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

Neurological manifestations associated with SARS-CoV-2 infection 111

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

the cell surface, other different transmission

routes could facilitate SARS-CoV-2 arrival

on the nervous system structures 20. The

olfactory-neural transport may be the route

used by SARS-CoV-2 to invade the brain (Fig.

1). A higher expression of ACE2 receptors

in neuronal cells exists in the olfactory cells

21,22. Curiously, in the central nervous sys-

tem, the ACE2 expression level is significant

in pons and medulla oblongata, the neuro-

anatomic regions responsible for the brain’s

respiratory centers 23. The axon of olfactory

neuron cells may form a pathway conducting

SARS-CoV-2 to the brain 22. A study evaluat-

ing ACE2 receptor expression in 85 human

tissues showed 21 different brain regions 23

Another hypothesis of the neuroinva-

sion mechanism of SARS-CoV-2 with indirect

routes includes the immunity pathway with

the malfunction of the immune system and

dysregulation of the vascular system 13,14,24

(Fig. 1). SARS-CoV-2 may infect the immune

cells and produce excessive immune respons-

es that trigger systemic hyperinflammation

25. In response, the immune cells release cy-

tokines that may damage blood vessels and

alter the permeability of the blood-brain

barrier 26. Consequently, infected immune

cells are vehicles for disseminating SARS-

CoV-2 to the nervous system 27. The cerebral

vascular endothelium has a self-regulatory

function in the vascular system. When SARS-

CoV-2 invades the vascular endothelium, it

can elevate cerebral blood pressure, caus-

ing the blood vessel to rupture and reducing

the functionality of the vascular system 28,29.

Fig. 1. Possible neuroinvasion mechanism post-SARS-CoV-2 infection.

112 Cevallos-Macías et al.

Investigación Clínica 64(1): 2023

The classical receptor-mediated endocytosis

pathway may allow the SARS-CoV-2 entry

into epithelial cells. A recent in vitro study

explored the hypothesis that SARS-CoV-2

spreads between permissive and nonper-

missive neuronal cells 30. SARS-CoV-2 likely

uses tunneling nanotubes membranous con-

duits rich in actin for intercellular invading

nonpermissive cells and potentiating infec-

tion in permissive cells. Future studies may

explore the permissive and nonpermissive

pathways of SARS-CoV-2.

Neurobiological manifestations in the

central and peripheral nervous systems

post-infection by COVID-19

In the post-infection by SARS-CoV-2,

the patients may present consequences in

the central and peripheral nervous systems.

However, the relationship between cause

and effect of the neurobiological manifes-

tations is still not elucidated entirely 24,29.

Cerebrovascular complications and psychi-

atry symptoms are reported in the central

system and peripheral nervous systems,

with demyelinating lesions and neuromus-

cular symptoms 31,32. Notably, patients with

comorbidities, severe infection, and ad-

vanced age are the most vulnerable to neu-

rological manifestation post-infection by

SARS-CoV-2 20,29,33-36.

SARS-CoV-2 causes direct damage to

the vascular endothelium and hyperinflam-

mation 37. Several studies have reported that

cerebrovascular disease is a common com-

plication after SARS-CoV-2 infection, with a

prevalence oscillating between 2.3%, 1.4%,

and 6% of infected patients 37-40. The com-

mon cerebrovascular manifestations are

hemorrhagic stroke, ischemic stroke, and

the development of coagulopathies such as

arterial and venous thrombosis 38,39. Brain

biopsies have shown thrombotic microangi-

opathies in critically state patients after CO-

VID-19 infection 38. In addition, hypoxemia

and imbalance of the renin-angiotensin sys-

tem could be involved in the development of

cerebrovascular disease manifestation after

COVID-19 28.

Inflammatory lesions of the brain pa-

renchyma, such as encephalitis, have also

been documented in patients post-infection

with COVID-19 41. A study showed autopsies

with the presence of cerebral edema in pa-

tients positive for the infection 42. The ge-

nome sequencing studies have shown the

presence of viral antigen of SARS-CoV-2 in

cerebrospinal fluid of patients with encepha-

litis and meningitis. In addition, cases of en-

cephalopathy have been reported in positive

COVID-19 patients 43,44. Seizures have also

been a complication in patients hospitalized

for COVID-19 45. Mechanisms such as releas-

ing inflammatory cytokines and stimulating

astrocytes and microglia could be involved in

seizures 46. The stimulation induced by the

union of SARS-CoV-2 with the ACE2 recep-

tor in neurons releases IL-6, a pro-inflam-

matory cytokine. Consequently, COVID-19

causes chronic inflammation, and neuronal

hyperexcitability can induce epilepsy 47.

In the context of neurological manifes-

tations, there have been consequences re-

ported in the peripheral nervous system in

post-COVID-19 patients 48,49. Anosmia (loss

of smell), ageusia (loss of taste), and hypos-

mia (decreased smell) are the main manifes-

tations reported in patients post-SARS-CoV-2

infection 31,48. A study showed that 50% of pa-

tients have taste and smell disorders at the

onset of COVID-19 49. Other work exhibits

a high prevalence of taste disorders 38.5%,

olfactory disorders 35.8%, myalgia 19.3 %

2, and Guillain Barre Syndrome 16.6%12 50.

The clinical symptoms of ageusia and anos-

mia could be considered predictors of SARS-

CoV-2 infection 51. A study conducted by Mao

et al., with a sample of 214 patients, reports

5.1% with anosmia and 5.6% with ageusia

29. Possibly, anosmia and ageusia manifesta-

tions arise from direct injury to olfactory

and taste receptors caused by SARS-CoV-2 52.

Furthermore, peripherally paresthesias,

dyssynergia (loss of motor coordination),

areflexia (loss of reflexes), and flaccid paraly-

sis have been observed in some SARS-CoV-2

positive patients 53. The most frequent mani-

Neurological manifestations associated with SARS-CoV-2 infection 113

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

festation is the Guillain Barré Syndrome,

characterized by an immune system reaction

that attacks peripheral neuron axons. Guil-

lain Barré Syndrome’s initial symptoms are

peripheral weakness and tingling. The pro-

gression of the disease can cause generalized

paralysis54. The diagnosis may confirm Guil-

lain Barré syndrome in an electroneurog-

raphy for the absence of the muscle action

potential in the axons of peripheral neurons

55. The first case reported of this syndrome

associated with COVID-19 was in Wuhan in a

61-year-old woman 56.

It is worth highlighting that muscu-

loskeletal symptoms such as myalgias and

paresthesias are also manifestations of the

peripheral nervous system associated with

SARS-CoV-2 12. An increase in musculoskel-

etal injury markers such as creatine kinase

and lactate dehydrogenase in the blood of

some COVID-19 patients was observed 2. A

study conducted in Wuhan showed that 32%

of patients presented the clinical symptom

of difficulty grasping objects after hospital-

ization for COVID-19 57. Indeed, studies sug-

gest that SARS-CoV-2 leads to deficiencies in

muscle strength and endurance, possibly due

to inflammatory effects 57,58. A case study re-

ports that post-infection patients correlated

the demyelinating lesions with neurologic

complications such as anosmia and dysgeu-

sia 31. On the other hand, despite the nega-

tive quarantine experience, it is impossible

to establish a cause-and-effect relationship

between neuropsychiatric conditions and

COVID-19 disease 59. Individual and environ-

mental factors such as the stress of confine-

ment or a genetic predisposition influenced

by stress can contribute to the development

of different neuropsychiatric disorders ob-

served in patients post- COVID-19 infection.

Neuroimaging studies with manifestations

associated with post-infection by SARS-

CoV-2

Widely used methods of neuroimag-

ing, such as magnetic resonance imaging

(MRI) and computed tomography, have

been utilized to diagnose neurobiologi-

cal manifestations associated with post-

infection by SARS-CoV-2 33,60,61. One study

evaluated with MRI 59 patients positive for

COVID-19 and diagnosed white matter le-

sions (39.0%), subacute infarctions (6.8%),

leukoencephalopathy (10.2%), and multiple

sclerosis (5.1%) 60. Another study found mi-

crohemorrhages related to thrombotic and

hypoxemic microangiopathy in 3.4% of the

patients 61. Recently, a longitudinal study

evaluated 785 participants post-infection by

COVID-19 at different times. The research

found a reduced tissue contrast and gray

matter thickness in the orbitofrontal cortex

and parahippocampal gyrus; additionally to

changes in functionally connected to the

primary olfactory cortex and a reduction in

the global brain. Besides, the work data re-

ported a more significant cognitive decline

over the evaluation period 11. Interestingly,

the study observed abnormalities in limbic

brain regions forming a mainly olfactory net-

work that may indicate a future vulnerability

of the limbic system in particular, including

memory 11.

In computed tomography of critical pa-

tients with post-infection by COVID-19 in-

tracerebral, intraventricular, and subarach-

noid hemorrhage, frontal hypo metabolism,

and cerebellar hypermetabolism were ob-

served 28,62. Curiously, a study evaluating 18

brains of patients who died 0 to 32 days after

the onset of symptoms of COVID-19 in the

histopathological analysis showed only hy-

poxic changes and did not show encephalitis

or other specific brain changes referable to

the infection 63. A study with post-mortem

brain magnetic resonance evaluation of 62

patients dead at a time < 24 hours by CO-

VID-19 demonstrated hemorrhagic and pos-

terior reversible encephalopathy syndrome

brain lesions 64. Additionally, the study

showed that the SARS-CoV-2 seems limited

to olfactory impairment, and the brainstem

evaluation findings do not support a brain-

related contribution to the respiratory dis-

tress of the patients 64.

114 Cevallos-Macías et al.

Investigación Clínica 64(1): 2023

Many studies have focused on searching

for biomarkers to express the central ner-

vous system injury induced by SARS-CoV-2

65-68. Neuronal and astrocyte injury mark-

ers, such as the neurofilament light chain

protein, showed a sustained increase with

maintenance. The glial fibrillary acidic pro-

tein showed an early peak in plasma and a

decrease in the follow-up of 47 positive pa-

tients for COVID-19 66. More recently, higher

serum concentrations of neurofilament light

chains were associated with worse clinical

outcomes in 142 hospitalized patients posi-

tive for COVID-19 67. The serum concen-

trations of neurofilament light chains may

represent a neuroaxonal injury marker that

could predict the extent of neuronal damage

66,67.

Some studies attempt to correlate the

presence of neuroinflammation and vascu-

lar injury in patients post-infection by CO-

VID-19. For example, cerebrospinal fluid

markers of inflammation, such as neopterin

and beta microglobulin, were increased in a

study that evaluated six patients 68. Also, high

levels of antiphospholipid antibodies have

been shown in positive cases of encephalo-

myelitis 69. Finally, studies carried out with

PCR report the presence of anti-SARS-CoV-2

antibodies and SARS-CoV-2 RNA in the cere-

brospinal fluid 70,71. Of note is the presence of

anti-SARS-CoV-2 and SARS-CoV-2 RNA in the

cerebrospinal fluid in patients with severe

complications such as encephalitis, menin-

gitis, and demyelinating disease 71. Current-

ly, it is impossible to affirm the sensitivity of

the positive SARS-CoV-2 PCR method in ce-

rebrospinal fluid. In cases of clinical patient

examination of the cerebrospinal fluid for

viruses such as tick-borne encephalitis, the

diagnosis for PCR is not standard because it

has low sensitivity. In addition, the presence

of the encephalitis virus may be transient in

the cerebrospinal fluid. Therefore, it is not

yet clear which is the best diagnostic ap-

proach to diagnose SARS-CoV-2 CNS infec-

tion or the parainfectious immune reaction

associated with SARS-CoV-2. So far, there

are no reports on the intrathecal synthesis

of SARS-CoV-2-specific IgG 72.

Limitations

Our study also has several limitations.

First, this review’s characteristic and pur-

pose is the literature update. Second, it

does not realize a systematic review of

post-infection by SARS-CoV-2 to assess the

observational and or randomized clinical

trials of literature. This paper did not ex-

plore the link between SARS-CoV-2 and the

neurocognitive deficit. Various factors may

influence the correlation of cognitive disor-

ders in people infected by SARS-CoV-2- For

example, the stress caused by isolation, the

pandemic restrictions, online teaching, and

the return to regular activities 73-75. In addi-

tion, different studies report memory loss,

cognitive deterioration, depression, and

deficits in executive functioning evaluated

in different periods after infecting by CO-

VID-19 74,76-78. Nonetheless, is not possible

to differentiate whether the cognitive im-

pairment found in patients post-COVID-19

infection corresponded to mild cognitive

impairment or dementia 79.

Conclusions and Future Directions

This review discussed the primary

evidence underlining the neurobiologi-

cal manifestations associated with post-

infection by SARS-CoV-2. Of particular

relevance, compelling evidence suggests

that post-infection by SARS-CoV-2 patients

presents neurological manifestations in

the central and peripheral nervous system.

In support, several observational studies

have shown cerebrovascular complications

and inflammatory lesions in the peripheral

system, causing demyelinating lesions and

neuromuscular symptoms 31,32,41. The dura-

tion of neurological manifestations after

COVID-19 infection seems to vary during

the first six months after the illness onset

80. Given this, some studies have investigat-

ed the possible neuroinvasion mechanism

of SARS-CoV-2, and postulated hypotheses

Neurological manifestations associated with SARS-CoV-2 infection 115

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

to explain the virus penetration across the

blood-brain barrier. However, clinical stud-

ies assessing the specific manifestations as-

sociated with post-infection by SARS-CoV-2

are still scarce, and their results are some-

times controversial.

The discrepant results from observa-

tional studies call for the need to conduct

future studies. Considering the risk factors

and comorbidities in patients, this should

be done before affirming the association

between neurological manifestations and

post-infection by SARS-CoV-2. Neurological

complications are associated with the worst

mortality rates 81.

According to a recent systematic analy-

sis, most research published on neurocogni-

tive deficits following SARS-CoV-2 infection re-

cruited subjects before the world’s population

was utterly immunized 82. Another systematic

review showed that non-specific inflammatory

CSF abnormalities were common in patients

with post-COVID-19 infection and nervous sys-

tem syndromes. The study suggests that neuro-

degeneration biomarkers and a link to neuro-

nal damage with long-term consequences are

unknown 83. On the other hand, in brain MRI,

the heterogeneity of the studies about neuro-

logic damage in patients after COVID-19 infec-

tion precludes any generalization of the find-

ings 84. Therefore, new research may assess the

potential of post-infection by SARS-CoV-2 to

cause neurological manifestations in patients

in the current context after worldwide vaccina-

tion. In this sense, there are several publica-

tions related to SARS-CoV-2 vaccination and

neurological disorders such as the thrombotic

thrombocytopenic syndrome 85,86. Finally, the

new studies should focus on research to under-

stand the therapeutic method of early treat-

ment, adequate diagnosis, and risk group for

neurological manifestations post-infection by

SARS-CoV-2 87.

Funding

This study was supported by the Institu-

to de Investigación and Facultad de Ciencias

de la Salud, Universidad Técnica de Manabí,

Portoviejo, Ecuador.

Conflicts of interest

The authors declare that they have no

potential conflicts of interest to disclose re-

lated to this study.

Number ORCID of authors

• Diana Cevallos Macías (DCM):

0000-0002-3532-5935

• Aline Siteneski (AS):

0000-0001-6692-7253

• Gilberto Vizcaíno (GV):

0000-0003-2785-1879

Authorship contribution statement

• DCM: conceptualization; original

draft and writing of the manuscript.

• GV: writing and preparing the final

draft of the manuscript.

• AS: supervision, writing, and prepa-

ring the final draft of the manuscript.

• All authors of this paper have read

and approved the final version of the

submitted manuscript.

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