Invest Clin 64(1): 108- 122, 2023 https://doi.org/10.54817/IC.v64n1a08

Corresponding author. Aline Siteneski. Instituto de Investigación y Facultad de Ciencias de la Salud, Universidad

Técnica de Manabí, Portoviejo, 130105, Ecuador. Phone: 00 (593) 959266284. E-mail: aline.siteneski@gmail.com

Neurological manifestations associated with

SARS-CoV-2 infection: an updated review.

Diana Cevallos-Macías1, Gilberto Vizcaíno Salazar1,2 and Aline Siteneski1,2

1Facultad de Ciencias de la Salud, Carrera de Medicina, Universidad Técnica de Manabí,

Portoviejo, Ecuador.

2Instituto de Investigación y Facultad de Ciencias de la Salud, Universidad Técnica

de Manabí, Portoviejo, Ecuador.

Keywords: Neurological manifestations; neuroinvasive mechanism; COVID-19;

SARS-CoV-2.

Abstract. SARS-CoV-2 is a single-stranded RNA virus that belongs to the

group of seven coronaviruses that affect humans, and its infection causes the

COVID-19 disease. The association between the COVID-19 condition and risk

factors of neurological manifestations is unclear to date. This review aims

to update the main neurological manifestations associated with SARS-CoV-2

disease. First, we present the hypothesis of the neuroinvasion mechanisms of

SARS-CoV-2. Then, we discuss the possible symptoms related to patients with

COVID-19 infection in the central and peripheral nervous systems, followed by

the perspectives of diagnosis and treatment of possible neurological manifesta-

tions. The hypothesis of the neuroinvasion mechanism includes direct routes,

as the virus crosses the blood-brain barrier or the ACE2 receptor pathway role,

and indirect pathways, such as malfunctions of the immune system and vascular

system dysregulation. Various studies report COVID-19 consequences, such as

neuroanatomic alterations and cognitive impairment, besides peripheral condi-

tions, such as anosmia, ageusia, and Guillain Barré Syndrome. However, the het-

erogeneity of the studies about neurologic damage in patients after COVID-19

infection precludes any generalization of current findings. Finally, new studies

are necessary to understand the adequate diagnosis, therapeutic method of

early treatment, and risk group of patients for neurological manifestations of

COVID-19 post-infection.

Neurological manifestations associated with SARS-CoV-2 infection 109

Vol. 64(1): 108 - 122, 2023

Manifestaciones neurológicas asociadas con la infección

por SARS-CoV-2: una revisión actualizada.

Invest Clin 2023; 64 (1): 108 – 122

Palabras clave: manifestaciones neurológicas; mecanismo neuroinvasivo; COVID-19;

SARS-CoV-2.

Resumen. El SARS-CoV-2 es un virus de ARN monocatenario que perte-

nece al grupo de los siete coronavirus que afectan a los humanos y cuya in-

fección causa la enfermedad COVID-19. La asociación entre la infección por

COVID-19 y factores de riesgo de manifestaciones neurológicas aún no está

clara. Esta revisión tiene como objetivo actualizar la descripción de las princi-

pales manifestaciones neurológicas asociadas a la infección por SARS-CoV-2.

Presentamos la hipótesis de los mecanismos de neuroinvasión del SARS-CoV-2.

Luego discutimos los posibles síntomas asociados a los pacientes con infección

por COVID-19 en el sistema nervioso central y periférico y, posteriormente,

las perspectivas de diagnóstico y tratamiento de las posibles manifestaciones

neurológicas. La hipótesis del mecanismo de neuroinvasión incluye rutas di-

rectas cuando el virus cruza la barrera hematoencefálica o tiene acción vía del

receptor ACE2 y vías indirectas tales como el mal funcionamiento del sistema

inmunitario y la desregulación del sistema vascular. Diversos estudios reportan

consecuencias del COVID-19, como la presencia de alteraciones neuroanató-

micas y deterioro cognitivo, además de condiciones periféricas como anosmia,

ageusia y Síndrome de Guillain Barré. La heterogeneidad de los estudios sobre

el daño neurológico en pacientes después de la infección por COVID-19 impide

cualquier generalización de los hallazgos actuales. Finalmente, son necesarios

nuevos estudios enfocándose en comprender el diagnóstico adecuado, el méto-

do terapéutico de tratamiento temprano y el grupo de riesgo para las manifes-

taciones neurológicas de la pos infección por COVID-19.

Received: 03-09-2022 Accepted: 26-09-2022

INTRODUCTION

The COVID disease emerged in Wu-

han-China in 2019 with rapid transmission

and caused severe consequences in society,

economies, and healthcare systems 1. Until

July 2022, more than 500 million confirmed

cases of COVID-19 and around 6.3 million

deaths have been reported worldwide 2. In

this scenario, the data for 2020 showed that

the United States had the highest number

of cases and deaths from COVID-19 3. The

agent responsible for these high rates of

morbidity and mortality is SARS-CoV-2. This

is a single-stranded RNA virus that belongs

to the group of seven coronaviruses that af-

fect humans 4. The symptomatology associ-

ated with COVID-19 is respiratory, mainly

fever and cough, and the infection can lead

to pneumonia 5.

The association between COVID-19 in-

fection and risk factors of neurological man-

ifestations is unclear to date. Recent studies

report that SARS-CoV-2 causes damage to

the central and peripheral nervous systems6.

Complications such as encephalopathy,

110 Cevallos-Macías et al.

Investigación Clínica 64(1): 2023

stroke, atypical, neurocognitive disorders,

and neuropsychiatric symptom as delirium

and confusion are common in severe infec-

tions 7. Post-infection peripheral conditions

such as anosmia, ageusia, and Guillain Barré

Syndrome have also been previously report-

ed 8. Apparently, the COVID-19 neurologic

manifestation seems familiar and may pres-

ent as the only symptom without any other

manifestation of respiratory system involve-

ment 9.

Brain analysis of images before and af-

ter infection with SARS-CoV-2 suggests that

COVID-19 is associated with neuroanatomic

alterations and cognitive impairment 10. In

fact, a neuroimaging study with 401 patients

with SARS-CoV-2 positive showed structural

alterations of the brain, such as longitudinal

cortical volume loss and changes in regions

11. Due to the wide variation of symptoms, in-

dividuality, and previous comorbidities in the

people, the association between COVID-19

with some neurological manifestations is

challenging. In addition, there exists the ne-

cessity to evaluate the duration and revers-

ibility of neuroimaging changes observed

in studies 10. Thus, the aim of this review is

update of main neurological manifestations

associated with SARS-CoV-2 infection. First,

we present the hypothesis of the neuroinva-

sion mechanisms of SARS-CoV-2. Then, we

discuss the possible symptoms related to

the COVID-19 infection in the central and

peripheral nervous systems. Furthermore,

we show the perspectives diagnosis of neu-

rological manifestation post-SARS-CoV-2 in-

fection.

Literature Data Searching

This review presents a mechanistic

overview of the clinical research regarding

the effects of SARS-CoV-2 on the nervous

system. To review possible symptoms asso-

ciated with the COVID-19 infection in the

central and peripheral nervous systems, we

selected clinical and epidemiological stud-

ies published over two years and two months

(May 2020 to July 2022) period. The search

included original manuscripts and contem-

porary reviews published in English, as-

sessed by specific search terms in the title

or abstract of the manuscripts available

through PubMed. The search terms used

were “SARS-CoV-2 and blood-brain barrier”,

“SARS-CoV-2 and neuroinvasion mecha-

nisms”, “SARS-CoV-2 and peripheral ner-

vous system”, and “SARS-CoV-2 and central

nervous system”. Additionally, “COVID-19

and blood-brain barrier”, “SARS-CoV-2 and

neuroinvasive mechanisms,” “COVID-19 and

peripheral nervous system”, and “COVID-19

and central nervous system” We performed a

specific screening of the clinical studies that

investigated neurobiological manifestations

after SARS-CoV-2 in the central and periph-

eral nervous systems.

Hypothesis for the neuroinvasion

mechanisms of post-infection

by SARS-CoV-2

Although the neuroinvasion mecha-

nism of SARS-CoV-2 is uncharted, some hy-

potheses have been postulated to explain

how the virus crosses the blood-brain barrier

(BBB) 12 (Fig. 1). The BBB is a multilayer

highly effective system that protects the ner-

vous system from an invasion of pathogenic

agents and promotes immune responses 13,14.

Some studies postulate that SARS-CoV-2 can

infect the endothelial cells, which are cells

that compose the BBB and the choroid plex-

us region that produce the cerebrospinal flu-

id 15,16. Through the infection, SARS-CoV-2

accesses the nervous system to the pathway

known as the hematogenous pathway 2, gen-

erating a hyperinflammation stage and loss

of BBB permeability 17,18.

The most accepted hypothesis of the

neuroinvasion mechanism 2 postulates that

the SARS-CoV-2 agent predominantly ex-

ploits human protein receptors to the angio-

tensin-converting enzyme receptor (ACE2

receptor) 19,20. This receptor expresses on

the cell surface of various human cells, in-

cluding glial cells and neurons. Additionally,

to the direct encroach of nerve endings on