 editors in various capacities. Incoming coeditors
include Fernando Barinagarrementeria and Sergio Iván
Valdes, and eleven Associate Editors will serve in im-
portant advisory roles: Minerva López and Elma Pare-
des as Associate Editors in Neurology; Pablo León and
Ramiro Ruiz-Garcia as Associate editors of Neuropshy-
chiatry; Edgar Nathal as Associate Editor of Neurosur-
gery; Francisco Pellicer as Associate Editor of Basic
Neuroscience; Fabiola Serrano-Arias and Juan Manuel
Márquez-Romero as Associate editor of Endovascular
therapy; Melissa Chávez-Castillo as Associate Editor of

*Correspondence: Date of reception: 25-05-2022 Available online: 08-07-2022

Antonio Arauz-Góngora, Date of acceptance: 05-06-2022 Rev Mex Neuroci. 2022;23(4):117-118
E-mail: antonio.arauz@prodigy.net.mx DOI: 10.24875/RMN.M22000090 www.revmexneurociencia.com
2604-6180 / © 2022 Academia Mexicana de Neurología A.C. Published by Permanyer. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

117
 Rev Mex Neuroci. 2022;23(4)
Neuropediatrics; and Miguel Barboza and Miguel
García-Grimshaw as Associate Editors of Biostatistics.
We are all planning the new sections that will be incor-
porated into the journal.
Revista Mexicana de Neurociencia must also play a
role educating the next generations, so we are working
on resident and fellow section that will include the par-
ticipation of residents in the editorial process.
We have also invited recognized authors to contribute
with reviews and original articles of specific topics. This
number of the Revista Mexicana de Neurociencia in-
cludes an update of stroke and atrial fibrillation by Ni-
cole Beaton Sur and José Romano of the University of
Miami and a review of Neurological complications of
interatrial blocks and Bayes’ Syndrome by Adrian Ba-
ranchuck and cols. of the Queen’s University of Cana-
da. Both, atrial fibrillation, interatrial block and Bayes’
syndrome are conditions that increase the incidence of
stroke ischemic events, cognitive impairment, and de-
mentia. Therefore, looking for AF in ischemic stroke
patients is mandatory, mainly in those older than 60 years.
Atrial block and Bayes’ syndrome are easily detectable
118
on an electrocardiogram and could explain several cases
classified as embolic stroke of undetermined source.
Therefore, it is highly recommended that neurologists re-
turn to review electrocardiograms in search of spe-
cific alterations of the p wave, especially in patients
with suspected cardioembolic cerebral infarction,
without AF.
It is a great honor to be the Editor-in-Chief of Revista
Mexicana de Neurociencia, the leading Mexican Jour-
nal of Neuroscience, for the next 5  years. My goal is
for the journal to be at the forefront of disseminating
neurological research and educational articles, to im-
prove medical care for each of the six people in the
world affected by neurological conditions.
It is for all of the above that we believe that Revista
Mexicana de Neurociencia, supported by our board of
directors and with the strengths of this great group of
editors, will achieve a new and better stage. We invite
you to participate with scientific and academic collab-
orations. Grounded in experience, we dare to establish
the necessary changes for the future of neuroscience.
Together, we can continue to grow our journal.
Revista Mexicana de Neurociencia

Original article

Pitfalls and caveats in the diagnostic pathway of people with

Parkinson’s disease
Amin Cervantes-Arriaga1,2, Cynthia Sarabia-Tapia1, Oscar Esquivel-Zapata1, Susana López-Alamillo1,
Etienne Reséndiz-Henriquez1, Teresa Corona1, and Mayela Rodríguez-Violante1,2*
1Clinical Neurodegenerative Research Unit; 2Movement Disorder Clinic, Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico

Abstract
Objective: We carried out a cross-sectional study to identify the factors involved in each stage of the diagnosis pathway that
may lead to a diagnostic delay in persons with Parkinson’s disease (PD). Materials and Methods: Consecutive patients with
PD were included. A  questionnaire assessing the recognition of the initial symptoms, pathway to seek attention diagnosis
and perception on the diagnostic time and identified barriers was applied. Diagnosis delay was defined as ≥ 12  months
between initial recognition of the symptom and the definitive diagnosis of PD. Results: A total of 114 patients (57.9% male)
with PD were included in the study. The overall median time of the diagnosis pathway was 14.5 (interquartile range [IQR]
31) months and the longest time in this pathway was between the first medical consultation and the definitive diagnosis of
PD, a median of 9 (IQR 14) months. The main appraisal of the first symptom was being “not worried” (48.2%). The mains
reasons for seeking medical attention were symptom worsening (42.1%). Patient’s perception on the diagnostic time was
reported as very adequate/adequate in 52.7%. Barriers delaying the diagnosis identified included the belief of spontaneous
symptoms relief and lack of trust in their doctor. Conclusion: Both the person with PD and the physician play a shared role
in the diagnosis of PD. Improving the awareness of the disease, as well as improving medical education on PD, could result
in a timely diagnosis.

Keywords: Parkinson’s disease. Delayed diagnosis. Diagnosis pathway. Primary health care. Diagnosis.

Escollos y salvedades en la vía de diagnóstico de las personas con enfermedad de

Parkinson
Resumen
Objetivo. Se llevó a cabo un estudio transversal para identificar los factores involucrados en cada etapa del camino diag-
nóstica que pueden conducir a un retraso diagnóstico en personas con enfermedad de Parkinson (EP).
Material y métodos. Se incluyeron pacientes consecutivos con EP. Se aplicó un cuestionario que evaluó el reconocimiento
de los síntomas iniciales, la vía para buscar el diagnóstico de atención y la percepción sobre el tiempo de diagnóstico y
las barreras identificadas. El retraso en el diagnóstico se definió como ≥12 meses entre el reconocimiento inicial del síntoma
y el diagnóstico definitivo de EP. Resultados. Se incluyeron a 114 pacientes (57,9% hombres) con EP. El tiempo medio del
diagnóstico fue de 14.5 (RIC 31) meses y el tiempo más largo en este proceso fue entre la primera consulta médica y el

*Correspondence: Date of reception: 13-05-2021 Available online: 08-07-2022

Mayela Rodríguez-Violante Date of acceptance: 20-09-2021 Rev Mex Neuroci. 2022;23(4):119-125
E-mail: mrodriguez@innn.edu.mx DOI: 10.24875/RMN.21000041 www.revmexneurociencia.com
2604-6180 / © 2021 Academia Mexicana de Neurología A.C. Published by Permanyer. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

119
 Rev Mex Neuroci. 2022;23(4)

diagnóstico definitivo de EP con una mediana de 9 (RIC 14) meses. La principal percepción del primer síntoma fue estar
“no preocupado” (48.2%). Los principales motivos de consulta médica fueron el agravamiento de los síntomas (42.1%). La
percepción del paciente sobre el tiempo de diagnóstico se informó como muy adecuada/adecuada en el 52.7%. Las ba-
rreras que retrasaron el diagnóstico identificadas incluyeron la creencia de una mejoría espontáneo de los síntomas y la
falta de confianza en su médico. Conclusiones. Tanto la persona con EP como el médico juegan un papel compartido en
el diagnóstico de EP. Mejorar la conciencia sobre la enfermedad, así como mejorar la educación médica sobre la EP, podría
resultar en un diagnóstico oportuno.

Palabras clave: Enfermedad de Parkinson. Diagnóstico tardío. Camino diagnóstico. Atención primaria. Diagnóstico.

Introduction Institute of Neurology and Neurosurgery in Mexico City

Parkinson’s disease (PD) is a complex multisystemic
neurodegenerative disorder affecting over 6 million
people globally1. PD is hallmarked by their cardinal
motor symptoms, but also non-motor symptoms are
part of the disease2,3.
The diagnostic pathway can be divided into three mile-
stones. The first stage is the recognition of the symp-
toms by the subject. Second, the subject needs to make
the decision to seek medical attention. Finally, the pri-
mary care physician (PCP) who provides the first contact
must suspect and confirm the diagnosis or, if needed,
refer the patient to the proper specialist4. Research has
shown that it takes patients more time to recognize their
motor symptoms and to realize they need medical atten-
tion, then it takes the general practitioner (GP) to diag-
nose PD5. The median time from motor symptom onset
to seeking a PCP has been reported to be around
7-11 months; while the time from the first visit to a final
diagnosis varies from 1 to 12 months4,6.
Factors currently known to delay the diagnosis in-
clude young onset of motor symptoms7, postural insta-
bility and gait disorder subtype4, and female gender8.
This diagnostic pathway is full of experiences some
of them can be negative leading to loss of trust in the
doctor, resulting in a lengthy and uncertain process9.
Benefits of a timely diagnosis include an early initiation
of symptomatic treatment, improved functionality, and
better quality of life10. Data regarding the patient’s ex-
periences in their diagnostic pathway are scarce. Gain-
ing insight into the possible factors that delay the diag-
nosis process may lead to developing effective
strategies. This study aims to improve our understand-
ing of the factors involved in each of the stages of the
diagnostic pathway of persons with PD (PwP).
Methods
A cross-sectional study was carried out. PwP attend-
ing the Movement Disorders Clinic at the National
120
from July to August 2019 were included in the study.
Participants considered for this study were diagnosed
with PD using the International Parkinson and Move-
ment Disorders Society clinical criteria11.
Data collected included demographic variables such
as gender, date of birth, current marital, employment
status, and years of education, and whether they had
any access to social security. A semi-structured ques-
tionnaire containing both open-ended and closed-end-
ed questions was designed to assess time form the first
identification of motor symptoms to the time of definitive
diagnosis. At present, no specific validated question-
naire for this purpose is available for PD, consequently,
a questionnaire was designed based on instruments
used on other diseases, mainly cancer12,13. Selection
of the time intervals and main correlated factors was
based on critically assessment of literature, conceptual
framework, and expert opinion.
A pilot testing was carried out to test the content va-
lidity (relevance, acceptability, and feasibility). A total of
two rounds of pilot testing were performed. This result-
ed in changes in the order of the items and clarification
of wording or phrasing.
The final questionnaire was divided into three parts.
The first part considered the recognition of the initial
symptom of PD; PwP provided information regarding
their first identified symptom.
The second part included a series of questions that
intended to understand the patient’s pathway to seek
attention with a health-care provider. This section in-
cluded the time of the first medical consultation, the
patient’s main reason for seeking for medical attention,
selected factors with potential influence on the symp-
tom experience, and healthcare-seeking behaviors.
The time of diagnosis, as well as the year of referral to
tertiary center, were also collected. Finally, the last part
intended to assess the patient’s perception on the di-
agnostic time, if it was considered timely, as well the
main reasons for a delayed diagnosis and identified
barriers.

In addition, the Movement Disorder Society Unified
PD rating scale at the first visit was used to define
the motor subtype into tremor dominant (TD), postural
instability and gait disturbance (PIGD), and indeter-
minate according to Stebbins et al.14 PD onset was
classified as classic PD (age of onset 41-59), ear-
ly-onset PD (EOPD) if age of onset was ≤ 40  years,
and late-onset PD (LOPD) if age of onset was ≥
60 years15,16.
The index time was defined for the study purposes
as the month and year the PwP recalled noticing the
motor symptoms associated with the disease for the
1st time. The first milestone collected was externaliza-
tion defined as the process of thoughts or worries into
an external form such as writing or speaking to a third
party. The second milestone was seeking medical at-
tention. The last milestone was definitive PD diagnosis.
Time between the milestones was measured in months
in all cases.
Delay in diagnosis for the study purpose was defined
as a span of 12 or more months between the initial
recognition of the symptoms and the definitive diagno-
sis of PD or the beginning of PD treatment17.
All PwP attending the clinic within the study period
were invited to participate. Those who voluntarily
agreed to participate were given a full explanation of
the study and signed an informed consent form. The
study was approved by the local ethics committee.
Statistical analysis
Kolmogorov–Smirnov test was used to test normality.
Data were described in measures of central tendency
(mean or median) and dispersion as standard deviation
(SD) or interquartile range (IQR) accordingly to their
distribution. Student’s t and analysis of variance (ANO-
VA) tests were used for the comparison of continuous
variables between groups. Mann–Whitney U or Krus-
kal–Wallis test was used for non-parametric variables
analysis. When needed, Bonferroni correction for mul-
tiple comparisons was used to adjust the p values. For
comparison between categorical variables, Chi-square
test was used. Statistical significance was considered
as p < 0.05.
Results
A total of 66 men (57.9%) and 48 women (42.1%) were
included in the study. The mean age was 65.4 ± 12.9 years,
and the mean disease duration was 9.5 ± 5.2 years. The
mean years of education were 9.7 ± 5.9 years. A total of
A. Cervantes-Arriaga et al.: Diagnostic pathway in PD
76 PwP (66.6%) were married/free union. Fifty-three
(46.5%) had access to social security, and only 33 (28.9%)
were currently employed. In addition, 24  (21.1%) had a
family history of PD.
Regarding PD, a total of 43 PwP (37.7%) were con-
sidered classic, 19  (16.7%) EOPD, and 52  (56.6%)
LOPD. The most common motor subtype was PIGD
(50.9%) followed by TD (36.8%).
Regarding the time elapsed between milestones, the
median time from symptom onset to externalization was
1 month with a range of 1-96 months. The median time
from the first milestone to seeking medical attention
was 2.5 (IQR 10.9) months. The median time from the
second milestone to diagnosis was 9 (IQR 14) months.
Overall, the median time from noticing the motor symp-
tom onset to the final PD diagnosis was 14.5 (IQR 31)
months. Table  1 shows the comparison of the time in
months for each milestone according to the main de-
mographic and clinical variables. In summary, age of
onset was statistically different across two of the time
milestones. PwP with EOPD had a greater time to seek
medical attention and time to final diagnosis. For PwP
with EOPD, the overall diagnosis pathway (median 48,
IQR 57) was longer when compared to the classic on-
set (median, 15. IQR 32, p = 0.01) and LOPD (median
12, IQR 18, p = 0.01).
The first part of the questionnaire assessing the rec-
ognition of the initial symptom showed that tremor was
the most frequent motor symptom noticed by the sub-
ject (59.6%) followed by bradykinesia and rigidity
(27.2%). Moreover, the main appraisal of the first symp-
tom was being “not worried” (48.2%) followed by “wor-
ried or stressed” (43.9%).
The second part of the questionnaire assessed the
pathway to seek attention with a health-care provider
and final diagnosis. The main reasons for seeking med-
ical attention were symptom worsening (42.1%) fol-
lowed by symptom onset (29.8%) and symptom per-
sistence (26.3%). The first contact physician was a GP
in 36.8%, a movement disorders specialist in 18%, and
a general neurologist also in 18% of the cases. The
specialty of the first contact physician did not had an
impact on the time from the first medical consultation
to the PD diagnosis (p = 0.16).
Finally, the third part of the questionnaire assessed
the PwP perception on the diagnostic time and its time-
liness. A total of 54 (47.4%) PwP were timely diagnosed
according to the study criteria, while 60 (52.6%) had a
delay on diagnosis. The only variables with a statisti-
cally significant difference between groups were age
and age at onset. PwP timely diagnosed were older
121
 Rev Mex Neuroci. 2022;23(4)

Table 1. Time milestones (months) according to the main demographic and clinical variables of the study sample
Variables Time to externalize Median (IQR) Time to seek medical Time to diagnosis Median (IQR)
attention Median (IQR)

Gender Median (IQR)

Male (n = 66) 1 (0.25) 6 (11.25) 14 (30)
Female (n = 48) 1 (0) 5 (11) 14.5 (42)
p† 0.244 0.654 0.858

Age at onset Median (IQR)

Classic (n = 43) 1 (3) 7 (13) 15 (32)
EOPD (n = 19) 1 (0) 18 (20) 48 (57)
LOPD (n = 52) 1 (0) 2 (11) 12 (18)
p‡ 0.177 0.003 0.006

Family history Median (IQR)

None (n = 82) 1 (0) 6 (11) 12.5 (30)
Parkinson’s disease (n = 24) 1 (0) 5 (11) 14.5 (50)
Essential tremor (n = 8) 1 (0) 13 (39.75) 27 (79)
p‡ 0.722 0.474 0.235

Comorbidities Median (IQR)

No (n = 68) 4.6 ± 13.8 13.4 ± 17 30.6 ± 31.5
Yes (n = 46) 2.8 ± 4.5 12.2 ± 23.8 25.1 ± 30.8
p† 0.94 0.19 0.25

Motor subtype Median (IQR)

PIGD (n = 58) 1 (0) 6 (18.5) 12 (26)
Tremor dominant (n = 42) 1 (0.25) 4.5 (11) 16 (31)
Indeterminate (n = 14) 1 (6.5) 12 (10.25) 30.5 (60)
p‡ 0.238 0.692 0.150

Education (years) Median (IQR)

< 12 (n = 71) 1 (0) 7 (13) 13 (30)
≥ 12 (n = 43) 1 (0) 4 (11) 18 (42)
p† 0.301 0.122 0.879

EOPD: early‑onset Parkinson’s disease; IQR: interquartile range; LOPD: late‑onset Parkinson’s disease; PIGD: postural instability and gait disturbance.
†Mann–Whitney U‑test; ‡Kruskal–Wallis test.

(68.4 ± 11.1 vs. 62.7 ± 13.9, p = 0.02) and had an older
age of onset (59.7 ± 12.4 vs. 52.4 ± 14.7, p = 0.01).
Finally, patient’s perception on the diagnostic time
was reported as very adequate/adequate in 52.7%,
average in 21.1%, and inadequate/very inadequate in
26.3%. When comparing those PwP with a time from
onset to diagnosis < 12 months with those ≥ 12 months,
no statistically significant difference was found in the
very adequate/adequate perception (61.1% vs. 45%,
p = 0.13). Similarly, no statistical difference was found
regarding the very inadequate/inadequate perception
between groups (22.2% vs. 30%, p = 0.47). Moreover,
the percentage of agreement between very ad-
equate/adequate perception and actual time to diagno-
sis < 12 months was only 50%.
The main reason for a delayed diagnosis given by
those PwP who responded average or worst (n = 54)
was misdiagnosis in 63%, followed by economical con-
straints in 11.1%, belief of spontaneous symptoms relief
in 7.4%, and lack of interest by the PwP in 7.4%.
122
On the other hand, the main barriers that might have
delayed seeking medical attention identified by the
PwP were belief of spontaneous symptoms relief in
28.9%, lack of trust in their doctor in 17.6%, fear of a
diagnosis in 11.4%, and limited access to health ser-
vices in 7.9%. Table  2 compares the main factors as-
sessed in the questionnaire between PwP diagnosed
before or after 1 year from symptom onset.
Discussion
PD is a chronic neurodegenerative disease affecting
activities of daily living as well as the health-related
quality of life of the persons with the disease. While no
cure has been found yet, it has been shown that symp-
tomatic treatment has a benefit in the PwP life, thus
supporting the need for an earlier diagnosis10. The di-
agnostic pathway begins in the patient’s end by recog-
nizing the symptoms, acknowledging their relevance,
and deciding to seek medical consultation. On the
 A. Cervantes-Arriaga et al.: Diagnostic pathway in PD

Table 2. Comparison of healthcare‑seeking behaviors and patient’s perception on the diagnostic pathway according
to the time from onset to diagnosis
Variables Time from onset to diagnosis ≤ 1 year Time from onset to diagnosis > 1 year p†

Symptom at onset
Tremor 31 (57.4) 37 (61.7) 0.64
Rigidity/bradykinesia 16 (29.6) 15 (25) 0.99
Gait disorder 3 (5.6) 2 (3.3) 0.56

Symptom appraisal
Not worried 24 (44.4) 31 (51.7) 0.44
Worried/stressed 27 (50) 23 (38.3) 0.21
Fear 2 (3.7) 5 (8.3) 0.30
Other 1 (1.9) 1 (1.7) 0.94

Reason for seeking medical care

Symptom onset 26 (48.1) 8 (13.3) <0.001
Symptom persistence 15 (27.8) 15 (25) 0.74
Symptom worsening 12 (22.2) 36 (60) <0.001
Other 1 (1.9) 1 (1.7) 0.94

First contact physician

General practitioner 18 (33.3) 24 (40) 0.46
Internist/geriatrist 3 (5.6) 4 (6.7) 0.80
Neurologist 13 (24.1) 13 (21.7) 0.76
Movement disorder specialist 14 (25.9) 12 (20) 0.45
Other 6 (11.1) 7 (11.7) 0.93

Previous knowledge of the disease

Yes 32 (59.3) 28 (46.7) 0.18
No 22 (40.7) 32 (53.3) 0.18

Diagnostic time perception

Very inadequate 6 (11) 8 (13.3) 0.71
Inadequate 6 (11.1) 10 (16.7) 0.39
Acceptable 9 (16.7) 15 (25) 0.29
Adequate 20 (37) 17 (28.3) 0.32
Very adequate 13 (24.1) 10 (16.7) 0.33
†Chi‑square test.

other hand, the journey to diagnosis ends at the doc-
tor’s side with a definitive diagnosis and the therapeutic
shared decision-making. Nevertheless, between these
two milestones, there are several, sometimes burden-
some, factors that can result in a diagnosis delay. We
aimed to identify some of these factors resulting in a
timely or delayed diagnosis in PwP.
In our study, the time from symptom onset to the
diagnosis of PD had a median of 14.5 months which is
within the range reported in the literature which is be-
tween 12 and 19 months.
The demographic and clinical determinants of the
diagnosis delay reported in the literature include gen-
der, age at onset, and motor subtype. Regarding gen-
der, some authors report a longer time in men com-
pared to women4, while other have found no
difference8. Interestingly, Vlaanderen et al. reported
similar finding stating that while no significant differ-
ences were found in neurologist consultations, women
with PD visited GP more often than men17. In our study
sample, no difference in the diagnosis pathway be-
tween men and women was found. It has also been
reported that PwP with PIGD subtype had a longer
time to seek medical care4. In our study, no difference
in the time to seek medical care between motor sub-
types was found. Finally, a longer time to diagnosis
has been reported in PwP with EOPD ranging from 25
to 60  months18-20. Our study confirmed this finding.
This can be partially explained by the still common
believe, in both general population and health provid-
ers, that PD is a disease only seen in the elderly, thus
not considering the possibility, and delaying medical
consultation. Another point to consider is that tremor
in younger persons has more differential diagnosis,
such as essential tremor, requiring longer diagnosis
work-up process.
Regarding the symptom recognition, tremor was the
most common symptom identified which might be
123
 Rev Mex Neuroci. 2022;23(4)
expected since it can usually be more easily identifiable
by the patient and their family. Interestingly, the most
common appraisal was being now worried in almost
have of the patients. Providing better health education
might lead to improvement in this stage of the diagnosis
pathway.
Regarding the reasons for seeking medical attention,
symptom worsening rather than its onset or persistence
was the most reported by the PwP. Again, rising aware-
ness of the relevance of the onset and persistence of
parkinsonism and tremor is needed. Almost 40% of the
subjects went to GP, while 36% went to neurologist/
movement disorder specialist. The choice of the first
contact health provider did not had an impact in the
time to diagnosis, although it might have been expected
it to be shorter in the specialist group. It might be pos-
sible that PwP seen by a GP had the full-blown clinical
picture while those attending a specialist had a more
atypical presentation, but our study design does not
allow to reach that conclusion and further studies on
this matter are needed.
Regarding the perception of the time to diagnosis,
half of the PwP reported a very adequate/adequate.
In contrast, Plouvier et al. reported that only 4.8% of
their patients reported being satisfied with their diag-
nosis pathway9. This striking difference is probably the
result of different constructs; Plouvier et al. assessed
the satisfaction with the whole diagnostic pathway. In
contrast, our study assessed the perception of the
amount of time from symptom onset to diagnosis.
More studies using a standardized measure are need-
ed on this matter. In addition, the percentage of agree-
ment between the study definition of a timely diagno-
sis and a positive perception by the PwP was only
50% which highlights the difficult of this construct as
Rees et al. have stated10.
When the PwP considered the diagnosis not being
timely, the main reason was misdiagnosis in over 60%.
Unfortunately, the number of doctors or number of di-
agnosis received before PD was not assessed in our
study. Still, misdiagnosis rate as reported by the PwP
was remarkably high underscoring the need for better
training at the health provider end. Other reasons at-
tributable to the PwP were belief of spontaneous symp-
toms relief and lack of interest but their frequency was
much lower.
Finally, the barriers delaying the diagnosis identified
by the PwP also included the belief of spontaneous
symptoms relief in a third of the cases, but also lack of
trust in their doctor. Patient-doctor relationship and
shared decision-making are a critical part of the
124
diagnosis pathway; also, it has been reported that when
PwP gets engaged in the process of their disease,
correlates to a greater quality of life21-23.
Our study has limitations. First, the lack of a dis-
ease specific validated tool for PD; our questionnaire
was based and adapted from instruments used in
other diseases. Efforts should be taken in developing
these tools for PwP exploring more in depth some of
the issues highlighted in our study. Second, recall
bias cannot be avoided with some variables, such as
the time of first motor symptom and the time of PD
diagnosis. Some cases were diagnosed at our center
but other were diagnosed elsewhere and then
referred.
Conclusion
Factors in both the PwP and the doctor side play a
role in delaying the diagnosis. Improving awareness of
the disease as well as improving medical education are
needed. The diagnosis pathway in PD can be improved
with combined efforts by the PwP and the health pro-
viders that should lead to a shorter time to diagnosis
and better quality of life.
Funding
This research has not received any specific grant
from public, commercial, or non-profit sector
agencies.
Conflicts of interest
The authors declare that they have no conflicts of
interest.
Ethical disclosures
Protection of human and animal subjects. The
authors declare that the procedures followed were in
accordance with the regulations of the relevant clinical
research ethics committee and with those of the Code
of Ethics of the World Medical Association (Declaration
of Helsinki).
Confidentiality of data. The authors declare that
they have followed the protocols of their work center on
the publication of patient data.
Right to privacy and informed consent. The au-
thors have obtained the written informed consent of the
patients or subjects mentioned in the article. The cor-
responding author is in possession of this document.

References
1. Dorsey ER, Elbaz A, Nichols E, Abd-Allah F, Abdelalim A, Adsuar JC,
et al. Global, regional, and national burden of Parkinson’s disease, 1990-
2016: a systematic analysis for the global burden of disease study 2016.
Lancet Neurol. 2018;17:939-53.
2. Moustafa AA, Chakravarthy S, Phillips JR, Gupta A, Keri S, Polner B,
et  al. Motor symptoms in Parkinson’s disease: a unified framework.
Neurosci Biobehav Rev. 2016;68:727-40.
3. Goldman JG, Postuma R. Premotor and nonmotor features of Parkin-
sonʼs disease. Curr Opin Neurol. 2014;27:434-41.
4. Breen DP, Evans JR, Farrell K, Brayne C, Barker RA. Determinants of
delayed diagnosis in Parkinson’s disease. J Neurol 2013;260:1978-81.
5. Löhle M, Ramberg CJ, Reichmann H, Schapira AH. Early versus delayed
initiation of pharmacotherapy in Parkinson’s disease. Drugs. 2014;74:645-57.
6. Han Y, Zhang X, Chen T, Wang Z, Sun H. Survey of diagnosis and
therapy in the Parkinson’s disease. Chin J Health Care Med.
2008;10:18-20.
7. Arriaga AC, Violante MR, Ordóñez AC, Latapi G, Ruiz ML, Bellmann IE,
et al. Tiempo desde el inicio de los síntomas motores hasta el diagnós-
tico de enfermedad de Parkinson (EP) en México. Gac Med Mex.
2014;150:242-7.
8. Saunders-Pullman R, Wang C, Stanley K, Bressman SB. Diagnosis and
referral delay in women with Parkinson’s disease. Gend Med.
2011;8:209-17.
9. Plouvier AO, Olde Hartman TC, de Bont OA, Maandag S, Bloem BR,
van  Weel C, et al. The diagnostic pathway of Parkinson’s disease: a
cross-sectional survey study of factors influencing patient dissatisfaction.
BMC Fam Pract. 2017;18:83.
10. Rees RN, Acharya AP, Schrag A, Noyce AJ. An early diagnosis is not the
same as a timely diagnosis of Parkinson’s disease. F1000Res. 2018;7:1106.
11. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al.
MDS clinical diagnostic criteria for Parkinson’s disease: MDS-PD clinical
diagnostic criteria. Mov Disord. 2015;30:1591-601.
12. Unger-Saldaña K, Peláez-Ballestas I, Infante-Castañeda C. Development
and validation of a questionnaire to assess delay in treatment for breast
cancer. BMC Cancer. 2012;12:626.
A. Cervantes-Arriaga et al.: Diagnostic pathway in PD
13. Rasmussen S, Søndergaard J, Larsen PV, Balasubramaniam K,
Elnegaard S, Svendsen RP, et al. The Danish symptom cohort: question-
naire and feasibility in the nationwide study on symptom experience and
healthcare-seeking among 100  000 individuals. Int J Fam Med.
2014;2014:187280.
14. Stebbins GT, Goetz CG, Burn DJ, Jankovic J, Khoo TK, Tilley BC. How
to identify tremor dominant and postural instability/gait difficulty groups
with the movement disorder society unified Parkinson’s disease rating
scale: comparison with the unified Parkinson’s disease rating scale: PIGD
and the MDS-UPDRS. Mov Disord. 2013;28:668-70.
15. Arevalo GG, Jorge R, Garcia S, Scipioni O, Gershanik O. Clinical and
pharmacological differences in early-  versus late-onset Parkinson’s di-
sease. Mov Disord. 1997;12:277-84.
16. Quinn N, Critchley P, Marsden CD. Young onset Parkinson’s disease.
Mov Disord. 1987;2:73-91.
17. Vlaanderen FP, de Man Y, Krijthe JH, Tanke MA, Groenewoud AS,
Jeurissen PP, et al. Sex-specific patient journeys in early Parkinson’s
disease in the Netherlands. Front Neurol 2019;10:794.
18. Borsche M, Balck A, Kasten M, Lohmann K, Klein C, Brüggemann N.
The sooner, the later delayed diagnosis in Parkinson’s disease due to
Parkin mutations. Parkinsonism Relat Disord. 2019;65:284-5.
19. Ruiz-Lopez M, Freitas ME, Oliveira LM, Munhoz RP, Fox SH, Rohani M,
et al. Diagnostic delay in Parkinson’s disease caused by PRKN muta-
tions. Parkinsonism Relat Disord 2019;63:217-20.
20. Lay-Son L, Eloiza C, Trujillo-Godoy O. Latencia diagnóstica en la enfer-
medad de Parkinson: estudio en 200 pacientes de novo en un hospital
público de Chile. Rev Médica Chile. 2015;143:870-3.
21. The Global Parkinson’s Disease Survey (GPDS) Steering Committee.
Factors impacting on quality of life in Parkinson’s disease: results from
an international survey: factors Affecting HRQL in PD. Mov Disord.
2002;17:60-7.
22. Shimbo T, Goto M, Morimoto T, Hira K, Takemura M, Matsui K, et al.
Association between patient education and health-related quality of life
in patients with Parkinson’s disease. Qual Life Res. 2004;13:81-9.
23. Grosset KA, Grosset DG. Patient-perceived involvement and satisfaction
in Parkinson’s disease: effect on therapy decisions and quality of life.
Mov Disord. 2005;20:616-9.
125
 Revista Mexicana de Neurociencia

ORIGINAL ARTICLE

Cognitive impairment in people with COVID-19 with

mild-moderate symptoms in Ecuador
Alejandro Checa*, Eliana Navas, Verónica Valencia, and Jessica Alcívar
Mental Health Unite, Hospital de Especialidades Eugenio Espejo, Quito, Ecuador

Abstract
Background: Complications of COVID-19 can include neurological, psychiatric, psychological, and psychosocial sequelae.
Little is known about the consequences of COVID-19 on the cognitive functions of patients in the subacute phase of the
disease. Objective: The objective of the study was to determine if there is an incidence of cognitive impairment in patients
with COVID-19 with mild to moderate symptoms in the remission phase. Method: This is a cross-sectional study conducted
between April 2021 and August 2021 at the Eugenio Espejo Hospital in Quito, Ecuador. The Montreal Cognitive Assessment
test was applied to COVID-19 patients with mild to moderate symptoms. Results: A total of 50 subjects were recruited, 88%
(n = 44) presented cognitive deterioration and only 12% (n = 6) showed a normal score. Conclusions: In our cohort study,
patients with COVID-19 with mild-moderate symptoms are at high risk of cognitive impairment.

Keywords: COVID-19. Cognitive impairment. Mild to moderate.

Deterioro cognitivo en personas con COVID-19 con síntomas leves-moderados en

Ecuador
Resumen
Antecedentes: Las complicaciones de COVID-19 pueden incluir secuelas neurológicas, psiquiátricas, psicológicas y psico-
sociales. Se sabe poco sobre las consecuencias del COVID-19 en las funciones cognitivas de los pacientes en la fase
subaguda de la enfermedad. Objetivo: Determinar si existe incidencia de deterioro cognitivo en pacientes con COVID-19
con síntomas leves a moderados en la fase de remisión. Método: Se trata de un estudio de tipo transversal realizado entre
abril de 2021 y agosto de 2021 en el Hospital Eugenio Espejo de Quito, Ecuador. Se aplicó el MoCA test a los pacientes
con COVID-19 con síntomas de leve a moderado. Resultados: Un total de 50 sujetos fueron reclutados, el 88% (n = 44)
presentó deterioro cognitivo y apenas el 12% (n = 6) evidenció una puntuación normal. Conclusiones: En nuestro estudio
de cohorte los pacientes con COVID-19 con sintomatología leve-moderada tienen un alto riesgo de presentar deterioro
cognitivo.

Palabras clave: COVID-19. Deterioro cognitivo. Leve a moderado.

*Correspondence: Date of reception: 07-09-2021 Available online: 08-07-2022

Alejandro Checa Date of acceptance: 14-10-2021 Rev Mex Neuroci. 2022;23(4):126-129
E-mail: alcz_11@yahoo.es DOI: 10.24875/RMN.21000060 www.revmexneurociencia.com
2604-6180 / © 2021 Academia Mexicana de Neurología A.C. Published by Permanyer. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

126

Introduction
As the coronavirus disease (COVID-19) pandemic
continues to be a multidimensional threat to humanity,
more evidence has emerged of the neurological involve-
ment associated with it1. The neuroinvasive properties
of COVID-19 have allowed the hypothesis of several
pathogenic mechanisms related to acute and chronic
neurological sequelae2. Neuroimmune interaction may
be important not only in the pathogenesis of neurolog-
ical manifestations, but also in the implications of sys-
temic hyperinflammation and its consequences at the
cognitive level3. While COVID-19 primarily affects the
respiratory system, other organs, including the brain,
may be involved2. In Western clinical studies, relatively
mild neurological dysfunction, such as anosmia and
dysgeusia, is common, while severe neurological disor-
ders such as stroke and meningoencephalitis are less
common4. It is unclear how much COVID-19 infection
contributes to the incidence of central nervous system
damage due to comorbidities in the affected population.
Clinically defined cases of acute disseminated enceph-
alomyelitis have been rarely verified, cases of
Guillain-Barré syndrome and acute necrotizing enceph-
alopathy have been reported in patients with COVID-195.
Common neuropathological findings in patients include
microglial activation with microglial nodules in a subset,
lymphoid inflammation, acute hypoxic-ischemic chang-
es, and astrogliosis; subacute cerebral infarcts, sponta-
neous hemorrhage and microthrombi, and occasional
infarcts of the anterior pituitary have also been noted6.
Complications of COVID-19 can include neurological,
psychiatric, psychological, and psychosocial sequelae.
Little is known about the consequences of COVID-19
on the cognitive functions of patients in the subacute
phase of the disease7. Much remains to be learned
about the effects of direct viral infection of brain cells
and whether COVID-19 persists in the long term, con-
tributing to chronic symptoms. More research is needed
to understand the causal mechanisms of a probable
cognitive deterioration associated with this pathology,
so our study proposal focuses on investigating the cog-
nitive profile of the hospitalized patient with COVID-19,
which would be an important contribution in the under-
standing of disease and a better understanding of the
interaction of COVID-19 with its human host.
Subjects and methods
This was a cross-sectional study, conducted between
April 2021 and August 2021 at the Eugenio Espejo
A. Checa et al.: Cognitive impairment in COVID-19
Hospital in Quito, Ecuador. This hospital has been one
of those designated for the care of patients with
COVID-19 by the Ministry of Public Health. The study
has the approval of the competent entities and the in-
formed consent of all the participants was obtained
patients with mild to moderate COVID-19 infection. That
is, patients with a relationship between arterial oxygen
pressure and inspired oxygen fraction (PaO2/FiO2) be-
tween 201 and 299, in the remission phase of acute
symptoms, that is, after 21 days from the beginning of
the symptoms were invited to participate in the re-
search; all subjects had a positive polymerase chain
reaction test for COVID-19 performed at the institution
designated by the Ministry of Public Health of Ecuador.
After signing the informed consent, the participants
were evaluated using the Montreal Cognitive Assess-
ment (MoCA) test8. The test was applied by a neuro-
psychologist and two resident physicians in psychiatry
duly trained for its application. It was considered as a
cutoff point < 26 cognitive impairment and ≥ 26 normal.
In addition, this test is validated in Spanish in different
Latin American countries9. Participants with a history
of mental, neurological and oncological diseases were
excluded in the study; in addition to those who are ex-
periencing reactive mental illness. The age range of the
subjects was between 18 and 65 years. The captured
data were entered into an electronic database and de-
scriptive statistics, the statistical analysis contemplated
a 95% confidence interval, using Chi-square, for which
the SPSS version 23 program was used. In all cases,
a p < 0.05 is significant.
Results
A total of 50 subjects were recruited, mostly men
58% (n = 29), of which 86.21% (n = 25) had cognitive
impairment and only four participants had a normal
test. As for the female sex, 90.48% (n = 19) showed
cognitive deterioration and only 9.52% (n = 2) had a
normal performance. The participants who were be-
tween 51 and 65 years old are 34% (n = 17), whereas
the subjects between 36 and 50  years old were 46%
(n = 23) and the remaining 20% (n = 10) between 18
and 35 years old. Of the participants between 51 and
65 years old, 82.35% (n = 14) presented cognitive de-
terioration in relation to their counterpart without dete-
rioration 17.64% (n = 3), on the other hand, of the group
between 36 and 50  years old 95% (n = 22) present
cognitive deterioration and only one subject presented
the normal test, finally, of the participants between 18
127
 Rev Mex Neuroci. 2022;23(4)
and 35 years old, 80% (n = 8) were impaired and 20%
(n = 2) it is not.
The patients with university education were 50%
(n = 25), of these 88% (n = 23) presented cognitive
deterioration. Those with secondary education were
36% (n = 18), of which 83.33% (n = 15) had some de-
gree of deterioration and only 14% (n = 7) had primary
education, all showing deterioration cognitive.
Of the sample collected, 88% (n = 44) presented
cognitive deterioration and only 12% (n = 6) showed a
normal score. Of the 44 subjects with cognitive impair-
ment, 58.81% n = (25) had a score between 20 and 25
in the MoCA test, 34.09% n = (15) had a score between
10 and 19 in the test and in 9.09% n = (4) a score lower
than 9 was found.
There was no statistically significant relationship after
applying the Chi-square test between cognitive impair-
ment and sex (p = 0.647), nor was there evidence of a
relationship between age and cognitive impairment
(p = 0.302), in the same way there was no relationship
between education and cognitive impairment (p = 0.515).
Discussion
In this study, it has been possible to verify a preva-
lence of 88% of cognitive impairment in patients treated
at the Eugenio Espejo Hospital in Quito, Ecuador, sim-
ilar incidences can be verified in studies where the
same test has been applied in the population under
similar conditions10. In this sense, it is important to
mention that most of these patients did not report cog-
nitive alterations and therefore these types of problems
go unnoticed.
The sequelae of cognitive disorders are increasingly
seen as a major challenge in the COVID-19 pandemic.
However, most of the evidence of cognitive alterations
after COVID-19 infection and invasion of the virus by
the central nervous system comes from severely affect-
ed individuals in the acute phase of the disease11 in this
study is verified the presence of cognitive impairment
in patients with mild and moderate symptoms.
It is believed that direct viral entry and systemic
mechanisms such as cytokine storm contribute to neu-
roinflammation in patients with COVID-19, the etiology
of cognitive impairment would be multifactorial, among
these factors would be age12. Age seems to be a risk
factor13. However, in this study, there seems to be no
statistically significant relationship associated with age,
which is clinically significant since there is the same
incidence in young and old patients.
128
The clinical presentation of COVID-19 and its long-term
effects are still a matter of study, the implications on men-
tal health in the short and long term require clarification14,
it is not clear if the cognitive deterioration persists over
time or if there is remission of symptoms. COVID-19 in-
fection can cause long-term effects on immune processes
within the CNS by causing microglial dysfunction15. Our
study shows that there is cognitive impairment in the re-
mission phase of symptoms. Therefore, it is necessary to
continue investigating relatively recent onset pathology.
Apparently, there are no significant differences in the
incidence of cognitive impairment in people with
COVID-19 related to sex16, however studies on the sub-
ject are scarce, in any case our data show that there
is no difference.
As has been noted, there is a similar prevalence of
cognitive impairment in patients with different levels of
education, so it does not seem to be a protective factor.
No scientific literature could be found in this regard, so
data must be taken with caution.
Although it is true that the use of the psychometric
instrument could have increased the number of diag-
nosed patients, we believe that the criteria used allowed
us to select the most clinically significant cases. We
consider as a serious limitation that it was not possible
to increase the sample due to the considerable decrease
in diagnosed cases due to vaccination against COVID-19
in Ecuador and there was no control group either. In any
case, our data support the fact that there is a high inci-
dence of cognitive impairment in patients with COVID-19
with mild to moderate symptoms in the remission phase.
Conclusions
In our cohort study, patients with COVID-19 with mild
to moderate symptoms have a high risk of presenting
cognitive impairment, a better understanding of the
causal processes and evolution over time is required
to develop preventive and therapeutic interventions.
Funding
The authors declare that the research was funded by
the Mental Health Unit of the Hospital de Especiali-
dades Eugenio Espejo and no contribution of any kind
has been received from any other entity.
Conflicts of interest
The authors declare that they have no conflict of
interest.

Ethical disclosures
Protection of human and animal subjects. The
authors declare that no experiments were performed
on humans or animals for this study.
Confidentiality of data. The authors declare that no
patient data appear in this article.
Right to privacy and informed consent. The au-
thors declare that no patient data appear in this
article.
References
1. Septyaningtrias DE, Susilowati R. Neurological involvement of COVID-19:
from neuroinvasion and neuroimmune crosstalk to long-term consequen-
ces. Rev Neurosci. 2021;32:427-42.
2. Fisicaro F, Di Napoli M, Liberto A, Fanella M, Di Stasio F, Pennisi M,
et al. Neurological sequelae in patients with COVID-19: a histopatholo-
gical perspective. Int J Environ Res Public Health 2021;18:1415.
3. Wang SC, Su KP, Pariante CM. The three frontlines against COVID-19:
brain, behavior, and immunity. Brain Behav Immun. 2021;93:409-14.
4. Lou JJ, Movassaghi M, Gordy D, Olson MG, Zhang T, Khurana MS,
et al. Neuropathology of COVID-19 (neuro-COVID): clinicopathological
update. Free Neuropathol. 2021;2:2.
5. Chen CC, Chiang PC, Chen TH. The biosafety and risk management in
preparation and processing of cerebrospinal fluid and other neurological
specimens with potential coronavirus infection. Front Neurol. 2020;11:613552.
6. Nagu P, Parashar A, Behl T, Mehta V. CNS implications of COVID-19:
a comprehensive review. Rev Neurosci. 2021;32:219-34.
A. Checa et al.: Cognitive impairment in COVID-19
7. Alemanno F, Houdayer E, Parma A, Spina A, Del Forno A, Scatolini A,
et al. COVID-19 cognitive deficits after respiratory assistance in the su-
bacute phase: a COVID-rehabilitation unit experience. PLoS One.
2021;16:e0246590.
8. Pedraza OL, Salazar AM, Sierra FA, Soler D, Castro J, Castillo P, et al.
Confiabilidad, validez de criterio y discriminante del montreal cognitive
assessment (MoCA) test, en un grupo de adultos de Bogotá. Acta Mé-
dica Colombiana. 2016;41:221-8.
9. Loureiro C, García C, Adana L, Yacelga T, Rodríguez-Lorenzana A,
Maruta C. Uso del test de evaluación cognitiva de montreal (MoCA) en
América Latina: revisión sistemática. Rev Neurol. 2018;66:1-10.
10. Patel R, Savrides I, Cahalan C, Doulatani G, O’Dell MW, Toglia J, et al.
Cognitive impairment and functional change in COVID-19 patients under-
going inpatient rehabilitation. Int J Rehabil Res. 2021;44:285-8.
11. Borsche M, Reichel D, Fellbrich A, Lixenfeld AS, Rahmöller J, Vollstedt EJ,
et al. Persistent cognitive impairment associated with cerebrospinal fluid
anti-COVID-19 antibodies six months after mild COVID-19. Neurol Res
Pract. 2021;3:34.
12. Toniolo S, Scarioni M, Di Lorenzo F, Hort J, Georges J, Tomic S, et al.
Dementia and COVID-19, a bidirectional liaison: risk factors, biomarkers,
and optimal health care. J Alzheimers Dis. 2021;82:883-98.
13. Cristillo V, Pilotto A, Cotti Piccinelli S, Zoppi N, Bonzi G, Gipponi S,
et al. Age and subtle cognitive impairment are associated with long-term
olfactory dysfunction after COVID-19 infection. J  Am Geriatr Soc.
2021;69:2778-80.
14. Orrù G, Bertelloni D, Diolaiuti F, Mucci F, Di Giuseppe M, Biella M, et al.
Long-COVID syndrome? A study on the persistence of neurological,
psychological and physiological symptoms. Healthcare (Basel).
2021;9:575.
15. Stefano GB, Büttiker P, Weissenberger S, Martin A, Ptacek R, Kream RM.
Editorial: the pathogenesis of long-term neuropsychiatric COVID-19 and
the role of microglia, mitochondria, and persistent neuroinflammation: a
hypothesis. Med Sci Monit. 2021;27:e933015.
16. Korompoki E, Gavriatopoulou M, Hicklen RS, Ntanasis-Stathopoulos I,
Kastritis E, Fotiou D, et al. Epidemiology and organ specific sequelae of
post-acute COVID19: a narrative review. J Infect. 2021;83:1-16.
129
 Revista Mexicana de Neurociencia

ORIGINAL ARTICLE

Clinical and environmental risks factors associated with

Parkinson’s disease in Yucatan
Luis E. Parra Medina1*, Manuel J. Gurubel-Maldonado1, Gloria Arankowsky-Sandoval1,
José L. Góngora-Alfaro1, Roberto Leal-Ortega2, and Jorge E. Salazar-Ceballos3
1Autonomous University of Yucatan, Department of Neurosciences, Centro de Investigaciones Regionales Dr. Hideyo Noguchi; Neurology Service

at: 2Hospital Faro del Mayab; 3Hospital Regional del ISSSTE Elvia Carrillo Puerto. Mérida, Yucatan, Mexico

Abstract
Objective: The objective of the study is to identify the risk and protective factors associated with Parkinson’s disease (PD)
in inhabitants of Yucatan. Methods: Case control study. A questionnaire with the main risk and protective factors for PD
described in the literature was applied to cases and controls. Results: The sample consisted of 85 cases and 124 controls.
In the univariate logistic regression analyzes, it was found that the following factors were significantly associated with a higher
risk of developing PD: family history of PD (OR = 5.28, p = 0.001), personal history of diabetes (OR = 2.35, p = 0.01), the
number of head trauma (OR = 1.35, p = 0.02), number of general anesthesia received (OR = 1.27, p = 0.050), exposure to
organic solvents (OR = 2.73, p = 0.02) and the years of exposure to organic solvents (OR = 1.05, p = 0.01):
Conclusions: The findings of this research indicate that the inhabitants of the state of Yucatan are exposed to the following
risk factors: having a relative with PD, personal history of diabetes, number of head traumas, exposure to organic solvents,
years of exposure to organic solvents and number of general anesthesia received.

Keywords: Case-control study. Parkinson’s disease. Risk and protection factors. Head trauma. General anesthesia.

Factores de riesgo clínicos y ambientales asociados a la enfermedad de Parkinson en

Yucatán
Resumen
Objetivo: Identificar los factores de riesgo y de protección asociados con padecer la enfermedad de Parkinson (EP) en
habitantes de Yucatán. Métodos: Estudio de casos y controles. Se aplicó un cuestionario con los principales factores de
riesgo y protección de EP descritos en la literatura tanto a los casos como a los controles. Resultados: La muestra es-
tuvo constituida por 85 casos y 124 controles. En los análisis de regresión logística univariados se encontró que los si-
guientes factores se asociaron significativamente a un mayor riesgo de desarrollar la EP: antecedente familiar de EP
(RM = 5.28, p  = 0.001), antecedentes de diabetes (RM = 2.35, p = 0.01), el número traumatismos craneoencefáli-
cos (RM = 1.35, p = 0.02), número de anestesias generales recibidas (RM = 1.27, p = 0.050), la exposición a solventes
orgánicos (RM = 2.73, p = 0.02) y los años de exposición a solventes orgánicos (RM = 1.05, p = 0.01): Conclusiones:
Los hallazgos de esta investigación indican que los habitantes del estado de Yucatán están expuestos a los siguientes
factores de riesgo: tener un familiar con EP, antecedentes personales de diabetes, el número de traumatismos

*Correspondence: Date of reception: 13-01-2022 Available online: 08-07-2022

Luis Enrique Parra Medina Date of acceptance: 07-02-2022 Rev Mex Neuroci. 2022;23(4):130-136
E-mail: leparramed@gmail.com DOI: 10.24875/RMN.22000007 www.revmexneurociencia.com
2604-6180 / © 2022 Academia Mexicana de Neurología A.C. Published by Permanyer. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

130
 L.E. Parra Medina et al.: Risk factors associated with Parkinson’s disease in Yucatan
craneoencefálicos, la exposición a solventes orgánicos, los años de exposición a solventes orgánicos y número de anes-
tesias generales recibidas.
Palabras clave: Estudio de casos y controles. Enfermedad de Parkinson. Factores de riesgo y protección. Traumatismos
craneoencefálicos. Anestesia general.
Introduction
It is estimated that there are approximately 6.2 million
people with Parkinson’s disease (PD) in the world, by
the time 2040 there will be 14.2 million people with PD
and due to its rapid increase, some authors have con-
sidered declaring it a non-infectious pandemic1. Two
hundred years have passed after the first description
of PD by James Parkinson and various hypotheses
have been put forward about its cause, but none have
been conclusively proven2-4.
PD is currently believed to have a multifactorial or-
igin, being the result of a complex interaction between
genetic and environmental factors, some of which
confer risk, while others provide protection2,3,5. Among
the clinical risk factors associated with the develop-
ment of PD, the following have been frequently de-
scribed: family history of PD and essential tremor, a
personal history of diabetes, head trauma, general
anesthesia, and other factors5-8. Among the environ-
mental risk factors associated with PD, the following
have been described: exposure to organic solvents,
pesticides, herbicides, consumption of well water, and
others5,9,10. As protective factors, caffeine consump-
tion, smoking, and sports have been found, among
others11,12.
The Mexican population is aging, which allows us to
suppose that, in the future, PD could be a public health
problem, so it is necessary to have epidemiological
data on this disease to anticipate trends and plan care
needs13. Likewise, each region has its own social, cul-
tural, and environmental characteristics. Yucatan is a
region with a high impact of water contamination due
to it has a karst type soil favoring contaminants entry
into the phreatic level. There is evidence of contamina-
tion of the Yucatan aquifer, the only source of fresh
water in the area, by organochlorine pesticides, as well
as its bioaccumulation in the blood of women with can-
cer and breast milk, due to agricultural activities14,15.
This would be the second on risk and protective fac-
tors associated with PD in Mexico, which could provide
knowledge about the study dynamics of PD in different
regions of Mexico, allowing the identification of people
who would be at risk of Parkinson16.
Objective
The objective of the study is to identify the risk and
protective factors associated with Parkinson’s disease
in inhabitants of the state of Yucatan.
Material and methods
This is an epidemiological, observational, analytical, ret-
rospective, case-control study. The protocol was reviewed
and approved by the Ethics Committee of the Research
Center “Dr. Hideyo Noguchi” in Mérida. Participants who
met the inclusion criteria and who agreed to participate by
signing an informed consent were included in the study.
The study was conducted from May 2016 to May 2019.
This was a non-probability convenience sample. The
sample consisted of patients diagnosed with Parkinson’s
disease by a neurologist. In the original design, it was
intended to gather a sample of 100 patients and 100 con-
trols, if the number of cases were less than 100, two
controls would be used for each case. However, in the
study period, only 85 cases and 124 controls were inter-
viewed. A questionnaire designed to collect data on clin-
ical and environmental variables considered as possible
risk or protective factors for Parkinson’s disease was ap-
plied to the cases and controls. The inclusion criteria
were: patients diagnosed with PD by a neurologist; pa-
tients who have resided in Yucatan for at least 10 years
prior to the date of their PD diagnosis; patients who signed
an informed consent letter to participate in the study.
The elimination criteria were: patients who did not
respond completely and correctly to the questionnaire
designed for the study; patients who decided to with-
draw voluntarily before completing the questionnaire;
patients whose diagnosis was reversed or modified by
a neurologist.
The control group was made up of participants
matched with the group of cases by sex and age (± 3
years). Their inclusion criteria were: people who do not
have PD, people who have resided in Yucatan for at
least 10 years before the date of the PD diagnosis of
their respective control; people who signed an in-
formed  consent letter to participate in the study. The
elimination criteria were: people who did not respond
completely and correctly to the questionnaire designed
131
 Rev Mex Neuroci. 2022;23(4)
for the study; people who decided to withdraw volun-
tarily before completing the questionnaire.
The clinical and environmental variables that were
analyzed as possible risk factors associated with PD
were: family history of PD, family history of essential
tremor, head trauma, number of head trauma, num-
ber of times of unconsciousness due to head trau-
ma, having been exposed to general anesthesia and
the number of times this occurred, using pesticides,
herbicides, and organic solvents, as well as the
number of years of exposure to these, and well wa-
ter consumption. The variables that were analyzed
as possible protective factors were: smoking, con-
sumption of caffeinated beverages, and physical
activity.
Statistics analysis
The statistical analysis of the risk factors was carried
out using the statistical package Statistical Package for
the Social Sciences (SPSS). Univariate and multivariate
logistic regression analyzes were performed on the vari-
ables under study to determine their contribution as
possible risk and protection factors for PD. To calculate
the strength of the association between each of factors
and PD, the odds ratio (OR) was used, with a 95%
confidence interval. In all cases, a test was considered
significant when it was p <0.05.
In the first phase, to estimate the relative risk of each
of the variables, a univariate logistic regression analy-
sis was performed individually with each one of them.
Finally, with those factors that were significant in the
univariate analysis, multiple logistic regression models
were made in order to create models with those vari-
ables that remained significant and to be able to adjust
for those confounding factors that could affect the risk
estimation.
Results
The sample consisted of 85 cases and 124 controls.
The mean age (± standard deviation) of the cases was
65.6 ± 10.1 years and the age of the controls was
64.3  ± 10.5 years. Fifty-one patients had two controls,
22 patients only one control, matched by age and sex,
the remaining 12 patients had no control by age and
sex. In the cases, 58 (68.2%) were men and 27 (31.7%)
were women, which corresponds to a ratio of 2.1 men
for every woman.
132
Univariate logistic regression
Table  1 shows the results of the univariate logistic
regression analysis of clinical and environmental risk
factors that in previous studies have been associated
with a higher risk of developing PD, and Table 2 shows
the results of univariate logistic analyzes of protective
factors frequently associated with a lower risk of devel-
oping PD. The relative risk estimates revealed that a
higher risk of developing PD was significantly associ-
ated with family history of PD, personal history of dia-
betes, the number of head trauma, the number of gen-
eral anesthesia received, organic solvents exposure
and number of years of organic solvents exposure. Due
to head trauma may be associated with reverse cau-
sality bias, only head trauma occurring 10 or more
years before the diagnosis of PD were considered in
the analyzes. In the case of controls, only trauma that
preceded 10 years to the age of diagnosis of their re-
spective peers with PD were considered. In this study,
none of the factors that are considered protective for
the development of PD had a significant association
(Table 2). Table 3 summarizes the risk factors associ-
ated with Parkinson’s disease resulting from the univar-
iate logistic regression analysis.
Multiple logistic regression
In the conditional multiple logistic regression ana-
lyzes, a model was created (Table 4) that included the
following variables: family history of PD (OR = 5.84)
and number of years of solvents exposure (OR = 1.05).
Variables that were not significant were not included in
the model.
As mentioned in the background, having a history of
smoking or consuming coffee has been shown to be
associated with a lower risk of developing PD. Although
in the present study neither of these two variables were
associated with a reduced risk of developing Parkin-
son’s disease, two multiple logistic regression models
were made with the variables that were associated with
a higher risk of PD but adjusting for the history of smok-
ing and caffeine consumption (Table  5). Making this
adjustment, in both models having a relative with PD
and the number of years of exposure to solvents were
maintained as risk factors.
Discussion
Various epidemiological studies reinforce the hypoth-
esis that PD is a neurodegenerative disorder of
 L.E. Parra Medina et al.: Risk factors associated with Parkinson’s disease in Yucatan

Table 1. Estimation of the association of clinical and Table 3. Summary of risk factors associated with PD
environmental factors with the risk of PD resulting from resulting from the univariate logistic regression analysis
the univariate logistic regression analysis Variable OR CI (95%) p
Variable OR CI (95%) p
Family history of PD 5.28 2.00‑13.95 0.001
Clinical risk factors
Family history of PD 5.28 2.00‑13.95 0.001 Diabetes 2.35 1.15‑4.81 0.01
Family history of essential tremor 0.65 0.24‑1.67 0.37
Number of head trauma 1.35 1.03‑1.77 0.02
Diabetes 2.35 1.15‑4.81 0.01
Head trauma 1.43 0.82‑2.49 0.20 Number of general anesthesia 1.27 1.00‑1.61 0.050
Number of head trauma 1.35 1.03‑1.77 0.02 received
Unconsciousness due to head 1.87 0.77‑4.55 0.16
trauma Solvents exposure 2.73 1.13‑6.58 0.02
Number of times of 1.53 0.75‑3.10 0.23
unconsciousness due to head Number of years of solvents 1.05 1.00‑1.09 0.01
trauma exposure
Personal history of receiving 1.58 0.90‑2.75 0.10
PD: Parkinson’s disease OR: odds ratio CI: confidence interval.
general anesthesia
Number of general anesthesia 1.27 1.00‑1.61 0.050
received

Environmental risk factors

Solvents exposure 2.73 1.13‑6.58 0.02
Number of years of solvents 1.05 1.00‑1.09 0.01 Table 4. Multiple logistic regression model of the
exposure association of risk factors with the presence of PD
Pesticides exposure 0.90 0.51‑1.80 0.96
Variable OR CI (95%) p
Number of years of pesticides 1.01 0.98‑1.03 0.31
exposure Family history of PD 5.83 2.18‑15.54 0.000
Herbicides exposure 1.68 0.78‑3.62 0.18
Number of years of herbicides 1.03 0.98‑1.07 0.19 Number of years of solvents 1.05 1.01‑1.10 0.008
exposure exposure
Well water consumption 0.65 0.37‑1.14 0.13
PD: Parkinson’s disease OR: odds ratio CI: confidence interval.
PD: Parkinson’s disease OR: odds ratio CI: confidence interval.

Table 5. Multiple logistic regression model of the factors

Table 2. Estimation of the association of protective associated with a higher risk of PD adjusted for tobacco
factors with the risk of PD resulting from the univariate and coffee consumption
logistic regression analysis
Variable OR CI (95%) p
Protection factors
Family history of PD 5.75 2.15‑15.36 0.000
Variable OR CI (95%) p
Number of years of 1.05 1.01‑1.10 0.008
Smoking 0.86 0.48‑1.54 0.61 solvents exposure

Number of years of smoking 0.98 0.96‑1.01 0.27 PD: Parkinson’s disease OR: odds ratio CI: confidence interval.

Caffeine consumption 0.94 0.54‑1.63 0.82

Number years of caffeine 1.00 0.98‑1.01 0.84

consumption

Physical activity 1.53 0.84‑2.80 0.16 Family history of Parkinson’s disease

PD: Parkinson’s disease OR: odds ratio CI: confidence Interval.
multifactorial origin, which results from a complex inter-
action between the genetic characteristics of individu-
als, the chronic degenerative pathologies they suffer
from, various habits, and multiple environmental fac-
tors, which can increase or reduce the risk of
Parkinson2,3,5.
Having a family history PD was associated with a
5.28 times higher risk of PD, which was approximately
1.6 times higher than the risk reported in other studies
in various parts of the world6,17,18 but six times lower
than the risk of a study conducted in Italy5. A study in
Cuba reported an odds ratio of 7.22, being 1.3 times
higher than that reported in our study19.
In the multivariate analyzes, having a relative with PD
remained a risk factor for developing PD with an OR of
5.83, which is approximately three and seven times
133
 Rev Mex Neuroci. 2022;23(4)
lower compared to the multivariate analyzes of studies
carried out in India (OR: 21.40) and Italy (OR: 41.70)
respectively5,9.
In the meta-analysis by Noyce et al., which added 26
case-control studies, reported a significant association
between having a first-degree relative with PD and the
risk of developing the disease, with a pooled odds ratio
of 3.23 (95% CI 2.65-3.93)20, which is approximately
half the risk reported in our study.
Solvents exposure
Solvents are substances found in fuels, paints, glues,
lubricants, degreasers, and cleaning products, all of
which have been linked to an increased risk of PD, in
part due to anecdotal reports of parkinsonism in people
highly exposed to solvents21.
The association between solvents and the develop-
ment of PD has been studied mostly in epidemiological
studies of the case-control type22. Most of the relative
risk estimates are reported in a range of 1.0 to 1.8, but
in these studies the solvents were treated, as in our
study, as a single entity without distinguishing the
chemicals10,22-25. In general, the observed associations
of PD with solvents have been modest and very similar
to those reported in our work, and apparently, there are
only reports of univariate analysis.
The only study to date that has evaluated the asso-
ciation between PD and exposure to different types of
organic solvents present in chemical products is a
case-control study conducted with 99 pairs of twins (49
monozygotic and 50 heterozygotes), where for each
pair one had Parkinson’s disease and the other did not,
finding that the most suggestive solvents as possible
etiological agents were trichlorethylene (TCE), perchlo-
rethylene (PERC) and carbon tetrachloride (CCl4)21. A
significantly higher risk of PE was associated with tri-
chlorethylene exposure (OR = 6.1, 95% CI: 1.2-33;
p = 0.034), while perchlorethylene exposure (OR = 10.5, 95%
CI 0.97-113, p = 0.053;) and carbon tetrachloride (RM =
2.3, 95% CI 0.9-6.1, p = 0.088) had tendencies to be
significant. However, the risk estimates were based on
a very small number of exposed subjects22. TCE, PERC,
and CCl4 have been used extensively around the world
for decades. TCE has been used as a degreasing,
cleaning agent, additive in many common household
products, including correction fluid for typewriters, ad-
hesives, paints and carpet cleaners, and stain
removers21.
For future studies, we suggest identifying frequently
used chemicals in our country that contain some of the
134
possible etiological agents associated with the devel-
opment of PD. We also recommend the use of protec-
tion in people exposed to this class of substances.
Personal history of diabetes mellitus
In the present study, a 2.35 times higher risk of de-
veloping PD was found when the participants had a
history of diabetes, which is higher than the study by
Schernhammer et al. who found a 1.33 higher risk of
PD and is contradictory with the study by Powers et al.,
who reported that diabetes is a protective factor8,26.
Traumatic brain injuries
In the univariate analysis, we found a 1.3 times higher
risk of developing PD associated with the number of
times they received head trauma (one or more times),
which is consistent with two similar studies with multi-
variate analyzes. In the Goldman’s study, it is reported
that people who have received one head injury had a
2.8 times greater risk of developing PD. While Gao’s
study was found a risk similar to the present study, with
an odds ratio of 1.40 when the subjects had received
a single head trauma and an OR of 2.33 when they had
received two or more head trauma27,28. No univariate
analysis reports were found.
Postural instability, stiffness, and bradykinesia are
diagnostic criteria for PD and, naturally, the presence
of these motor symptoms can cause falls in patients,
reporting that up to 90% have fallen at least once29.
Consequently, studies evaluating head trauma as a risk
factor for developing PD will only consider trauma be-
fore the onset of motor symptoms of the disease, since
failure to do so could incur a reverse causality bias by
including in the analysis of head trauma that occurred
as a consequence of the early motor disorders of
PD6,29-31. In a nested casecontrol study carried out with
24,412 people with a diagnosis of PD and 243,363 con-
trols, an increase in the risk of falls was found up to 10
years before the diagnosis of PD32. which could cause
head trauma. Finally, studies that seek to establish
whether head injuries represent a risk factor for the
development of PD should eliminate head trauma that
occurred 10 years before the diagnosis of the
disease.
General anesthesia
In the univariate analysis, a 1.2 times higher risk of
developing PD was found associated with the number
of general anesthesia received (one or more times),
which agrees with De Michele’s univariate analysis,
 L.E. Parra Medina et al.: Risk factors associated with Parkinson’s disease in Yucatan
which reported an odds ratio of 1.05, while Zorzon in
their multivariate analysis reported a odds ratio of 2.25,33.
General anesthesia has been suggested as a risk
factor associated with Parkinson’s disease in some
case-control studies, but not all5,34. A meta-analysis
with 6 case-control studies found no association of
general anesthesia with Parkinson’s disease20. In a
retrospective cohort study that included 490,156 anes-
thesiologists and 499,388 internists, anesthesiologists
were found to have a higher risk of dying from Parkin-
son’s disease than internists.7 In experimental models,
mechanisms have been described that relate exposure
to anesthetic gases such as halothane, isoflurane, and
nitrous oxide with the development of PD35.
Study limitations
Due to the coronavirus pandemic (COVID-19) it was
not possible to reach the sample size (n = 100). The
small sample size of the cases (n = 86) reduces the
power of the statistical analyses. To compensate for the
above, in some cases two controls were used for each
one, which is recommended by Gail, using the case
saving rule. Therefore, it is suggested to increase the
sample size for future studies36.
Epidemiological case-control studies have been used
successfully to investigate possible associations between
various variables and the risk of developing certain mul-
tifactorial diseases, such as PD. However, they have bi-
ases inherent in their methodology, such as memory bias
in elderly patients and reverse causality by not consider-
ing that the possible factors associated with PD could be
a consequence and not a cause of the disease. In addi-
tion, another potential source of bias in this type of study
is related to the collection of data in the interviews, where
the interviewers, knowing the hypotheses, can, con-
sciously or not, influence the interviewees to provide
answers consistent with those hypotheses.
It is necessary to reach a consensus regarding the
methodology of epidemiological studies of risk and pro-
tective factors associated with PD, to avoid or reduce
biases. For greater veracity in future studies, it is sug-
gested to increase the sample size. If feasible, the in-
tensity and duration of the factors associated with PD
should be estimated, such as exposure to pesticides
and organic solvents, tobacco, and caffeine consump-
tion. Likewise, to reduce the reverse causality bias, only
factors before the onset of the prodromal phase of PD
should be considered, which is conservatively estimat-
ed to begin about 10 years before diagnosis, so this
value could be used as a point cut-off point11.
Conclusions
The findings of this research indicate that the inhab-
itants of the state of Yucatan are exposed to the follow-
ing risk factors for developing PD: family history of PD,
personal history of diabetes, the number of head trau-
ma, exposure to solvents organics, number of years of
exposure to organic solvents, and the number of gen-
eral anesthesia received. It is necessary to reach a
consensus regarding the methodology of epidemiolog-
ical studies of risk and protective factors associated
with PD, to avoid or reduce biases.
Funding
There authors report no financial source for this
project.
Conflicts of interest
The authors declare that they have no conflicts of
interest.
Ethical disclosures
Protection of human and animal subjects. The au-
thors declare that the procedures followed were in accor-
dance with the regulations of the relevant clinical research
ethics committee and with those of the Code of Ethics of
the World Medical Association (Declaration of Helsinki).
Confidentiality of data. The authors declare that
they have followed the protocols of their work center on
the publication of patient data.
Right to privacy and informed consent. The au-
thors have obtained the written informed consent of the
patients or subjects mentioned in the article. The cor-
responding author is in possession of this document.
References
1. Dorsey ER, Sherer T, Okun MS, Bloem BR. The emerging evidence of
the Parkinson pandemic. J Parkinsons Dis. 2018;8:S3-8.
2. Przedborski S. The two-century journey of Parkinson disease research.
Nat Rev Neurosci. 2017;18:251-9.
3. Caggiu E, Arru G, Hosseini S, Niegowska M, Sechi G, Zarbo IR, et al.
Inflammation, infectious triggers, and Parkinson’s disease. Front Neurol.
2019;10:122.
4. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J,
et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013.
5. Zorzon M, Capus L, Pellegrino A, Cazzato G, Zivadinov R. Familial and
environmental risk factor in Parkinson’s disease: a case-control study in
north-east Italy. Acta Neurol Scand. 2002;105:77-82.
6. Nicoletti A, Vasta R, Mostile G, Nicoletti G, Arabia G, Iliceto G, et al.
Head trauma and Parkinson’s disease: results from an Italian case-con-
trol study. Neurol Sci. 2017;38:1835-9.
7. Peretz C, Alexander BH, Nagahama SI, Domino KB, Checkoway H.
Parkinson’s disease mortality among male anesthesiologists and inter-
nists. Mov Disord. 2005;20:1614-7.
135
 Rev Mex Neuroci. 2022;23(4)
8. Schernhammer E, Hansen J, Ruggjerg K, Wermuth L, Ritz B. Diabetes
and the risk of developing Parklinson’s disease in Denmark. Diabetes
Care. 2011;34:1102-8.
9. Sanyal J, Chakraborty DP, Sarkar B, Banerjee TK, Mukherjee SC,
Ray BC, et al. Environmental and familial risk factors of Parkinson’s di-
sease: a case control study. Can J Neuro Sci. 2010;37:637-42.
10. Seidler A, Hellenbrand W, Robra BP, Vieregge P, Nischan P, Joerg J,
et  al. Possible environmental, occupational, and other etiologic factors
for Parkinson’s disease: a case-control study in Germany. Neurology.
1996;46:1275-84.
11. Parra-Medina LE, Álvarez-Cervera FJ, Góngora-Alfaro JL. Potenciales
fuentes de sesgo en los estudios de factores de riesgo y protección
asociados a la Enfermedad de Parkinson. Arch Neurocien. 2020;25:6-18.
12. Paillard T, Rolland Y, de Suoto Barreto P. Protective effects of physical
exercise in Alzheimer’s disease and Parkinson’s disease. A narrative
review. J Clin Neurol. 2015;11:212-9.
13. Rivera-Silva G, Rodríguez-Reyes L, Treviño-Alanís MG. El envejecimien-
to de la población mexicana. Rev Med Inst Mex Seguro Soc. 2017;56:116.
14. Perera-Rios J, Ruiz-Suarez E, Bastidas-Bastidas PJ, May-Euán F, Ui-
cab-Pool G, Leyva-Morales JB, et al. Agricultural pesticide residues in
water from a karstic aquifer in Yucatan, Mexico, pose a risk to children’s
health. Int J Environ Health Res. 2021;20:1-15.
15. Rodríguez AG, López MI, Del Valls-Casillas TA, León JA, Datta-Banik S.
Impact of pesticides in karst groundwater. Review of recent trends in
Yucatan, Mexico. Groundw Sustain Dev. 2018;7:20-9.
16. Ventura-Chávez R, Reyna-Gil AI, García S. Factores asociados a la
enfermedad de Parkinson en pacientes de la Comarca Lagunera, Méxi-
co. Rev Mex Neuroci. 2019;20:174-9.
17. Elbaz A, Grigoletto F, Baldereschi M, Breteler MM, Manubens-Bertran JM,
Lopez-Pousa S, et al. Familial aggregation of Parkinson’s disease: a
population-based case-control study in Europe. EUROPARKINSON study
group. Neurology. 1999;52:1876-82.
18. McCann SJ, LeCouteur DG, Green AC, Brayne C, Johnson AG, Chan D,
et al. The epidemiology of Parkinson’s disease in an Australian popula-
tion. Neuroepidemiology. 1998;17:310-7.
19. Benítez JL, Mesa FC, Orta A, Sendín LP. Factores de riesgo de la en-
fermedad de Parkinson idiopática. Estudio de casos y controles en un
área urbana de Ciudad Habana, Cuba. Rev Mex Neuroci. 2001;2:293-7.
20. Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH,
Giovannoni G, Lees AJ, et al. Meta-analysis of early nonmotor features
and risk factors for Parkinson’s disease. Ann Neurol. 2012;72:893-901.
21. Goldman SM, Quinlan PJ, Ross GW, Marras C, Meng C, Bhudhikanok GS,
et al. Solvent exposures and Parkinson disease risk in twins. Ann Neurol.
2012;71:776-84.
136
22. Lock EA, Zhang J, Checkoway H. Solvents and Parkinson disease: a
systematic review of toxicological and epidemiological evidence. Toxicol
Appl Pharmacol. 2013;266:345-55.
23. DePalma G, Mozzoni P, Mutti A, Calzetti S, Negrotti A. Case-control
study of interactions between genetic and environmental factors in Par-
kinson’s disease. Lancet. 1988;352:1986-7.
24. Ohlson CG, Hogstedt C. Parkinson’s disease and occupational exposure
to organic solvents, agricultural chemicals and mercury-a case-referent
study. Scand J Work Environ Health. 1981;7:252-6.
25. Firestone JA, Lundin JI, Powers KM, Smith-Weller T, Franklin GM, Swan-
son PD, et al. Occupational factors and risk of Parkinson’s disease: a
population-based case-control study. Am J Ind Med. 2010;53:217-23.
26. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr.,
Swanson PD, Checkoway H. Diabetes, smoking, and other medical con-
ditions in relation to Parkinson’s disease risk. Parkinsonism Relat Disord.
2006;12:185-9.
27. Goldman SM, Tanner CM, Oakes D, Bhudhikanok GS, Gupta A, Langs-
ton JW. Head injury and Parkinson’s disease risk in twins. Ann Neurol.
2006;60:65-72.
28. Gao J, Liu R, Zhao E, Huang X, Nalls MA, Singleton AB, et al. Head
injury, potential interaction with genes, and risk for Parkinson’s disease.
Parkinsonism Relat Disord. 2015;21:292-6.
29. Fasano A, Canning CG, Hausdorff JM, Lord S, Rochester L. Falls in
Parkinson’s disease: a complex and evolving picture. Mov Disord.
2017;32:1524-36.
30. Bhidayasiri R, Brenden N. 10 Commonly asked questions about Parkin-
son disease. Neurologist. 2011;17:57-62.
31. Chen H. The changing landscape of Parkinson epidemiologic research.
J Parkinsons Dis. 2018;8:1-12.
32. Nyström H, Nordström A, Nordström P. Risk of injurious fall and hip
fracture up to 26 y before the diagnosis of Parkinson disease: nested
case-control studies in a nationwide cohort. PLoS Med.
2016;13:e1001954.
33. De Michele G, Filla A, Volpe G, de Marco V, Gogliettino A, Ambrosio G,
et al. Environmental and genetic risk factors in Parkinson’s disease: a
case-control study in Southern Italy. Mov Disord. 1996;11:17-23.
34. Hofman A, Collette HJ, Bartelds AI. Incidence and risk factors of Parkin-
son’s disease in The Netherlands. Neuroepidemiology. 1989;8:296-9.
35. Mastrangelo G, Comiati V, dell’Aquila M, Zamprogno E. Exposure to
anesthetic gases and Parkinson’s disease: a case report. BMC Neurol.
2013;13:194.
36. Gail M, Williams R, Byar DP, Brown C. How many controls? J Chronic
Dis. 1976;29:723-31.
Revista Mexicana de Neurociencia

Original article

Somatodyspraxia: A novel term proposition as a primary factor

of apraxia and its applicability in the PAINT Neuropsychological
Rehabilitation Model for brain injury
Adriana Castillo-Sánchez-Lara1* and Christopher Ruben-Castillo2
1Reaprende, Centro de Rehabilitación Neuropsicológica; 2Department of Vascular Surgery, Instituto Nacional de Ciencias Médicas y Nutrición
Salvador Zubirán. Mexico City, Mexico

Abstract
This article proposes the term Somatodyspraxia to refer to the difficulties in body management and postural adjustments for
performing actions, due to alterations in somatosensory and proprioceptive processing, as a consequence of acquired brain
injury. In addition, we propose Somatoapraxia as a primary factor for apraxia and describe its applicability for a Neuropsy-
chological Rehabilitation Model for apraxia. The explanatory models of apraxia, the somatosensory and proprioceptive alte-
rations underlying various types of apraxia, and their manifestation in different neurological conditions, are taken into
consideration. Recognizing Somatodyspraxia as a clinical component of patient’s life allows its integration for the improvement
of current existing rehabilitation programs.

Keywords: Somatodyspraxia. Apraxia. Acquired brain injury.

Somatoapraxia: una nueva propuesta de término como factor principal de la apraxia y

su aplicabilidad en el modelo de rehabilitación neuropsicológica PAINT para lesiones
cerebrales
Resumen
En este artículo se presenta el término “somatoapraxia” para referirse a la dificultad en el manejo corporal y ajustes postu-
rales en la realización de acciones, debido a alteración en el procesamiento somatosensorial y propioceptivo como conse-
cuencia de daño cerebral adquierido. Además, se plantea la somatoapraxia como un factor primario de las apraxia y su
aplicabilidad en un modelo de rehabilitación neuropsicológica. Se consideran las alteraciones somatosensoriales y propio-
ceptivas como subyacentes a varios tipos de apraxia y su manifestación en diferentes patologías neurológicas. El recono-
cimiento de la somatoapraxia como componente clínico de la apraxia y la afección a la vida de los pacientes, permite
mejorar los programas de rehabilitación existentes.

Palabras clave: Somatoapraxia. Apraxia. Lesión cerebral adquirida.

*Correspondence: Date of reception: 27-09-2021 Available online: 08-07-2022

Adriana Castillo-Sánchez-Lara Date of acceptance: 27-11-2021 Rev Mex Neuroci. 2022;23(4):137-148
E-mail: adriana.castillo.sanchezlara@gmail.com DOI: 10.24875/RMN.21000067 www.revmexneurociencia.com
2604-6180 / © 2021 Academia Mexicana de Neurología A.C. Published by Permanyer. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

137
 Rev Mex Neuroci. 2022;23(4)
Introduction
We propose the novel term “Somatoapraxia” to be
the alteration in somatosensory and proprioceptive pro-
cessing, after acquired brain injury, which makes it
problematic to manage the body schema and carry out
the necessary postural adjustments for the execution
of tasks or actions. It differs from apraxia, since apraxia
has been defined as a disorder that involves the inabil-
ity to execute learned and purposeful movements, on
command or by imitation, due to alteration in the con-
cept of movement or in the logical motor sequence of
previously learned movements1,2.
In adults, different descriptive models for apraxia
have been proposed, which encompass different etiol-
ogies: failure in visual input, memory, semantics, or in
the management of space and time3. In children with
learning disabilities, Ayres proposed a similar term,
somatodyspraxia4, to refer to the inability to interpret
and organize sensory information that allows an ade-
quate and effective response to multiple environmental
stimuli5. However, this only considers the origin of the
problem to be due to planning and conceptualization
factors of ideational apraxia. Furthermore, in adults
with acquired brain injury, alterations in sensory and
proprioceptive processing that impact daily living activ-
ities have been described1; however, they have not
been considered as part of a theoretical model.
A somatosensory and proprioceptive core concept,
which explains the complexity of the different types of
apraxia after acquired brain injury, has not been pro-
posed. Therefore, is our objective to present the term
“Somatoapraxia” as a novel core concept that exists as
principal factor in apraxia. We will also highlight the
terms applicability in a Neuropsychological Rehabilita-
tion Model for apraxia.
History of apraxia
The term apraxia was proposed by Steinthal in 1871,
to refer exclusively to the set of disorders that had as
the common characteristic, the inability to correctly ex-
ecute a motor activity on command6. However, the most
important person responsible for its recognition was
Hugo Karl Liepmann (1863-1925), who distinguished
different functional components responsible for praxis
processing. He believed that the learning of motor skills
required the acquisition of “movement formulas,” “inner-
vation patterns,” and “kinetic memories”3. Thus,
Liepmann characterized ideational apraxia, ideomotor
apraxia, and limb or kinetic apraxia as consequences
138
of brain injury in adults7. Liepmann proposed ideational
or conceptual apraxia as an interruption in the activation
of the space-time plan, therefore, the idea of movement
is not possible. Conversely, in an ideomotor apraxia the
spatio-temporal plans are preserved, but they cannot
guide the innervation engrams to execute movements
because they are disconnected from them; the patient
knows what to do, but not how to do it. Finally, when
the interruption of the innervation engrams interferes
with the selection of muscular synergies to perform
movements, there is kinetic apraxia of the limbs7.
Even then, Liepman considered that praxis requires
the idea or plan of movement, which must be recovered
and associated through the left sensorimotor cortical
connections, which in turn carry information to the left
primary motor areas. When the left limb performs the
movement, the information is transmitted from left to
right through the corpus callosum and activates the
right motor cortex8.
Explanatory models of apraxia
In recent decades, complex cognitive models of prax-
is processing have been developed to explain and clas-
sify apraxia. The description of the mechanisms under-
lying this disorder has been diverse. Heilman, González
Rothi and Valenstein9 in 1982, and González Rothi,
Heilman, and Warson10 in 1985, proposed that there
are at least two types of mechanisms that describe
apraxia: (1) a degraded memory trace that produces
difficulties in the reception and production of gestures,
and (2) a memory discharge dysfunction that generates
alterations in their production3.
Roy and Square, in 1985, proposed that praxis pro-
cessing is mediated by a system that involves two
components, both conceptual and of production9. The
first includes three types of knowledge: (1) about the
operation of tools and objects, (2) about the indepen-
dent actions of objects, and (3) about the sequential
organization of actions. They considered that move-
ments are dependent on the interaction between the
conceptual knowledge of the tools, objects and actions
(semantic action), and the structural information con-
tained in the motor programs. In this context, apraxia
is the result of a failure in the production system, while
an alteration in the conceptual system implies difficul-
ties in the recognition of the specific utility of tools and
the mechanical requirements of an action that allows
us to achieve an objective10,11.
Similarly, a model of apraxia was proposed by
Geschwind12 in 1965, based on the disconnection of
 A. Castillo-Sánchez-Lara, C. Ruben-Castillo: Somatodyspraxia and the PAINT model
the left premotor cortex and Wernicke’s area13. Accord-
ing to this model, apraxia is the result of lesions in the
supramarginal gyrus or the arcuate fasciculus.
Ayres4 based on her studies in children, identified a
population with learning disabilities who showed diffi-
culties in interpreting the sensory information of their
bodies and their environment. Based on her research
and clinical experience, she described how the nervous
system translates somatosensory information into ac-
tion, and postulates that proper integration of proprio-
ception and the vestibular aspect are critical for adap-
tive behavior14. Ayres emphasized somatosensation
and its relationship with the body schema as the basis
for praxis in children; however, she proposes that praxis
is based of only three components: ideation (concep-
tualization of actions), motor planning, and motor exe-
cution. Furthermore, she describes somatodyspraxia
as a problem in the organization of the motor plan, such
as, ideational apraxia.
Although different models have been described to
explain apraxia, somatoapraxia has not been consid-
ered as a primary factor of the different apraxia. We
consider that when somatosensory and proprioceptive
processing is altered, after acquired brain injury, the
management of the body schema and the necessary
postural adjustments to carry out tasks or actions,
(praxis), becomes difficult. Based on this theory, we
present the term somatodyspraxia as a primary factor
in apraxia and its applicability in a Neuropsychological
Rehabilitation Model for apraxia.
Somatodyspraxia as a primary factor in
apraxia
In somatodyspraxia the ability to execute an action
is altered. This ability requires that the brain is capable
of knowing bodily functions and conceptualize the ob-
jective of a motor action. In somatodyspraxia, the man-
agement of the body schema and postural adjustment
is absent. In the execution of praxis, the processing of
information from the proprioceptive, somatosensory,
kinesthetic, and vestibular systems is required to deter-
mine how the body is designed and how it will function
for the performance of a task or action. This sensory
processing allows using exteroceptive and interocep-
tive information to regulate and adapt movement and
give appropriate motor and postural responses15 nec-
essary in performing praxis.
In Somatodyspraxia, the integration of propriocep-
tive, somatosensory signals, as well as body scheme
that allow estimating body movements is altered,
resulting in gait apraxia16. The proprioceptive system
allows us to perceive the movements of the joints, to
know the position of the body, the force generated by
the muscles, and the speed and direction of our move-
ments17. System alterations complicate the reception of
normal impulses from the muscles and joints18. Pro-
cessing alterations of proprioceptive sensations result
in disruption of postural stability and lack of knowledge
of the body’s position in space19,20. In addition, neuronal
principles show that for adequate postural control of the
head, the interaction of the vestibulospinal tracts, which
selectively activate the muscles of the neck and trunk,
are crucial21. Information that travels from the skin to
the central nervous system (CNS) is useful to generate
human balance. When the cutaneous afferent inputs
are not transmitted to the CNS, it can cause an imbal-
ance22, and subsequently gait apraxia.
In somatodyspraxia, there is alteration of tactile in-
formation, which contributes to the manipulation and
grasping of objects, plays a role in linking present and
past sensations necessary for the performance of prax-
is23. These difficulties can lead to apraxic agraphia, in
which the subject struggles in the simple task of prop-
erly grasping a pencil and guiding movements to trace
letters. The same can happen in adult patients with
acquired brain injury, who experience difficulties to ad-
equately perform activities of daily living24.
Somatodyspraxia can cause problems in the body
schema and in postural adjustments necessary for
dressing. The patient may have problems when trying
to put on a sweater, having difficulty in placing arms in
the corresponding sleeves, for example, because he
does not make the necessary postural adjustments. It
is also common for the patient to carry out the steps to
put on a garment incorrectly or in the wrong order, for
example, putting the pants on the arms, or putting on
a sweater first and then the shirt, or not knowing wheth-
er to tie their shoelaces or button a shirt. In addition,
they have difficulty in fastening and unbuttoning25,
causing dressing apraxia.
In somatodyspraxia, the internal and updated repre-
sentation of the position of the body and movement in
space are affected26. Clinical observations show that
patients with somatosensory and vestibular alterations
often make errors in movement trajectory and may
have trouble detecting and estimating body displace-
ment26. Signals from muscles, joints, skin, and eyes are
continuously integrated with vestibular input and evoke
postural and oculomotor responses. Alterations present
at this level, can lead to a constructional apraxia, a
concept that describes an alteration present when
139
 Rev Mex Neuroci. 2022;23(4)

carrying out activities such as assembling, building, or

drawing27.
Somatodyspraxia may be the primary factor in limb
apraxia, since a patient with acquired brain injury may
have problems in the body schema management and
postural adjustments to orient utensils and move it
properly, or he cannot use the appropriate cutlery for
the type of food or associate the object with the action
(e.g., using a knife instead of a spoon for soup or add-
ing salt instead of sugar to the coffee). Furthermore,
the subject may have difficulties in using objects, such
as the toothbrush and razor, trying to use the tooth-
brush to comb his hair. Furthermore, they may have
difficulties in properly orienting and positioning their
body, for example, to properly manipulate a hairband Figure 1. Somatoapraxia as a primary factor for apraxia.
to make a ponytail.
Orofacial apraxia, or buccofacial apraxia is charac-
terized by a loss of voluntary control of facial, lingual,
important role in the mechanisms responsible for the
and masticatory muscles in association to somatosen-
previously mentioned apraxias.
sory and proprioceptive disturbance. The typical patient
fails to produce the correct movement in response to
verbal command or to imitate correctly a movement Somatodyspraxia in acquired brain injury
performed by the examiner due to Somatodyspraxia.
In praxis, movements are complex and seem to
Sometimes, the person needs to use his hands to help
involve several brain regions, such as the premotor,
introduce food completely into the mouth and thus be
prefrontal, temporal, and parietal areas. The parietal
able to swallow. It may also happen that the patient
lobe has been shown to be involved in the acquisition
does not find the proper position of the phonation ap-
of movements for the use of tools13. In addition, the
paratus for the correct articulation of language, produc-
parietal cortex seems to be relevant in abnormalities of
ing an afferent motor aphasia27.
the somatosensory and proprioceptive systems, which
Similarly, patients with Somatodyspraxia may expe-
rience difficulties in the body schema and sense of the have been found altered in disturbances that affect the
body itself. Compound sensory, proprioceptive, extero- CNS, such as a cerebrovascular event (stroke)30,
ceptive, and interoceptive data, are required for sphinc- Traumatic brain injury (TBI)31, or neurocognitive impair-
ter control28. Like all body Functions, sphincter control ment32. Therefore, the somatosensory and propriocep-
is regulated by the Nervous System. At the level of the tive alterations in acquired brain injury lead to the pres-
entire lower urinary tract (bladder and urethra) there are ence of somatodyspraxia.
a series of sensory endings or exteroceptive (tactile, Because somatosensory and proprioceptive deficien-
painful, and thermal) and interoceptive (visceral or ab- cies are common in somatodyspraxia patients after
dominal distension) neuroreceptors located mainly in stroke, deterioration in postural function and level of
the trigone and urethral meatus29. Patients barely know independence may be present32. They often require
what position their body is in and, therefore, cannot assistance during bathing, shaving, and getting
receive afferent information from the sphincters. dressed33. Neuroimaging studies, which include posi-
In summary, the functional implications of somato- tron emission tomography and functional magnetic res-
dyspraxia are reflected in different activities such as onance imaging, have shown that lesions to the lower
walking, dressing, the construction of letters and draw- left and upper parietal lobe seem to be involved in the
ings, in the adequate movement of the organs of the alteration of movements for the use of tools13.
mouth for the articulation of language and swallowing, Alzheimer’s disease is associated with somatosenso-
and sphincter control, due to the lack of adequate in- ry processing and discrimination32 that can lead to so-
tegration of somatosensory and proprioceptive informa- matodyspraxia which impacts daily living activities,
tion, body schema and postural adjustments for the such as meals, housework, or driving. Commonly, in
execution of praxis (Fig.  1). The novel term plays an mild cognitive impairment, significant decline in the
140
 A. Castillo-Sánchez-Lara, C. Ruben-Castillo: Somatodyspraxia and the PAINT model
performance of these activities is observed, which may
progress rapidly into Alzheimer’s disease34. The prob-
lems in carrying out these activities, observed in this
population, may be related to the deterioration in praxis
due to a primary somatodyspraxia factor, which causes
struggles in action executing such as the use of cutlery
or judging how close the food is to the mouth35.
Similarly, patients with Parkinson’s disease experi-
ence somatosensory alterations and problems in pro-
prioceptive processing causing somatodyspraxia, due
to an affection of the basal nuclei and their connections
with postcentral and premotor areas13. These alterations
cause lack of precision in goal-directed movements and
altered postural reflexes that lead to problems in gait
and balance36. We observe temporal or spatial errors,
such as interrupted slow movements apraxic substitu-
tion errors, such as brushing teeth with a hairbrush, or
using a part of the body as an object37.
It is common that after a TBI, patients present disor-
ders of the somatosensory and proprioceptive sys-
tems31. Deficiencies in the ability to integrate informa-
tion from the sensory, motor and skeletal-muscular
sywstems can generate somatodyspraxia in patients
with TBI38. This causes difficulties in grasping or thumb
orientation for proper use of tools, due to alterations in
the postcentral and premotor areas of the contralateral
hemisphere to the injury39. Therefore, daily living activ-
ities become arduous.
Cerebellar ataxia arises due damage or dysfunction
affecting the cerebellum and/or its input/output path-
ways cerebellar dysfunction may result in significant
functional difficulties with upper and lower limb move-
ment, oculo-motor control, balance and walking. Con-
trary to somatodyspraxia, ataxia is associated with dys-
metria, cerebellar tremor, nystagmus, and dysarthria.
Its rehabilitation is centered in coordination and bal-
ance training, multifaceted inpatient rehabilitation, a
cycling regime, balance training, treadmill training, oc-
cupational therapy, and inspiratory muscle training35.
After brain injury, patients require neuropsychological
rehabilitation, which is a theoretical framework of inter-
ventions designed to improve cognitive, emotional, and
psychosocial functioning, due to changes in the brain.
The goal is to promote greater functional independence
in a wide variety of situations of daily life40. So far, few
studies have investigated the effectiveness of different
apraxia methods of intervention. This may be caused
by the erroneous belief that apraxia only occurs during
imitation, verbal command, and in the absence of the
object, without influencing daily life activities41. There
are some interventions proposed in the literature41,42,
which focus mainly on syndromic management strate-
gies such as ideomotor apraxia, orofacial apraxia, or
dressing apraxia. In addition, other rehabilitation tech-
niques have focused on the execution of gestures43.
However, improvement was observed only in the symp-
toms, without generalization. Conversely, Durand,
Gago Galvagno and Elgier44, treated neurocognitive
ability and not the symptom, they based the rehabilita-
tion on the body schema in patients with dressing
apraxia, during which they provide Kinesthetic-tactile,
propioceptive and spatial stimuli to guide the upper limb
during movement44.
Functional neuroanatomical bases for our
somatodyspraxia rehabilitation model
In praxis, movement depends on simple processes
integrated and organized in learned motor patterns1.
Therefore, execution of a praxis pattern requires a con-
stant flow of information between the cortical and sub-
cortical areas; thereby being a mechanism in which the
cortex serves as a station were information is classified
and integrated, while the subcortical structures provide
feedback to the entire system, rectifying input informa-
tion and the commands that will result in the execution
of specific responses.
The spinal cord acts as a communication bridge be-
tween the brain and the sensations received by the
body from the external world and the internal environ-
ment. Thus, the sensory information of different sub-
modalities is sent to the brain through the spinal tract.
Sensory nerve fibers of different sizes and functions
are arranged and distributed in nerve bundles or tracts.
Below, we show the most relevant afferent pathways
that reach the medulla and their function; this, to show
the relationships they maintain with the production of
action (praxis) and our proposal for neuropsychological
rehabilitation of praxis (Table 1). Somatodyspraxia pa-
tients show alterations in recognition and association
of multiple somatosensory and proprioceptive stimuli.
For rehabilitation, we suggest applying tactile stimuli to
the subject, such as pain, temperature, pressure, tex-
ture and vibration. We also seek to place him in un-
comfortable positions and carry out tasks such as pull-
ing, loading and pushing, in order to stimulate the
sensations of the muscles and joints leading to the goal
of movement and to promote knowledge of the parts of
the body to solve a task (praxia)48.
The brainstem has an important sensory and motor
function and acts as a primary distributor for somato-
sensory information from the spinal cord and the
141
 Rev Mex Neuroci. 2022;23(4)

Table 1. Functions and sensations of the Ascending pathways of the spinal cord and proposal for neuropsychological
rehabilitation in somatodyspraxia
Ascending Sensation Fiber connections Terminate in Proposal for neuropsychological
pathways rehabilitation of somatodyspraxia

Lateral Pain and temperature Reticular formation
spinothalamic Ventral posterolateral nucleus
tract of the thalamus
Somesthetic area (postcentral
gyrus of the cerebral cortex)
Postcentral Apply uncomfortable/painful stimuli
gyrus to feet and hands, due to their
cortical representation
Apply ice to the parts of the body
where you want to increase muscle
tone

Anterior Slight touch and Superior cerebellar peduncle Postcentral Apply large heavy cushions to the
spinothalamic pressure Cerebellum gyrus entire body
tract Use soft objects of different weights
as stimuli

Gracile and Discriminatory touch, Inferior cerebellar peduncle Postcentral Use objects with vibration
cuneate fasciculi vibratory sensitivity, Cerebellum gyrus Loading, Pulling, and Pushing Tasks
medial lemniscus conscious sensation
of muscles and joints

Anterior and Musculo‑articular Cerebral Working on unstable surfaces that

posterior unconscious cortex require postural adjustments against
spinocerebellar sensation gravitational force
tract

motor pathways of the cerebral cortex. The move-
ments produced by the brainstem involve the entire
body and are important for walking, eating, drinking,
swimming, grooming, and sexual behavior13. The cen-
tral part of the brainstem contains the nuclei of the
cranial nerves and bundles of sensory and motor fi-
bers. It is summarize the cranial nerves that related
to the brainstem and their function; this, to show the
relationship they have to produce action (praxis) and
our proposal for neuropsychological rehabilitation of
praxis (Table 2).
The cerebellum is involved in the synergy of move-
ment through the spinocerebellar, vestibulocerebellar,
and cerebrocerebellar bundles, by means of which
movements are grouped correctly for the execution of
acts that require special adjustments to establish and
maintain balance and to regulate muscle tone, neces-
sary for praxis. Our proposal for the rehabilitation of
somatodyspraxia recommends working on the control
of static and dynamic balance with the use of balance
boards, balls and unstable surfaces. In addition, we
suggest working on regulating motor rhythm, through
activities for motor coordination of hands, fingers and
feet. The most relevant pathways that reach the cere-
bellum and their function are shown, to specify the
relationship they maintain with the production of action
(praxis) and our proposal for neuropsychological reha-
bilitation of praxis (Table 3).
142
Sensory information from the brainstem (somatosen-
sory, auditory, vestibular, and taste) reaches the thala-
mus and information from visual and olfactory pathways
is added. The thalamus is associated with the integra-
tion of somatosensory information (touch, pressure,
pain, and temperature), which is processed in the ven-
tral posteromedial nuclei (head and neck) and ventral
posterolateral nuclei (body). Then, it is transmitted to
the somatosensory cortex of the parietal lobe. Auditory
information is processed in the medial geniculate nuclei
and sent to the auditory cortex in the temporal lobe.
Vestibular information reaches the posterior ventral nu-
clei and is directed to the somatosensory cortex of the
parietal lobe. The posteromedial ventral nuclei receive
information from the sense of taste, which is directed
to the gustatory area in the parietal lobe. Visual
information reaches the lateral geniculate nuclei and is
subsequently projected into the visual cortex in the
occipital lobe. The olfactory information is received in
the central part of the dorsal medial nuclei, and then it
is projected toward the orbitofrontal cortex. For the re-
habilitation of somatopraxis, according to our model,
we suggest that the subject performs an activity that
integrates proprioceptive stimuli of the head and body,
vestibular, visual, and auditory. For example, standing
on a balance board that forces him to make postural
adjustments against gravitational force; throwing bags
of different weights, textures, and shapes into a
 A. Castillo-Sánchez-Lara, C. Ruben-Castillo: Somatodyspraxia and the PAINT model

Table 2. Functions and quality of the cranial nerves and proposal for neuropsychological rehabilitation in
somatodyspraxia
Cranial nerves Function Quality Proposal for neuropsychological rehabilitation of
somatodyspraxia

Arousal/consciousness Reticular formation Activities to improve alertness

Oculomotor nerve (III) Motor function, involved in the Motor Visual tracking activities
Trochlear nerve (IV) muscular control of the eyes
Abducens nerve (VI)

Facial nerve (VII) Facial expression, gland Sensitive Facial muscle massage

discharge and taste sensation Somatosensory stimuli in the facial oral tract
Orofacial movements

Trigeminal nerve (V) Sensitivity of the face, nose, Mixed Tongue proprioceptive exercises, such as pushing
teeth, jaw movements to the front, to the sides, pulling the tongue, or
carrying an object, like a pencil

Vestibulocochlear Vestibular Information Sensitive Exercises, such as going up a ramp, going down,
nerve (VIII) head down to pick up balls

Glossopharyngeal Sensitivity and movement of the Mixed Stimulate the inside of the cheeks and gums with
nerve (IX) tongue and pharynx cotton swabs, tongue depressors, teethers, or
vibration brushes

Vagus nerve (X) Sensory and motor actions of Mixed Cardiovascular exercises that favor inhalation and
organs, such as the heart, blood expiration
vessels, and viscera

Accessory nerve (XI) Control of neck and tongue Motor Stimulate muscle tone of the neck with
Hypoglossal nerve (XII) muscles proprioceptive exercises
Swallowing exercises

container, to see where the stimulus is directed and to
listen when it falls, all integrated into a single action
(praxis)48. The most relevant nuclei of the thalamus and
their functions are shown, as well as their relation-
ship  with the production of action (praxis) and our
proposal for neuropsychological rehabilitation of praxis
(Table 4).
The basal nuclei are important in motor learning39.
They play an important role in inhibiting unwanted
movements and promoting the desired ones, initiating
the production of movements directed toward a goal,
and modulating the force of the movements13 neces-
sary for the execution of praxis. For neuropsychological
rehabilitation of somatopraxis, according to our model,
we suggest performing activities to inhibit movement,
processing speed, and modulation of movement.
Shown, are the basal nuclei, as well as their functions
and the relationship they maintain with the production
of action (praxis), as well as our proposal for neuropsy-
chological rehabilitation of praxis (Table 5).
Regarding the cortical areas involved, the parietal lobe
comprises a multiplicity of areas and can vary in differ-
ent parts of the parietal cortex. The most important are
involved with the trajectory of movement of various parts
of the body, orientation of the extremities, the control of
body parts, the identification, size, and shape of objects,
as well as the location and orientation of the object. For
the rehabilitation of somatopraxis, we propose using
objects of different textures and sizes to stimulate differ-
ent parts of the patient’s body. We also suggest using
objects with different temperatures, for example ice to
stimulate cold, and others that stimulate pain. In addition,
in our neuropsychological rehabilitation model, we pro-
pose carrying out activities that stimulate the internal
representation of the body or body schema, such as
jumping around, rolling your body on the floor or on a
large cushion. Activities that require pulling, loading, and
pushing, for proprioceptive stimulation, should also be
included, for example, moving therapy equipment, huge
cushions, and/or supporting your own weight from a
trapeze48.
As mentioned above, praxis is an integrative function,
in which the harmonious work of different neural sys-
tems promotes learning and maturation of each of the
aspects involved in the production of voluntary and
involuntary movement. The execution of praxis must be
143
 Rev Mex Neuroci. 2022;23(4)

Table 3. Functions and fiber connections of the thalamic nuclei and proposal for neuropsychological rehabilitation in
somatodyspraxia
Thalamic Nuclei Function Fiber connections Proposal for neuropsychological
rehabilitation of somatoapraxia

Anterior Emotional tone, recent memory Mamillothalamic tract, cingulate Use stimuli that have emotional
mechanisms gyrus, hypothalamus value

Dorsomedial Integration of somatic, visceral and Prefrontal cortex, Proprioceptive stimuli that stimulate
olfactory information, and hypothalamus, other thalamic interoception
relationship with emotional nuclei
sensations

Dorsolateral, Unknown Cerebral cortex, other thalamic

posterolateral, nuclei
pulvinar

Ventral anterior Influences the activity of the motor Reticular formation, substantia Motor activities that stimulate body
cortex nigra, striatum, premotor cortex, schema
other thalamic nuclei

Ventral lateral Influences the motor activity of the Reticular formation, substantia Apply motor activities that seek the
motor cortex nigra, striatum, premotor cortex, integration of vestibular, visual and
other nuclei of the thalamus, proprioceptive senses
cerebellum, and red nucleus

Ventral Relay for common sensations Trigeminal lemniscus, taste Promote the recognition and
posteromedial (VPM) toward consciousness fibers expression of the sensations
experienced with the material

Ventral Relay for common sensations Medial and spinal lemniscus Promote the recognition and
posterolateral (VPL) towards consciousness expression of the sensations
experienced with the material

Intralaminar Influences states of consciousness Reticular formation, Vertical vestibular, like jumping and
and alertness spinothalamic and hopping
trigeminothalamic tracts

Midline Unknown Reticular formation

Reticular The cortex regulates the thalamus Cerebral cortex, reticular Stimulate the state of attention
formation

Medial geniculate Hearing Inferior colliculus Apply auditory stimuli during the
body integrated activity

Lateral geniculate Optic tract

body

analyzed as a functional system, which requires the
communication of the cortex, subcortex, and spinal
cord. The integrated system forms a neural network
involved in different actions, which when suffering se-
lective damage through a pathological process can
produce Somatopraxis.
Proposal of a neuropsychological
rehabilitation model for apraxia
Based on the definition of somatodyspraxia, alter-
ations in the processing of somatosensory and proprio-
ceptive information lead to difficulties in understanding
144
the body schema and the relationship of the body itself
with respect to objects, making postural adjustments
for the correct execution of movements, and therefore
carrying out many of the activities of daily living, such
as dressing, eating, or combing hair.
In this article, we propose that somatodyspraxia is
the primary factor of apraxia and we present a neuro-
psychological intervention model for Apraxia and Som-
atodyspraxia that focuses on the stimulation of the
somatosensory and proprioceptive systems, body
schema, and postural adjustments.
The intervention program in this approach is based
on a neuroanatomical and neurophysiological theory.
 A. Castillo-Sánchez-Lara, C. Ruben-Castillo: Somatodyspraxia and the PAINT model

Table 4. Areas and functions of the cerebellum and proposal for neuropsychological rehabilitation in
somatodyspraxia
Area Function Fiber connections Terminate in Proposal for
neuropsychological
rehabilitation of
somatodyspraxia

Spinocerebellum Regulation of face and hand Medial (vermis) Dorsal nucleus Motor activities using
movements balance boards, balls and
Coordination of swings
extremities (hands, fingers,
and feet).

Vestibulocerebellum Control of static and Vermian regions, Spinal cord and Visual tracking activities
dynamic balance flocculonodular lobe, fastigial motor nuclei favoring the vestibular
Eye movement nucleus system
Anterior spinothalamic tract

Cerebrocerebellum Learning and maintenance Cerebral cortex Lateral areas of Encourage adaptive
of motor skills Ventral lateral nucleus of the the responses
Error correction thalamus contralateral
Rhythm regulation hemisphere

Table 5. Functions and pathways of the Basal nuclei and proposal for neuropsychological rehabilitation in
somatodyspraxia
Area Function Pathways Fiber connections Terminate in Proposal for
neuropsychological
rehabilitation of
somatodyspraxia

Caudate Static and dynamic Medial (vermis) Ipsilateral spinal Visual tracking activities
nucleus balance control cord favoring the vestibular
Eye movement system

Putamen Generation of speed and Vermian regions, Vestibular nucleus Spinal cord and Throw balls and sacks,
range of motion flocculonodular lobe, motor nuclei following a trajectory
Action control, fastigial nucleus
motivation and cognition Anterior
spinothalamic tract

Globus Motor control and Excitatory‑inhibitory Caudate nucleus Motor and Promote the inhibition of
pallidus coordination and putamen prefrontal motor stimuli upon verbal
cortex command

We recommend focusing on the stimulation the
proprioceptive and somatosensory systems, because
this specific information, after traveling through the so-
matosensory pathway and the thalamus, reaches pari-
etal areas which communicate with primary motor ar-
eas. The integration of this information in the CNS helps
regulate the production of adequate motor responses
for performing praxis. In addition to stimulating the so-
matosensory and proprioceptive systems, the patient’s
movement is guided and regulated through language.
By stimulating the somatosensory system with touch,
pain, pressure, vibration, and temperature stimuli, one
favors the understanding of the body schema, which is
necessary for the execution of movements such as
writing, dressing, eating and swallowing, the articula-
tion of words or sphincter control. Muscle and joint
activation by stimulating mouth and phonation appara-
tus movements favor for proprioception. Intervention
through the vestibular system and management of pos-
tural adjustments is necessary for the adequate head
and eyes movements for drawing, the integration of
two-dimensional and three-dimensional visual stimuli,
walking, handling objects, and even getting dressed.
In this section, we propose a neuropsychological re-
habilitation model for apraxia, based on the PAINT Mod-
el. Our model proposes conducting a comprehensive
145
 Rev Mex Neuroci. 2022;23(4)
Figure 2. Proposal of a Neuropsychological Rehabilitation
Model for apraxia.
rehabilitation program based on the stimulation of the
somatosensory and proprioceptive systems, body
schema and postural adjustments involved for the exe-
cution of praxis, as part of a complex functional system45
(Fig. 2).
One of the main objectives of our PAINT Neuropsy-
chological Rehabilitation Model is to stimulate the so-
matosensory system through all its functions: pain,
touch, temperature, pressure, texture, and propriocep-
tion, since the nervous system requires somatosensory
feedback to control voluntary movement. We base this
on the fact that, during voluntary movement, the CNS
is continuously receiving information from both, so-
matosensory signals derived from changes in the ex-
ternal environment and from the person’s postural
changes46. The integration of somatosensory informa-
tion is critical for motor control and movement recogni-
tion, and the correct performance of movements that
involve manipulating objects and purposive actions.
Another of the main objectives of our PAINT Neuro-
psychological Rehabilitation Model is to stimulate the
proprioceptive system, and perception or awareness of
the position and movement of body. Proprioception is
the body´s self-awareness that tells the body where it
is in space. We receive proprioceptive input from our
sensory receptors located in muscles, tendons, joints
and internal organs47, and it is crucil to the brain, as it
plays a large role in posture, body awareness, use of
tools and purposive actions. This information is pro-
cessed in the somatosensory areas of the posterior
parietal cortex. We propose activities that stimulate
proprioceptive senses, such as pushing and pulling
with the patient´s own weight, pulling a rope or heavy
146
mat; or resistance exercises that involve different body
segments, including the tongue48.
The PAINT Neuropsychological Rehabilitation Model
for apraxia also pursues the stimulation of the body
schema and postural adjustments of the subject. The
goal is to promote mobility of the upper and lower limbs,
as well as the use of both hands and feet in praxis.
This model for apraxia proposes stimulation of the body
schema by providing tactile-kinesthetic stimuli to the
upper and lower limbs. The therapist guides the move-
ments by placing him or herself behind the patient, so
that the actions are natural, while simultaneously giving
a verbal description of the movements, thus favoring
the correct connection between the movement and its
execution with the use of objects. Regarding the prob-
lems of managing the body in space, we seek to work
on understanding the place the body occupies in space
in relation to an object.
Our PAINT Neuropsychological Rehabilitation model
aims to stimulate postural adjustments by making dif-
ferent movements with the body or putting it in awkward
positions from which patients must move several body
segments such as the arm, leg or, even the head. This
allows the stimulation of postural adjustments against
gravitational force, through movements of the head and
body on surfaces such as balls, seesaws or suspended
equipment, with the goal of causing linear accelerations
and angular accelerations. Our Rehabilitation Model
seeks to integrate proprioceptive and visual informa-
tion, to establish diagrams of the position and dynamics
of body movements, the verticality within the three-di-
mensional gravitational field49, the position of the head
with respect to gravity and the detection of changes in
its movement45, as well as determining speed and di-
rection of the movements.
By understanding the concept of somatodyspraxia,
one can exploit it during patient rehabilitation after ac-
quired brain injury. The rehabilitation of the different
propioceptive and somatosensory components allows
the patient to recover vital neurological pathways for the
re-establishment of daily life activities. Our proposed
term of somatodyspraxia and its importance in the PAINT
Neuropsychological Rehabilitation model will allow med-
ical and rehabilitation personnel to have a better under-
standing of the neurological and neuropsychological con-
cepts that ultimately affect a patients quality of life.
Conclusion
Acquired brain injury commonly causes alterations in
different cognitive functions. Adults with brain injury
 A. Castillo-Sánchez-Lara, C. Ruben-Castillo: Somatodyspraxia and the PAINT model
can present a form of apraxia, which we have called
somatodyspraxia; an alteration in somatosensory and
proprioceptive processing, after acquired brain injury,
which makes it difficult to manage the body schema
and the postural adjustments necessary for the execu-
tion of tasks or actions. Patients with these types of
alterations have difficulty in carrying out activities of
daily life, which impacts their quality of life. The precise
recognition of somatodyspraxia in adults is relevant
because it can guide the establishment of a rehabilita-
tion program focused on the stimulation of the somato-
sensory system, proprioceptive system, body schema,
and postural adjustments.
Funding
None.
Conflicts of interest
None.
Ethical disclosures
Protection of human and animal subjects. The
authors declare that no experiments were performed
on humans or animals for this study.
Confidentiality of data. The authors declare that
they have followed the ´protocols of their work center
on the publication of patient data.
Right of privacy and informed consent. The au-
thors declare tjat no patient data appear in this
article.
References
1. Cubelli R. Definition: apraxia. Cortex. 2017;93:227-34.
2. Rubinstein W, Politis D. Revisión de los patrones de alteración práxicos
encontrados en diferentes tipos de demencia, sobre la base de un mo-
delo cognitivo. Rev Esp Neuropsicol 2005;7:167-85.
3. Rothi LJ, Heilman KM. Apraxia: the Neuropsychology of Action. Hove,
UK: Psychology Press; 2014.
4. Ayres AJ. Sensory Integration and Learning Disorders. Los Angeles:
Western Psychological Services; 1972.
5. Bellefeuille IB. Un trastorno en el procesamiento sensorial es frecuente-
mente la causa de problemas de aprendizaje, conducta y coordinación
motriz en niños. Bol Pediatr. 2006;46:197.
6. Steinthal H, Misteli F. Abriss der Sprachwissenschaft. Berlin: Nabu Press;
1871.
7. Pearce JM. Hugo Karl Liepmann and apraxia. Clin Med. 2009;9:466-70.
8. Leiguarda RC, Marsden CD. Limb apraxias. Higher-order disorders of
sensorimotor integration. Brain. 2000;123:860-79.
9. Roy EA, Square PA. Common considerations in the study of limb, verbal
and oral apraxia. In: Roy EA. Neuropsychological Studies of Apraxia and
Related Disorders. Holanda Septentrional. Holanda: Elsevier; 1985.
p. 111-61.
10. Heilman KM, Rothi LJ, Valenstein E. Two forms of ideomotor apraxia.
Neurology. 1982;32:342-6.
11. Rothi LJ, Heilman KM, Watson RT. Pantomime comprehension and
ideomotor apraxia. J Neurol Neurosurg Psychiatry. 1985;48:207-10.
12. Geschwind N. Disconnexion syndromes in animals and man. Part  II.
Brain. 1965;88:585-644.
13. Park JE. Apraxia: review and update. J Clin Neurol. 2017;13:317-24.
14. Lane SJ, Mailloux Z, Schoen S, Bundy A, May-Benson TA, Parham LD,
et al. Neural foundations of ayres sensory integration®. Brain Sci. 2019;
9:153.
15. Fagoaga J, Macías L. Fisioterapia en Pediatría. Madrid: Editorial Mc
Graw-Hill Interamericana; 2002.
16. Péruch P, Lopez C, Redon-Zouiteni C, Escoffier G, Zeitoun A, Sanjuan M,
et al. Vestibular information is necessary for maintaining metric properties
of representational space: evidence from mental imagery. Neuropsycho-
logia. 2011;49:3136-44.
17. Roley SS, Blanche EI, Schaaf RC. Understanding the Nature of Sensory
Integration with Diverse Populations. 1st. ed. Austin, Texas: Pro-Ed; 2001.
18. Proske U, Gandevia SC. The proprioceptive senses: their roles in signa-
ling body shape, body position and movement, and muscle force. Physiol
Rev. 2012;92:1651-97.
19. Otero BÁ, Angarita MM, Arias PZ. Percepciones de terapeutas ocupa-
cionales sobre el lenguaje y la comunicación de los niños con déficit de
integración sensorial. Rev Fac Med. 2010;58:263-71.
20. Sainburg RL, Ghilardi MF, Poizner H, Ghez C. Control of limb dynamics
in normal subjects and patients without proprioception. J  Neurophysiol
1995;73:820-35.
21. Nogueras AM. Bases Neurofisiológicas del Equilibrio Postural. [Tesis de
Doctorado]: Universidad de Salamanca; 2004. p. 78.
22. Kars HJ, Hijmans JM, Geertzen JH, Zijlstra W. The effect of reduced
somatosensation on standing balance: a systematic review. J  Diabetes
Sci Technol. 2009;3:931-43.
23. Ackerley R, Kavounoudias A. The role of tactile afference in shaping
motor behaviour and implications for prosthetic innovation. Neuropsycho-
logia. 2015;79:192-205.
24. Tejeda SS. Análisis de la Fiabilidad Interevaluador de Los Subtest de
Praxis Del Evaluation in Ayres Sensory Integration. [Tesis de Maestría]:
Universidad de Coruña; 2017. p. 46.
25. García-Peña M, Sánchez-Cabeza A. Alteraciones perceptivas y práxicas
en pacientes con traumatismo craneoencefálico: relevancia en las acti-
vidades de la vida diaria. Rev Neurol. 2004;38:775-84.
26. Jiménez SB. El Esquema Corporal. Función Básica del Cuerpo en el
Desarrollo Psicomotor y Educativo. Madrid: Tea Ediciones; 1982.
27. Luria AR. El Cerebro en Acción. Barcelona: Editorial Planeta; 1978.
28. Bumin G, Kavak ST. An investigation of the factors affecting handwriting
skill in children with hemiplegic cerebral palsy. Disabil Rehabil. 2010;
32:692-703.
29. Roncero CT, Agulló EM. Bases neurológicas de la continencia urinaria.
Clín Urol Comp. 2000;8:257-82.
30. Tyson SF, Hanley M, Chillala J, Selley AB, Tallis RC. Sensory loss in
hospital-admitted people with stroke: characteristics, associated factors,
and relationship with function. Neurorehabil Neural Repair. 2008;
22:166-72.
31. Lin LF, Liou TH, Hu CJ, Ma HP, Ou JC, Chiang YH, et al. Balance
function and sensory integration after mild traumatic brain injury. Brain
Inj. 2015;29:41-6.
32. Smith BC, D’Amico M. Sensory-based interventions for adults with de-
mentia and Alzheimer’s disease: a scoping review. Occup Ther Health
Care. 2020;34:171-201.
33. Franssen E, Arr-Jansman ET, Rowberry DJ. Activities in daily life (ADL).
In: Buijck B, Ribbers G, editor. The Challenges of Nursing Stroke
Management in Rehabilitation Centres. Cham: Springer; 2018.
p. 85-95.
34. Marshall GA, Amariglio RE, Sperling RA, Rentz DM. Activities of daily
living: where do they fit in the diagnosis of Alzheimer’s disease? Neuro-
degener Dis Manag. 2012;2:483-91.
35. Marsden J, Harris C. Cerebellar ataxia: pathophysiology and rehabilita-
tion. Clin Rehabil. 2011;25:195.
36. Papachristou I, Giatras N, Ussher M. Impact of dementia progression on
food-related processes: a qualitative study of caregivers’ perspectives.
Am J Alzheimers Dis Other Demen 2013;28:568-74.
37. Konczak J, Corcos DM, Horak F, Poizner H, Shapiro M, Tuite P, et al.
Proprioception and motor control in Parkinson’s disease. J  Mot Behav.
2009;41:543-52.
38. Vanbellingen T, Lungu C, Lopez G, Baronti F, Müri R, Hallett M, et al.
Short and valid assessment of apraxia in Parkinson’s disease. Parkinso-
nism Relat Disord. 2012;18:348-50.
39. Schultheis MT, Whipple EK. Driving after traumatic brain injury: evalua-
tion and rehabilitation interventions. Curr Phys Med Rehabil Rep.
2014;2:176-83.
40. McKenna C, Thakur U, Marcus B, Barrett AM. Assessing limb apraxia
in traumatic brain injury and spinal cord injury. Front Biosci 2013;5:
732-42.
41. Torres M, Rodríguez O, Nodarse J, Crespo M, González F, Quesada E,
et al. Actividades para la corrección de la apraxia constructiva en pa-
cientes con secuelas de enfermedad cerebro vascular. TOG. 2008;
5:1-13.
147
 Rev Mex Neuroci. 2022;23(4)
42. Dovern A, Fink G, Weiss P. Diagnosis and treatment of upper limb
apraxia. J Neurol. 2012;259:1269-83.
43. Buxbaum L, Harland K, Hallett M, Wheaton H, Heilman K, Rodríguez A,
et al. Treatment of limb apraxia: moving forward to improved action. Am
J Phys Med Rehabil. 2008;87:149-61.
44. Code C, Gaunt C. Treating severe speech and limb apraxia in a case of
aphasia. Br J Disord Commun. 1986;21:11-20.
45. Durand MF, Galvagno LG, Elgier AM. Rehabilitación de las actividades de la
vida diaria en pacientes con apraxia del vestir. Cuad Neuropsicol. 2017;3:42-53.
46. Castillo A. Modelo PAINT para la Rehabilitación Neuropsicológica. Mé-
xico: ALAREN; 2007. p. 145.
148
47. Umeda T, Isa T, Nishimura Y. The somatosensory cortex receives infor-
mation about motor output. Sci Adv. 2019;5:53-88.
48. Jacobs KM. Somatosensory system. In: Kreutzer JS, DeLuca J, Caplan B,
editors. Encyclopedia of Clinical Neuropsychology. New York: Springer;
2011.
49. Castillo A. Servir una Taza de Café es una Tarea Compleja: rehabilitación
Neuropsicológica de las Praxias. 1st ed. Ciudad de México, México: Fac
Psic Centro de Estudios Veracruz; 2021.
50. Dieterich M, Brandt T. The parietal lobe and the vestibular system. Han-
db Clin Neurol. 2018;151:119-40.
Revista Mexicana de Neurociencia

REVIEW ARTICLE

Stroke and atrial fibrillation: An update

Nicole Beaton Sur* and Jose G. Romano
School of Medicine, University of Miami Miller, Miami, Florida

Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice. AF is associated
with an increased risk of cardiovascular disease, heart failure, stroke, cognitive impairment and dementia, and mortality. Indi-
viduals with AF have a 5-fold risk of ischemic stroke, and AF-related strokes are associated with greater disability and
mortality compared with strokes from other causes. Moreover, the burden of AF and AF-related stroke on patients, their
caregivers, health-care systems, and society is significant and projected to increase in the coming decades due to the rap-
id growth of the ageing population. The care and management of patients with AF and AF-related stroke are challenging,
often involving complex decision-making to weigh the risks and benefits of various treatment and prevention strategies. This
topical review focuses on the latest science and advances in AF and AF-related stroke and identifies knowledge gaps and
future directions of continued research.

Keywords: Ischemic stroke. Hemorrhagic stroke. Atrial fibrillation. Prevention. Cerebrovascular disease. Anticoagulation.

Actualización en ictus y fibrilación auricular

Resumen
La Fibrilación Auricular (FA) es la arritmia sostenida mas común en la practica clínica. La FA se asocia a un riego
incrementado de enfermedad cardiovascular, falla cardiaca, enfermedad cerebrovascular, deterioro cognitivo y demencia. Los
individuos con FA tienen un riesgo cinco veces mayor de ictus, y los infartos isquémicos asociados a la FA causan mayor
discapacidad y mortalidad comparado con otras causas de ictus isquémico. Se estima que las consecuencias y la carga
de la FA y el ictus ocasionado por la FA en pacientes, sus familias, la sociedad y el sistema de salud, se incrementara de
manera importante en las próximas décadas dado el incremento de la población añosa, la cual tiene un riesgo aumentado
de FA. El manejo de los pacientes con ictus y FA es complejo dado el riesgo de hemorragia en pacientes con enfermedad
cerebrovascular, particularmente en las etapas tempranas después del ictus. Esta revisión temática se enfoca en avances
recientes en la terapéutica del ictus asociado a FA e identifica direcciones futuras de investigación.

Palabras clave: Ictus cerebral. Derrame cerebral. Fibrilación auricular. Prevención. Anticoagulación.

*Correspondence: Date of reception: 31-03-2022 Available online: 08-07-2022

Nicole Beaton Sur, Date of acceptance: 19-05-2022 Rev Mex Neuroci. 2022;23(4):149-156
E-mail: nbsur@med.miami.edu DOI: 10.24875/RMN.22000016 www.revmexneurociencia.com
2604-6180 / © 2022 Academia Mexicana de Neurología A.C. Published by Permanyer. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

149
 Rev Mex Neuroci. 2022;23(4)
Introduction
Atrial fibrillation (AF) is common, affecting an
estimated 37.6 million individuals globally in 20171, an
increase from 33.5 million individuals in 20102. The
prevalence of AF increases with age, nearly doubling
every decade after age 60 years3. As people are living
longer and the ageing population continues to grow
rapidly, the prevalence of AF is projected to nearly triple
by the year 20504. Similarly, the burden of AF posed
by the increased risk of cardiovascular disease, heart
failure, stroke, cognitive impairment and dementia, and
mortality is also expected to increase in parallel over
the ensuing decades4.
The treatment of patients with AF and AF-related
stroke is complex, and the burden on patients, caregiv-
ers, health-care systems, and society is high. Although
there have been significant scientific advances in the
area of AF and cardioembolic stroke recently, many key
knowledge gaps remain. In this topical review, an over-
view of AF and AF-related stroke will be discussed, with
an emphasis on treatment, prevention, screening, spe-
cial considerations, and future research directions.
Risk factors for AF and stroke
Increased age and male sex are the strongest
non-modifiable risk factors for AF. Male sex is associat-
ed with a 1.5-fold risk of developing AF and 2-fold higher
incidence compared with female sex5,6. Although the
overall incidence, prevalence, and age-adjusted lifetime
risk of AF is higher in men, there are more women than
men with AF due to differences in Regarding other
non-modifiable risk factors, the literature suggests that
white men have a higher incidence of AF; however, black
patients have a higher risk of death related to AF and a
higher risk of AF-related stroke7.
Common modifiable risk factors for AF include hyper-
tension, diabetes, obesity, cardiovascular disease, smok-
ing, and alcohol use. Similarly, these same risk factors
increase the risk of stroke in patients with AF. Women
with AF tend to be older and have more hypertension,
hyperlipidemia, and obesity, while men with AF tend to
have more coronary artery disease, left ventricular dys-
function, and chronic obstructive pulmonary disease5.
AF is associated with a 5-fold risk of ischemic stroke8,
one of the most feared and debilitating sequelae of the
arrhythmia. AF accounts for approximately 20-25% of
all ischemic strokes, though the frequency of AF in-
creases to approximately 40% in ischemic stroke pa-
tients ≥ 80  years old9. Risk factors for stroke in the
150
setting of AF include increased age, female sex, hyper-
tension, heart failure, diabetes, and history of cardio-
vascular or cerebrovascular ischemic events. Women
with AF have a higher risk of stroke compared with
men, which is thought to be mediated by increased age
and vascular risk factors10-14. Moreover, AF-related
stroke tends to be more severe in women, and more
women than men die or are disabled from AF-related
stroke every year15.
Risk stratification schemes, such as the CHA2DS2-VASc
score, assist in assessing the risk of stroke and systemic
embolism in AF patients, giving weight to common risk
factors (Table 1). The American Heart Association and
American Stroke Association guidelines recommend
using the CHA2DS2-VASc score for risk stratification to
guide the use of anticoagulants for the prevention of
stroke and systemic embolism16.
Mechanisms and clinical presentation of
stroke in AF
AF is characterized by irregular atrial activity, result-
ing in abnormal and irregular atrial contractions. Sev-
eral factors, such as enlarged atrial size, atrial fibrosis,
chronic inflammation, and upregulation of ion channel
subunits, contribute to the development and mainte-
nance of AF. Irregularities in atrial contraction associ-
ated with AF increase the risk of stasis of blood flow
and thrombus formation, thereby predisposing to stroke
and systemic embolism. Over 90% of thrombi second-
ary to AF arise from the left atrial appendage17. There
is emerging evidence suggesting that atrial cardiopa-
thy, characterized by structural, contractile, architectur-
al, or electrophysiological changes within the atria, may
contribute to stroke through thrombus formation even
in the absence of AF18,19. The lack of temporal associ-
ation between implantable device-detected AF and
stroke events supports the notion that the thrombi may
arise from the dysfunctional atria and atrial appendage
rather than from the AF itself20,21. In some cases, the
stroke itself may contribute to the development of AF,
and AF detected after stroke may have a different risk
profile for recurrent thromboembolic events19,22.
AF can be paroxysmal or sustained; however, the risk
of stroke is similar regardless of AF type. Although gen-
erally considered a “silent” condition, up to 60% of in-
dividuals report symptoms such as fatigue, dizziness,
palpitations, dyspnea, chest pain, generalized weak-
ness, and other less common symptoms23. Women tend
to be more symptomatic compared with men and they
report higher burden of symptoms and lower quality of
 N.B. Sur, J.G. Romano: Stroke and AF

Table 1. The CHA2DS2‑VASc score components and estimated yearly risk of stroke and systemic embolism
CHA2DS2‑VASc Points CHA2DS2‑VASc score Yearly risk of ischemic Yearly risk of stroke/TIA and
Risk Factor stroke (%) systemic embolism (%)

Congestive heart failure +1 0 0.2 0.3

Hypertension +1 1 0.6 0.9

Age < 65 years 0 2 2.2 2.9

Age 65‑74 years +1 3 3.2 4.6

Age ≥ 75 years +2 4 4.8 6.7

Diabetes +1 5 7.2 10.0

Vascular disease +1 6 9.7 13.6

Male sex 0 7 11.2 15.7

Female sex +1 8 10.8 15.2

Stroke/TIA/thromboembolism +2 9 12.2 17.4

Adapted from Friberg et al. 201211. TIA signifies transient ischemic attack.

life compared with men. Accordingly, women are more
likely than men to seek care for AF5. Given the relatively
silent and potentially paroxysmal nature of AF, it can be
challenging to detect. It is estimated that approximately
13% of individuals with AF have undetected AF24.
In up to 37% of cases, stroke is the first sign of AF25.
The symptoms of stroke secondary to AF are character-
ized by the sudden onset of neurological deficits that are
typically maximal at onset. The course of symptoms is
less likely to be progressive or stuttering as is sometimes
the case in strokes due to small or large vessel disease.
Patients with AF-related stroke present with greater se-
verity and higher frequency of large vessel occlusion
strokes compared to strokes from other causes.
Infarct patterns in AF-related stroke include large ter-
ritory wedge-shaped infarcts and/or smaller multifocal
infarcts in multiple arterial territories (Fig. 1). In addition,
patients with AF tend to have a higher burden of white
matter hyperintensities and evidence of cerebral small
vessel disease, including microhemorrhages26. Vessel
imaging in the acute stroke setting may show large ves-
sel occlusion. Hemorrhagic transformation of the infarct-
ed tissue is more common in cardioembolic strokes,
likely due to larger infarct size and increased patient age.
Treatment and outcomes of AF-related
stroke
Population-based studies in the US and Canada sug-
gest that ischemic stroke admissions with comorbid AF
have been steadily increasing over the past decade9,27.
Thrombolytic therapy and endovascular therapy remain
the hallmark of acute ischemic stroke treatment for el-
igible patients, regardless of the presence of AF. One
caveat is that patients with known AF who are on anti-
coagulation for stroke prevention may not be eligible for
intravenous thrombolysis, thus endovascular therapy
may be the only acute treatment option. In addition,
blood pressure management, heart rate and rhythm
control, and management of post-stroke complications
are crucial to in-hospital treatment of AF-related stroke.
Several studies have shown that rate control is not in-
ferior to rhythm control regarding cardiovascular out-
comes and mortality for the treatment of AF28,29, and
the focus of this section will be the use of anticoagu-
lants for stroke prevention.
Oral anticoagulants (OACs) for secondary
stroke prevention
Initiation of anticoagulation therapy in patients with
AF-related stroke is paramount for secondary stroke
prevention. Decision-making in this setting is challeng-
ing, given the risk of hemorrhage in the immediate
post-stroke period, weighed against the risk of recur-
rent ischemic stroke, or other ischemic events. The
estimated risk of a recurrent ischemic stroke is 1.5%
per day in the first 2  weeks after an acute stroke30,
while the risk of any radiographic hemorrhagic

151
 Rev Mex Neuroci. 2022;23(4)
a b
c
Figure 1. Imaging patterns in AF-related stroke. A: A non-
contrast head CT in a 85-year-old woman presenting with
aphasia and right-sided weakness, demonstrating a
wedge-shaped infarct in the left middle cerebral artery
distribution. B: The digital subtraction angiogram for the
same patient demonstrating an acute left middle cerebral
artery occlusion. C: A T2 FLAIR MRI in a 58-year-old man
with new onset AF and a large left hemispheric acute
infarct, as well as evidence of hyperintensities in bilateral
hemispheres suggestive of small vessel disease.
transformation ranges from 3.2% to 44% in the first
5  days depending on the use of thrombolytic
therapy31.
Vitamin K antagonists (VKAs) and direct OACs
(DOACs) are the mainstay of stroke prevention in pa-
tients with AF, each with their unique set of advantages
and risks (Table 2)32-36. Although VKAs, such as warfarin,
have been used for decades and are associated with a
two-thirds relative risk reduction of stroke and systemic
embolism compared with aspirin, the need for constant
serum level monitoring and multiple food and drug in-
teractions makes warfarin difficult to use. Patients with
AF on warfarin tend to have suboptimal time in the
therapeutic range37, and women tend to be more at risk
of stroke than men while on warfarin due to differences
in metabolism5.
DOACs, such as dabigatran, rivaroxaban, apixaban,
and edoxaban, have emerged into clinical practice in
the past decade. DOACs are as effective, if not more
effective, than warfarin for stroke and systemic embo-
lism prevention33-36. In addition, DOACs have a more
152
favorable safety profile and do not require constant
blood level monitoring, making them easier to use. In
2019, the American College of Cardiology and Ameri-
can Heart Association published updated guidelines
recommending DOACs as first line for eligible patients
with AF23. The main contraindication to DOACs in-
cludes patients with mechanical heart valves and mod-
erate-to-severe mitral valve stenosis23.
Timing of initiation of OACs
The timing of initiation of OACs for secondary stroke
prevention after acute stroke depends on many factors,
mainly the size of the infarct and the presence of hem-
orrhage on brain imaging. One decision-making algo-
rithm is illustrated in figure  2. As patients with recent
ischemic stroke were excluded from the clinical trials
on anticoagulation, much of the evidence is based on
observational studies and robust evidence is lacking in
this patient population. The AHA/ASA guidelines sug-
gest initiation of OACs immediately after TIA and
14 days after acute ischemic stroke event in most cas-
es, apart from very large infarcts (defined as either
NIHSS > 15 or an infarct involving the complete territory
of a vessel) with severe hemorrhagic transformation in
which delaying OAC initiation beyond 2  weeks is rea-
sonable. European guidelines from the pre-DOAC era
suggest a more granular approach to initiating OACs
depending on stroke severity, recommending initiation
of OACs 1 day after a transient ischemic attack, 3 days
after minor stroke (NIHSS < 8), 6  days in mild stroke
(NIHSS 8-15), and 12 days after severe stroke (NIHSS
> 15)38.
Data from observational studies suggest that in clin-
ical practice, DOACs are started on average 4-11 days
after ischemic stroke. Early start of DOACs in these
studies was associated with an average risk of intrace-
rebral hemorrhage (ICH) of 2.2% per year, which was
3-fold lower than the risk of ischemic stroke events over
the same time39.
Despite current guidelines, an estimated 50% of pa-
tients with acute stroke and AF are discharged from the
hospital without OAC, with evidence of sex and
race/ethnic differences in OAC utilization40. Risk of
bleeding, risk for falls, and goals of care (comfort mea-
sures/hospice care) are commonly cited reasons for not
starting OACs at stroke hospital discharge, and the rate
of OAC use may increase over time after hospital
discharge.
At present, there are several randomized controlled
trials underway evaluating various OAC initiation
 N.B. Sur, J.G. Romano: Stroke and AF

Table 2. Oral anticoagulants recommended for stroke prevention in AF

Anticoagulant Benefits Disadvantages

Vitamin K antagonists 67% relative risk reduction versus aspirin
– Warfarin 26% reduction in mortality versus aspirin
Can be used in patients with mechanical
valves and mod‑severe mitral stenosis
Point of care confirmation of anticoagulation
Reversible
Significant food and drug interactions
Need for blood level monitoring
Suboptimal time in therapeutic range
Low patient adherence

Direct oral anticoagulants (DOACs) About 19% relative risk reduction compared Contraindicated in mechanical valves and
Direct thrombin inhibitors with warfarin moderate‑to‑severe mitral stenosis
– Dabigatran 10% reduction in mortality compared with Reversal agents less readily available, costly
Factor Xa inhibitors warfarin Caution in renal and hepatic impairment
– Apixaban Easy to use, less food/drug interactions
– Rivaroxaban Lower rates of hemorrhage
– Edoxaban Reversible

Figure 2. One evaluation and management algorithm for decision-making in patients with acute stroke with indications
for anticoagulation. AC: anticoagulation; OAC: oral anticoagulation; CAA: cerebral amyloid angiopathy; CMB: cerebral
microbleed; HAS-BLED: Hypertension, abnormal liver/renal function, stroke history, bleeding history or predisposition,
labile INR, elderly, and drug/alcohol usage; ICH: intracerebral hemorrhage; IVC: inferior vena cava; DVT: deep venous
thrombosis; PE: pulmonary embolism; NIHSS: National Institutes of Health Stroke Scale.

protocols after acute ischemic stroke for patients with [United  Kingdom, EduraCT 2018-003859-38]; START
AF (ELAN, [Switzerland/International NCT03148457]; [United States, NCT03021928]; and AREST [United
TIMING [Sweden, NCT02961348]; OPTIMAS States, NCT02283294]).
153
 Rev Mex Neuroci. 2022;23(4)
Left atrial appendage occlusion (LAAO)
Since approximately 90% of thrombi in AF arise from
the left atrial appendage, LAAO is an attractive ap-
proach to secondary prevention in patients with AF in
which long-term anticoagulation is contraindicated. The
PROTECT AF trial showed non-inferiority of LAAO with
the WATCHMAN device compared with warfarin for the
endpoint of stroke, systemic embolism, and cardiovas-
cular death41. Similarly, the PREVAIL trial showed sig-
nificantly lower complication rates (2.2%), and non-in-
feriority of the WATCHMAN device for LAAO versus
warfarin for stroke and systemic embolism > 7  days
post-randomization. Although there is an upfront risk of
periprocedural complications (such as cardiac tampon-
ade) and a long-term risk of ischemic stroke with LAAO,
the overall risk seems to be offset by significantly lower
rates of hemorrhage in the long-term39. In patients with
AF undergoing cardiac surgery for other reasons, sur-
gical LAAO has also been shown to reduce the risk of
stroke and systemic embolism compared to those ran-
domized not to have LAAO, though the majority of
these patients also remained on anticoagulation during
follow-up42. The updated American and European
guidelines indicate LAAO as a Class IIb indication for
stroke prevention in AF patients undergoing cardiac
surgery or with a contraindication to long-term antico-
agulation23,43. It remains challenging to identify those
patients at such a high risk of stroke in whom LAAO is
preferred to anticoagulation. For example, recent data
suggest that even patients with AF and falls44, demen-
tia45, or microhemorrhages46 have a relatively low risk
of subsequent ICH and a greater risk of recurrent isch-
emic stroke.
ICH and anticoagulants in AF
The management of ICH in patients with AF who
require anticoagulation is another challenging scenar-
io, specifically if and when to resume anticoagulants.
Observational data suggest that resumption of OAC
after ICH is associated with reduced ischemic events
and mortality, without a significant increase in hemor-
rhagic events47. Moreover, observational studies sug-
gest that the optimal timing of resumption of OAC after
ICH is within 4-8  weeks, depending on individual pa-
tient characteristics, the size, and location of the ICH
(Fig.  2). However, the SoSTART randomized trial of
203 participants in the UK was unable to show
non-inferiority for resumption versus avoidance of OAC
after ICH (median time 115  days post-ICH): although
154
there was no significant difference in ICH recurrence,
the mortality in the start-OAC group was twice that in
the avoid-OAC group48. Several randomized clinical
trials are currently underway and expected to provide
more robust data on outcomes after resumption of
OAC initiation and LAAO versus best medical care
after ICH: ASPIRE (NCT03968393); PRESTIGE-AF
(NCT03996772); STATICH (NCT03186729); A3ICH
(NCT03243175); and ENRICH-AF (NCT03950076);
STROKECLOSE (NCT02830152).
Screening for AF
Current US Preventive Services Task Force recom-
mendations state that there is an insufficient evidence
to support widespread screening given the low frequen-
cy of AF in the general unselected population and in
individuals over age 50 years49-51. Nevertheless, signif-
icant technological advances over the past decade
have yielded newer devices which are easy to use,
commercially available and have high sensitivity and
specificity for detecting AF52.
Given that the risk factors for stroke and AF are sim-
ilar, the role of screening for AF in high-risk populations
(increased age and high-risk CHA2DS2-VASc score)
has become a recent research focus, especially in
post-stroke patients with various stroke subtypes. The
CRYSTAL-AF study of cryptogenic stroke patients
(mean age 62  years) showed an AF detection rate of
12% at 1  year with implantable loop recorders versus
2% with standard of care53. In the EMBRACE trial, also
in patients with cryptogenic stroke with a mean age of
73 years, the AF detection rate with a 30-day external
monitor was 16% versus 3% in the control group54.
More recently, the STROKE-AF and PER DIEM studies
have shown significantly higher AF detection rates with
the use of implantable loop recorders in post-stroke
patients with various non-AF stroke etiologies, com-
pared with the standard of care or 30-day external loop
recorder monitoring, respectively55,56. Several studies
have also shown favorable results in screening high-
risk patients for AF in the absence of recent stroke with
various protocols, from intermittent electrocardiogram
screening to implantable loop recorders50,51. One ques-
tion that remains to be answered, however, is the
amount or burden of device-detected AF that would
warrant initiation of anticoagulation. In other words, is
the risk-benefit balance the same for a patient with a
30-s episode of AF compared with a patient with > 24 h
of AF detected during screening?

Future directions
Significant scientific advances have been made in the
past few decades regarding the screening, prevention,
and treatment of patients with AF and AF-related stroke.
Nevertheless, the prevalence of both AF and AF-related
stroke, and the burden associated with each, are steadi-
ly increasing with the rapid growth of the ageing popu-
lation. Several questions remain unanswered and are
the focus of ongoing and future clinical trials. First, is
screening for AF in high-risk populations for the primary
prevention of stroke effective and cost-efficient? Sec-
ond, what is the minimum burden of device-detected AF
necessary to warrant anticoagulation? Third, should all
non-AF post-stroke patients be screened for AF with
implantable loop recorders, regardless of stroke sub-
type? Fourth, when is the optimal time to initiate oral
anticoagulation in patients with recent AF-related stroke
(both ischemic and hemorrhagic stroke)? Finally, the
association between AF, stroke, and the development of
cognitive impairment and dementia has been well es-
tablished in observational studies, and the underlying
pathophysiological mechanisms, and strategies for pre-
vention, are also the focus of ongoing research.
Funding
None.
Disclosures
Nicole Beaton Sur reports research salary support to
the Department of Neurology, University of Miami, for
role as PI of the Treatment Disparities in Stroke and AF
Study (Miami CTSI KL2 Career Development Award),
KL2TR002737 sub-investigator in the Florida Stroke
Collaboration (COHAN-R2), State of Florida, and per-
sonal funds as CME/Highlights section editor for the
journal Stroke, and as a member of the Acute Care Test
Materials Development Committee for the National
Board of Medical Examiners. She also serves as Edi-
torial Consultant for the journal JACC: Advances.
Jose Romano has no conflicts of interest related to
this topic. He reports research salary support to the
Department of Neurology, University of Miami for role
as PI (MPI) of the Transitions of Care Study (NIH/NIM-
HD) and Regional Coordinating Center for the Stroke
Trials Network (NIH/NINDS), as co-I of the Florida
Stroke Collaboration (COHAN-R2, State of Florida) and
Comparative Study in children with sickle cell (NIH/
NHLBI); and personal funds for role as member of an
N.B. Sur, J.G. Romano: Stroke and AF
Independent Data Monitoring Committee for a clinical
trial (Genentech).
Ethical disclosures
Protection of human and animal subjects. The
authors declare that the procedures followed were in
accordance with the regulations of the Relevant Clinical
Research Ethics Committee and with those of the Code
of Ethics of the World Medical Association (Declaration
of Helsinki).
Confidentiality of data. The authors declare that
they have followed the protocols of their work center on
the publication of patient data.
Right to privacy and informed consent. The au-
thors have obtained approval from the Ethics Commit-
tee for analysis and publication of routinely acquired
clinical data and informed consent was not required for
this retrospective and observational study.
References
1. Dai H, Zhang Q, Much AA, Maor E, Segev A, Beinart R, et al. Global,
regional, and national prevalence, incidence, mortality, and risk factors
for atrial fibrillation, 1990-2017: results from the global burden of disease
study 2017. Eur Heart J Qual Care Clin Outcomes. 2021;7:574-82.
2. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M,
Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: a global
burden of disease 2010 study. Circulation. 2014;129:837-47.
3. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al.
Prevalence of diagnosed atrial fibrillation in adults: national implications
for rhythm management and stroke prevention: the anticoagulation and
risk factors in atrial fibrillation (atria) study. JAMA. 2001;285:2370-5.
4. Lippi G, Sanchis-Gomar F, Cervellin G. Global epidemiology of atrial fi-
brillation: an increasing epidemic and public health challenge. Int J
Stroke. 2021;16:217-21.
5. Andrade JG, Deyell MW, Lee AYK, Macle L. Sex differences in atrial fi-
brillation. Can J Cardiol. 2018;34:429-36.
6. Schnabel RB, Yin X, Gona P, Larson MG, Beiser AS, McManus DD, et al.
50 year trends in atrial fibrillation prevalence, incidence, risk factors, and
mortality in the framingham heart study: a cohort study. Lancet. 2015;
386:154-62.
7. Volgman AS, Bairey Merz CN, Benjamin EJ, Curtis AB, Fang MC, Lindley KJ,
et al. Sex and race/ethnicity differences in atrial fibrillation. J  Am Coll
Cardiol. 2019;74:2812-5.
8. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk
factor for stroke: the framingham study. Stroke. 1991;22:983-8.
9. Otite FO, Khandelwal P, Chaturvedi S, Romano JG, Sacco RL, Malik AM.
Increasing atrial fibrillation prevalence in acute ischemic stroke and tia.
Neurology. 2016;87:2034-42.
10. Friberg J, Scharling H, Gadsboll N, Truelsen T, Jensen GB, Copenhagen
City Heart Study. Comparison of the impact of atrial fibrillation on the risk
of stroke and cardiovascular death in women versus men (the copenha-
gen city heart study). Am J Cardiol. 2004;94:889-94.
11. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes
for ischaemic stroke and bleeding in 182 678 patients with atrial fibrilla-
tion: the Swedish atrial fibrillation cohort study. Eur Heart J. 2012;33:
1500-10.
12. Mikkelsen AP, Lindhardsen J, Lip GY, Gislason GH, Torp-Pedersen C,
Olesen JB. Female sex as a risk factor for stroke in atrial fibrillation: a
nationwide cohort study. J Thromb Haemost. 2012;10:1745-51.
13. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the
cha2ds2-vasc score for refining stroke risk stratification in patients with
atrial fibrillation with a chads2 score 0-1: a nationwide cohort study.
Thromb Haemost. 2012;107:1172-9.
14. Wang TJ, Massaro JM, Levy D, Vasan RS, Wolf PA, D’Agostino RB,
et al. A risk score for predicting stroke or death in individuals with new-on-
set atrial fibrillation in the community: the framingham heart study. JAMA.
2003;290:1049-56.
155
 Rev Mex Neuroci. 2022;23(4)
15. Appelros P, Stegmayr B, Terent A. A review on sex differences in stroke
treatment and outcome. Acta Neurol Scand. 2010;121:359-69.
16. Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J,
Lombardi-Hill D, et al. 2021 guideline for the prevention of stroke in pa-
tients with stroke and transient ischemic attack: a guideline from the
american heart association/american stroke association. Stroke.
2021;52:e364-467.
17. Al-Saady NM, Obel OA, Camm AJ. Left atrial appendage: structure,
function, and role in thromboembolism. Heart. 1999;82:547-54.
18. Johansen MC, De Vasconcellos HD, Gottesman RF. Understanding atrial
cardiopathy: an under-recognized contributor to cardioembolic stroke.
Curr Treat Options Neurol. 2019;21:32.
19. Kamel H, Okin PM, Elkind MS, Iadecola C. Atrial fibrillation and mecha-
nisms of stroke: time for a new model. Stroke. 2016;47:895-900.
20. Brambatti M, Connolly SJ, Gold MR, Morillo CA, Capucci A, Muto C, et al.
Temporal relationship between subclinical atrial fibrillation and embolic
events. Circulation. 2014;129:2094-9.
21. Daoud EG, Glotzer TV, Wyse DG, Ezekowitz MD, Hilker C, Koehler J,
et  al. Temporal relationship of atrial tachyarrhythmias, cerebrovascular
events, and systemic emboli based on stored device data: a subgroup
analysis of trends. Heart Rhythm. 2011;8:1416-23.
22. Fridman S, Jimenez-Ruiz A, Vargas-Gonzalez JC, Sposato LA. Differen-
ces between atrial fibrillation detected before and after stroke and tia: a
systematic review and meta-analysis. Cerebrovasc Dis. 2022;51:152-7.
23. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr.,
et al. 2019  AHA/ACC/HRS focused update of the 2014  AHA/ACC/HRS
guideline for the management of patients with atrial fibrillation: a report
of the american college of cardiology/American heart association task
force on clinical practice guidelines and the heart rhythm society. J Am
Coll Cardiol. 2019;74:104-32.
24. Turakhia MP, Shafrin J, Bognar K, Trocio J, Abdulsattar Y, Wiederkehr D,
et al. Estimated prevalence of undiagnosed atrial fibrillation in the united
states. PLoS One. 2018;13:e0195088.
25. Jaakkola J, Mustonen P, Kiviniemi T, Hartikainen JE, Palomaki A, Harti-
kainen P, et al. Stroke as the first manifestation of atrial fibrillation. PLoS
One. 2016;11:e0168010.
26. Ryden L, Sacuiu S, Wetterberg H, Najar J, Guo X, Kern S, et al. Atrial
fibrillation, stroke, and silent cerebrovascular disease: a population-based
mri study. Neurology. 2021;97:e1608-19.
27. Jewett GA, Lindsay MP, Goia C, Zagorski B, Kamal N, Kapral MK, et al.
National trends in hospital admission, case fatality, and sex differences
in atrial fibrillation-related strokes. Int J Stroke. 2020;15:521-7.
28. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T,
et al. A  comparison of rate control and rhythm control in patients with
recurrent persistent atrial fibrillation. N Engl J Med. 2002;347:1834-40.
29. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB,
et al. A  comparison of rate control and rhythm control in patients with
atrial fibrillation. N Engl J Med. 2002;347:1825-33.
30. Hart RG, Coull BM, Hart D. Early recurrent embolism associated with
nonvalvular atrial fibrillation: a retrospective study. Stroke. 1983;14:688-93.
31. Jaillard A, Cornu C, Durieux A, Moulin T, Boutitie F, Lees KR, et al.
Hemorrhagic transformation in acute ischemic stroke. The mast-e study.
Mast-e group. Stroke. 1999;30:1326-32.
32. Stroke prevention in atrial fibrillation study. Final results. Circulation.
1991;84:527-39.
33. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A,
et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl
J Med. 2009;361:1139-51.
34. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M,
et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl
J Med. 2011;365:981-92.
35. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al.
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N  Engl J
Med. 2011;365:883-91.
36. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL,
et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl
J Med. 2013;369:2093-104.
37. Pokorney SD, Simon DN, Thomas L, Fonarow GC, Kowey PR, Chang P,
et al. Patients’ time in therapeutic range on warfarin among us patients
with atrial fibrillation: results from orbit-af registry. Am Heart J.
2015;170:141-8, e141.
156
38. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J,
et al. Ehra practical guide on the use of new oral anticoagulants in pa-
tients with non-valvular atrial fibrillation: executive summary. Eur Heart
J. 2013;34:2094-106.
39. De Marchis GM, Sposato LA, Kuhne M, Dittrich TD, Bonati LH, Fischer U,
et al. New avenues for optimal treatment of atrial fibrillation and stroke
prevention. Stroke. 2021;52:1490-9.
40. Sur NB, Wang K, Di Tullio MR, Gutierrez CM, Dong C, Koch S, et al.
Disparities and temporal trends in the use of anticoagulation in patients
with ischemic stroke and atrial fibrillation. Stroke. 2019;50:1452-9.
41. Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M,
et al. Percutaneous closure of the left atrial appendage versus warfarin
therapy for prevention of stroke in patients with atrial fibrillation: a rando-
mised non-inferiority trial. Lancet. 2009;374:534-42.
42. Whitlock RP, Belley-Cote EP, Paparella D, Healey JS, Brady K,
Sharma M, et al. Left atrial appendage occlusion during cardiac surgery
to prevent stroke. N Engl J Med. 2021;384:2081-91.
43. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ,
Blomstrom-Lundqvist C, et al. 2020 esc guidelines for the diagnosis
and management of atrial fibrillation developed in collaboration with
the european association for cardio-thoracic surgery (eacts): the task
force for the diagnosis and management of atrial fibrillation of the
european society of cardiology (esc) developed with the special con-
tribution of the european heart rhythm association (ehra) of the esc.
Eur Heart J. 2021;42:373-498.
44. Banerjee A, Clementy N, Haguenoer K, Fauchier L, Lip GY. Prior history
of falls and risk of outcomes in atrial fibrillation: the loire valley atrial fi-
brillation project. Am J Med. 2014;127:972-8.
45. Subic A, Cermakova P, Religa D, Han S, von Euler M, Kareholt I, et
al. Treatment of atrial fibrillation in patients with dementia: a cohort
study from the swedish dementia registry. J  Alzheimers Dis.
2018;61:1119-28.
46. Wilson D, Ambler G, Shakeshaft C, Brown MM, Charidimou A, Al-Shahi
Salman R, et al. Cerebral microbleeds and intracranial haemorrhage risk
in patients anticoagulated for atrial fibrillation after acute ischaemic stroke
or transient ischaemic attack (cromis-2): a multicentre observational co-
hort study. Lancet Neurol. 2018;17:539-47.
47. Kuramatsu JB, Huttner HB. Management of oral anticoagulation after
intracerebral hemorrhage. Int J Stroke. 2019;14:238-46.
48. So SC. Effects of oral anticoagulation for atrial fibrillation after sponta-
neous intracranial haemorrhage in the uk: a randomised, open-label,
assessor-masked, pilot-phase, non-inferiority trial. Lancet Neurol.
2021;20:842-53.
49. Force US, Davidson KW, Barry MJ, Mangione CM, Cabana M,
Caughey AB, et al. Screening for atrial fibrillation: us preventive services
task force recommendation statement. JAMA. 2022;327:360-7.
50. Svendsen JH, Diederichsen SZ, Hojberg S, Krieger DW, Graff C, Kron-
borg C, et al. Implantable loop recorder detection of atrial fibrillation to
prevent stroke (the loop study): a randomised controlled trial. Lancet.
2021;398:1507-16.
51. Svennberg E, Friberg L, Frykman V, Al-Khalili F, Engdahl J, Rosenqvist M.
Clinical outcomes in systematic screening for atrial fibrillation (strokes-
top): a multicentre, parallel group, unmasked, randomised controlled trial.
Lancet. 2021;398:1498-506.
52. Ding EY, Marcus GM, McManus DD. Emerging technologies for identif-
ying atrial fibrillation. Circ Res. 2020;127:128-42.
53. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA,
Morillo CA, et al. Cryptogenic stroke and underlying atrial fibrillation.
N Engl J Med. 2014;370:2478-86.
54. Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, et al.
Atrial fibrillation in patients with cryptogenic stroke. N  Engl J Med.
2014;370:2467-77.
55. Bernstein RA, Kamel H, Granger CB, Piccini JP, Sethi PP, Katz JM, et al.
Effect of long-term continuous cardiac monitoring vs usual care on de-
tection of atrial fibrillation in patients with stroke attributed to large-  or
small-vessel disease: the stroke-af randomized clinical trial. JAMA.
2021;325:2169-77.
56. Buck BH, Hill MD, Quinn FR, Butcher KS, Menon BK, Gulamhusein S,
et al. Effect of implantable vs prolonged external electrocardiographic
monitoring on atrial fibrillation detection in patients with ischemic stroke:
the per diem randomized clinical trial. JAMA. 2021;325:2160-8.
Revista Mexicana de Neurociencia

Review Article

Neurological complications of interatrial blocks and Bayes’

syndrome
Juan M. Farina1, Andrés F. Miranda-Arboleda2,3, Pablo A. Lomini4, and Adrián Baranchuk2
1Department of Cardiovascular and Thoracic Surgery, Mayo Clinic Arizona, Phoenix, USA; 2Division of Cardiology, Queen’s University, Kingston,
Ontario, Canada; 3Cardiology Department, Pablo Tobón Uribe Hospital, Medellín, Colombia; 4Medicine Faculty, Universidad de Buenos Aires (UBA),
UDH Hospital Dr. Prof. Alejandro Posadas, Buenos Aires, Argentina

Abstract
Interatrial blocks (IABs) are a variety of abnormalities in the interatrial conduction. Bayes’ syndrome is a clinical entity based
on the association between advanced IABs and supraventricular tachyarrhythmias, being atrial fibrillation (AF) the most
frequent. Due to its negative effects on left atrial electromechanical function, both IABs and Bayes’ syndrome are associated
with thromboembolic phenomena, causing cardiovascular and neurological complications. In regard to neurological involve-
ment, patients with these conditions have an increased incidence of ischemic events, cognitive impairment, and dementia.
These observations triggered the question whether the use of early anticoagulation therapy (before the documentation of
AF) could prevent thromboembolic events in patients with IABs diagnosis. This review aims to summarize the most recent
evidence describing the association of IABs and Bayes’ syndrome with neurological events. Potential early therapeutic options
to prevent these undesirable clinical consequences will be also discussed.

Keywords: Interatrial block. Bayes’ syndrome. Stroke. Dementia.

Complicaciones neurológicas en los bloqueos interauriculares y el síndrome de Bayés

Resumen
Los bloqueos interauriculares son una variedad de anomalías en la conducción interauricular. El síndrome de Bayes es una
entidad clínica basada en la asociación entre bloqueo interauricular avanzado y taquiarritmias supraventriculares, siendo la
fibrilación auricular la más frecuente. Debido a sus efectos negativos sobre la función electromecánica de la aurícula iz-
quierda, tanto el bloqueo interauricular como el síndrome de Bayes se asocian a fenómenos tromboembólicos, provocando
complicaciones cardiovasculares y neurológicas. En cuanto a la afectación neurológica, los pacientes con estas condiciones
tienen una mayor incidencia de eventos isquémicos, deterioro cognitivo y demencia. Estas observaciones generaron la
pregunta de si el uso de la terapia de anticoagulación temprana (antes de la documentación de la fibrilación auricular)
podría prevenir eventos tromboembólicos en pacientes con diagnóstico de bloqueo interauricular. Esta revisión tiene como
objetivo resumir la evidencia más reciente que describe la asociación del bloqueo interauricular y el síndrome de Bayes
con eventos neurológicos. También se discutirán posibles opciones terapéuticas tempranas para prevenir estas consecuen-
cias clínicas indeseables.

Palabras clave: Bloqueo interauricular. síndrome de Bayes. Carrera. Demencia.

*Correspondence: Date of reception: 10-03-2022 Available online: 08-07-2022

Adrián Baranchuk Date of acceptance: 24-03-2022 Rev Mex Neuroci. 2022;23(4):157-161
E-mail: Adrian.Baranchuk@kingstonhsc.ca DOI: 10.24875/RMN.M22000087 www.revmexneurociencia.com
2604-6180 / © 2022 Academia Mexicana de Neurología A.C. Published by Permanyer. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

157
 Rev Mex Neuroci. 2022;23(4)
Introduction
Interatrial blocks (IABs) include a variety of distur-
bances in interatrial conduction and are the most fre-
quent and well-known blocks at the atrial level1. IAB is
more frequently found in elderly patients (with a preva-
lence of 8% in septuagenarians) and patients with
structural heart disease2. These rhythm abnormalities
result in varying refractory periods and slower conduc-
tion velocities within the atrial myocardium, a potential
substrate for the development of atrial arrhythmias.
IABs are classified as (Fig. 1)1:
– Partial IAB (first degree): The ECG shows that the
P-wave duration is ≥ 120 ms, and usually is bimodal
(“notched”) in leads I, II, III, and aVF.
– Advanced IAB (third degree): The diagnosis is
made when a P-wave duration is ≥ 120 ms, and the
morphology of the P-wave in the inferior leads (II, III,
and aVF) is biphasic or “positive-negative.”
– Intermittent IAB (second degree): IAB may occur tran-
siently on a beat-to-beat basis or associated with chang-
es in heart rate or following pauses induced by prema-
ture contractions. The P-wave morphology may show
transient morphology changes in the same recording.
Advanced IAB is an increasingly recognized surrogate
of atrial dysfunction and a trigger of atrial dysrhythmias,
mainly atrial fibrillation (AF)3. The combination between
IAB and supraventricular arrhythmias is known as
Bayes’ syndrome1.
Recent studies have demonstrated a strong relation-
ship between IAB or Bayes’ syndrome and thromboem-
bolic phenomena, with cardiovascular and neurological
consequences. Regarding neurological involvement,
patients with IAB or Bayes’ syndrome have an in-
creased incidence of ischemic events, cognitive impair-
ment, and dementia4-6. These observations triggered
the hypothesis that the early use of anticoagulation and
antiarrhythmic therapy could have benefits in patients
with IAB before the documentation of AF7.
This review aims to summarize the most recent evi-
dence describing the association of IAB (and Bayes’
syndrome) with neurological events, focusing on stroke,
dementia, and cognitive impairment. Potential early
therapeutic options to prevent these undesirable clini-
cal consequences will also be discussed.
IABs and stroke
Cardiac embolism is a common cause of ischemic
stroke. Pathophysiological mechanisms that can explain
the link between IABs and stroke are multiple and are
158
mainly related to the potential development of supraven-
tricular arrhythmias and impaired left atrium contractility7.
Advanced IAB was shown to be a significant predictor
of both new-onset and recurrent AF3. As is known, AF is
one of the most frequent causes of stroke and can be
detected in nearly 25% of all patients with stroke by se-
quentially combining different electrocardiographic meth-
ods8. The rationale for the association between IAB and
AF is probably related with atrial remodeling and fibrosis
seen in both conditions; in IAB the delayed left atrium ac-
tivation produces an abnormal contraction against a closed
mitral valve, increasing left atrium pressure. This leads to
progressive dilation, more fibrosis, an increase in pro-in-
flammatory markers and favors the occurrence of AF4.
Furthermore, IAB has shown to be a predictor of em-
bolic stroke even when there is no documentation of AF9.
In a big-scale study, the incidence of ischemic stroke
was more than two-fold in patients with advanced IAB
as compared to those without, even after the adjustment
for traditional risk factors and symptomatic AF10. Similar
investigations found a significantly high frequency (be-
tween 61 and 80%) of IAB in patients with sinus rhythm
and a history of stroke11,12. This link between stroke and
IAB in the absence of documented AF (or other atrial
arrhythmias) can be explained by the specific electro-
mechanical disorders in this condition. In advanced IAB,
depolarization follows a caudo-cranial route, first toward
the AV node and then in a retrograde direction through
the left atrium resulting in poor left atrial electromechan-
ical function13. This impaired functioning of the left atrium
can predispose to clot formation and embolic phenom-
ena, even in the absence of other atrial arrhythmias.
The association between advanced IAB and stroke
has been demonstrated in different settings and condi-
tions, including the general population, very elderly
patients, and patients with high CHADS2 score4,14. Also
in patients with a history of an embolic stroke of un-
known source, advanced IAB predicted the recurrence
of a cerebrovascular event15.
The detection of IAB should be considered in the risk
stratification of patients in sinus rhythm that are at high
risk of stroke, even if they have no documented AF. In
addition, in patients that present with ischemic stroke
and IAB is present in the ECG, the search for AF must
be intensified9.
IABs and silent cerebrovascular disease
Clinical implications of silent cerebrovascular disease
include an increased risk for future symptomatic isch-
emic stroke, memory impairment, and cognitive
 J.M. Farina et al.: Interatrial blocks and Bayes’ syndrome

A B C

Figure 1. Classification of typical atrial block. A: partial interatrial block (first degree): P wave duration >120 ms but there
is no typical biphasic morphology in II, III, and aVF (red star). B: intermittent interatrial block (second degree): Note how
the P wave switches from type II atypical IAB by morphological criteria (black stars), given by biphasic P waves in III and
aVF, to a normal intermittent atrial conduction with the disappearance of the negative component in II, III, and aVF (red
star). C: advanced atrial block (third degree): P wave >120 ms with a biphasic component in II, III, and aVF (red star).

decline. At least two publications reported the associ-
ation between IAB and silent brain infarctions.
In a case–control study, IAB was significantly associ-
ated with the incidence of asymptomatic cerebrovascular
disease using Magnetic Resonance Imaging (MRI) ex-
amination. IAB was present in 59% of the patients with
silent brain ischemia. Older age, uncontrolled hyperten-
sion, and higher CHA2DS2-VASc were significantly more
common in patients with silent vascular disease16.
A cross-sectional study observed an association be-
tween advanced IAB and the total burden of asymptom-
atic cerebral small vessel disease in 499 patients with no
documented AF. This association was independent of left
atrium diameters, left ventricle ejection fraction, left ven-
tricle wall thickness, and other possible confounding fac-
tors. Interestingly, this study constructed a small vessels
disease score to better represent the burden of cerebral
damage, instead of a single MRI manifestation17.
Screening for IAB might help to improve risk stratifi-
cation of individuals at an elevated risk of subclinical
cerebrovascular diseases.
IABs and cognitive impairment
The association of AF with cognitive impairment and
dementia has been previously described18. In patients
in sinus rhythm with IAB and in those with Bayes’ syn-
drome the association seems to be very similar. In fact,
recently published data confirm the association of
P-wave duration with cognitive impairment and demen-
tia19. Pathophysiological mechanisms that explain these
associations are probably multifactorial and include
symptomatic ischemic stroke and silent cerebral in-
farcts, but also hemorrhages and hypoperfusion due to
hemodynamic alterations that lead to reduced cardiac
output and decreased diastolic cerebral arterial flow4,20.
In the prospective BAYES registry, which included
patients aged 70 years and older with structural heart
disease in sinus rhythm, an association (independent
of age, sex, and other confounding factors) between
IAB and cognitive impairment was found5. Interestingly,
the relationship between IAB and cognitive impairment
was also present during follow-up and was independent
of AF and the history of stroke.
The Advanced Characterization of Cognitive Impairment
in Elderly with IABs (CAMBIAD study) was a case–control
multicenter study conducted in 265 subjects aged 70 years
and older in sinus rhythm without significant structural
heart disease. This study included 143  cases with mild
cognitive impairment (Mini-Mental State Examination
score 20-25) and 122 controls with normal cognitive
159
 Rev Mex Neuroci. 2022;23(4)

C D

Figure  2. Neurological manifestations of interatrial blocks. Schematic diagram on the causes and mechanisms of
neurological manifestations in interatrial blocks. A: three-dimensional reconstruction of a cardiovascular magnetic
resonance showing extensive biatrial fibrosis. The image depicts the degree of fibrosis in a color scale (dense fibrosis
in red). B: advanced interatrial block. Note the characteristics of the P wave, with a duration >120 ms and a biphasic
component. C: atrial fibrillation as one of the finals manifestations of electrical and anatomical abnormalities in the left
atrium. D: evidence of atrial fibrosis in a bipolar three-dimensional mapping of the left atrium. Purple color represents
normal tissue colored areas (yellow, green, blue, and red) correspond to low-voltage fibrotic tissue.

function. Patients with cognitive impairment had longer
P-wave duration, higher prevalence of IAB, and higher
prevalence of advanced IAB when compared to controls.
IAB was independently associated with mild cognitive im-
pairment, both for partial and advanced IAB but with a
stronger association in the case of advanced IAB21.
An association with dementia has also been suggest-
ed, particularly in patients with advanced IAB2. In the
Cardiac and Clinical Characterization of Centenarians
study, the prevalence of dementia progressively in-
creased when passing from normal P-wave, to partial
IAB, advanced IAB, and AF. Therefore, a systematic
assessment of the cognitive status at baseline and
during follow-up in patients with advanced IAB or
Bayes’ syndrome should be considered2.
Role of early therapeutic interventions
The rationale of considering anticoagulation in pa-
tients with IAB and no documentation of AF relies on
160
several observations. First, some studies using im-
plantable devices have demonstrated a lack of a clear
temporal relationship between cryptogenic stroke and
paroxysmal AF, supporting the hypothesis of the impor-
tance of a prothrombogenic state in the left atrium,
even in the absence of AF22. Furthermore, advanced
IAB and AF share multiple clinical and pathophysiolog-
ical similarities; both processes present the same ana-
tomical substrate (fibrotic atrial cardiomyopathy)
(Fig. 2), which can induce blood stasis, hypercoagula-
tion, and more atrial fibrosis7,23,24. Finally, IABs have
demonstrated to be a risk factor for stroke and cere-
brovascular diseases even in the absence of AF9-12.
There are ongoing studies aiming to compare the
efficacy of anticoagulation in patients with advanced
IAB with no prior documentation of AF. The results of
these studies will allow determining the efficacy of this
early therapeutic intervention in patients with advanced
IAB and no demonstrated AF. If positive results are
 J.M. Farina et al.: Interatrial blocks and Bayes’ syndrome
found, a global strategy for anticoagulation to prevent
stroke in patients without AF should be considered.
Regarding antiarrhythmic treatment in IAB with no AF
documentation the current situation is similar. Consid-
ering the clear and strong association of IAB with atrial
arrhythmias, the idea of considering antiarrhythmic
treatment when IABs are detected seems reasonable.
Indeed, this idea was suggested in a small series, and
anti-arrhythmic treatment of patients with advanced IAB
has shown to reduce AF occurrence13,25. However, no
randomized data are available at present times and
whether antiarrhythmic treatment should be used to
prevent arrhythmias in asymptomatic patients with IAB
needs still to be tested in large prospective trials.
Conclusion
The presence of IABs is strongly associated with
negative neurological consequences, mainly as a result
of cardioembolic events. These conduction abnormali-
ties need to be included in the diagnosis work-up when
there is no clear cause for neurological symptoms. The
use of early anticoagulation and antiarrhythmic treat-
ment to prevent these undesirable consequences
needs to be further evaluated in large trials.
Conflicts of interest
None.
Funding
None.
Ethical disclosures
Protection of human and animal subjects. The
authors declare that the procedures followed were in
accordance with the regulations of the Relevant Clinical
Research Ethics Committee and with those of the Code
of Ethics of the World Medical Association (Declaration
of Helsinki).
Confidentiality of data. The authors declare that
they have followed the protocols of their work center on
the publication of patient data.
Right to privacy and informed consent. The au-
thors have obtained approval from the Ethics Commit-
tee for analysis and publication of routinely acquired
clinical data and informed consent was not required for
this retrospective and observational study.
References
1. Bayés de Luna A, Baranchuk A, Alberto Escobar Robledo L,
van Roessel AM, Martínez-Sellés M. Diagnosis of interatrial block. J Ge-
riatr Cardiol. 2017;14:161-5.
2. Martínez-Sellés M, Massó-van Roessel A, Álvarez-García J, de la Villa BG,
Cruz-Jentoft AJ, Vidán MT, et al. Interatrial block and atrial arrhythmias
in centenarians: prevalence, associations, and clinical implications. Heart
Rhythm. 2016;13:645-51.
3. Tse G, Wong CW, Gong M, Wong WT, Bazoukis G, Wong SH, et al.
Predictive value of inter-atrial block for new onset or recurrent atrial fibri-
llation: a systematic review and meta-analysis. Int J Cardiol. 2018;250:152-6.
4. Martínez-Sellés M, Elosua R, Ibarrola M, de Andrés M, Díez-Villanueva P,
Bayés-Genis A, et al. Advanced interatrial block and P-wave duration are
associated with atrial fibrillation and stroke in older adults with heart di-
sease: the BAYES registry. Europace. 2020;22:1001-8.
5. Martínez-Sellés M, Martínez-Larrú ME, Ibarrola M, Santos A, Díez-Villa-
nueva P, Bayés-Genis A, et al. Interatrial block and cognitive impairment
in the BAYES prospective registry. Int J Cardiol. 2020;321:95-8.
6. Iomini P, Martínez-Sellés M, Elosua R, Bayés-de-Luna A, Baranchuk A.
Síndrome de Bayés, accidente cerebrovascular y demencia. Arch Peru
Cardiol Cir Cardiovasc. 2021;2:213-23.
7. Baranchuk A, Alexander B, Cinier G, Martinez-Selles M, Tekkesin AI,
Elousa R, et al. Bayés’s syndrome: time to consider early anticoagula-
tion? North Clin Istanb. 2018;5:370-8.
8. Sposato LA, Cipriano LE, Saposnik G, Vargas ER, Riccio PM, Hachinski V,
et al. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack:
a systematic review and meta-analysis. Lancet Neurol. 2015;14:377-87.
9. Bayés de Luna A, Martínez-Sellés M, Bayés-Genís A, Elosua R, Baranchuk
A. Surface ECG interatrial block-guided treatment for stroke prevention:
rationale for an attractive hypothesis. BMC Cardiovasc Disord. 2017;17:211.
10. O’Neal W, Kamel H, Zhang ZM, Chen LY, Alonso A, Soliman EZ, et al.
Advanced interatrial block and ischemic stroke: the atherosclerosis risk
in communities study. Neurology. 2016;87:352-6.
11. Ariyarajah V, Puri P, Apiyasawat S, Spodick DH. Interatrial block: a novel risk
factor for embolic stroke? Ann Noninvasive Electrocardiol. 2007;12:15-20.
12. Lorbar M, Levrault R, Phadke JG, Spodick DH. Interatrial block as a
predictor of embolic stroke. Am J Cardiol. 2005;95:667-8.
13. Chhabra L, Devadoss R, Chaubey VK, Spodick DH. Interatrial block in
the modern era. Curr Cardiol Rev 2014;10:181-9.
14. Wu JT, Wang SL, Chu YJ, Long DY, Dong JZ, Fan XW, et al. CHADS2
and CHA2DS2-VASc scores predict the risk of ischemic stroke outcome
in patients with interatrial block without atrial fibrillation. J  Atheroscler
Thromb. 2017;24:176-84.
15. Carrillo-Loza K, Baranchuk A, Serrano F, Hasseb S, Espinosa Lira F,
Soriano E, et al. Advanced interatrial block predicts recurrence of embo-
lic stroke of undetermined source. Neurologia (Engl Ed). 2021 Oct
13:S2173-5808(21)00162-0. doi: 10.1016/j.nrleng.2019.10.008. Epub
ahead of print. PMID: 34656503.
16. Çinier G, Tekkeşin Aİ, Çelik TY, Mercan O, Tanboğa HI, Günay MB, et al.
Value of interatrial block for the prediction of silent ischemic brain lesions.
J Atr Fibrillation. 2018;11:2037.
17. Wang Z, Qin H, Chen G, Mok VC, Dai Y, Cai Y, et al. Association be-
tween advanced interatrial block and small vessel diseases in the brain.
Quant Imaging Med Surg. 2020;10:585-91.
18. Diener HC, Hart RG, Koudstaal PJ, Lane DA, Lip GY. Atrial fibrillation
and cognitive function: JACC review topic of the week. J Am Coll Cardiol.
2019;73:612-9.
19. Gutierrez A, Norby FL, Maheshwari A, Rooney MR, Gottesman RF,
Mosley TH, et al. Association of abnormal P-wave indices with dementia
and cognitive decline over 25 years: ARIC-NCS (the atherosclerosis risk
in communities neurocognitive study). J Am Heart Assoc. 2019;8:e014553.
20. Conen D, Rodondi N, Müller A, Beer JH, Ammann P, Moschovitis G,
et al. Relationships of overt and silent brain lesions with cognitive function
in patients with atrial fibrillation. J Am Coll Cardiol. 2019;73:989-99.
21. Herrera C, Bruña V, Abizanda P, Díez-Villanueva P, Formiga F, Torres R, et
al. Relation of interatrial block to cognitive impairment in patients ≥70 years
of age (from the CAMBIAD case-control study). Am J Cardiol. 2020;136:94-9.
22. Martin DT, Bersohn MM, Waldo AL, Wathen MS, Choucair WK, Lip GY,
et al. IMPACT Investigators. Randomized trial of atrial arrhythmia moni-
toring to guide anticoagulation in patients with implanted defibrillator and
cardiac resynchronization devices. Eur Heart J. 2015;36:1660-8.
23. Benito EM, De Luna AB, Baranchuk A, Mont L. Extensive atrial fibrosis
assessed by late gadolinium enhancement cardiovascular magnetic re-
sonance associated with advanced interatrial block electrocardiogram
pattern. Europace. 2017;19:377.
24. Bisbal F, Baranchuk A, Braunwald E, de Luna AB, Bayés-Genís A. Atrial
failure as a clinical entity: JACC review topic of the week. J  Am Coll
Cardiol. 2020;75:222-32.
25. Baranchuk A, Villuendas R, Bayes-Genis A, Goldwasser D, Chiale P, de Luna
AB, et al. Advanced interatrial block: a well-defined electrocardiographic
pattern with clinical arrhythmological implications. Europace. 2013;15:1822.
161