Figure 1 – Flowcha=
rt
identifying the study selection process to make up the integrative review. =
Redenção - CE, Brazil, 2020
=
![](3D"1108-TextodoartigoEN_enviarHTML_arquivos/image002.jpg")
Source: =
The
authors
UNDERSTANDING NEUROLOGICAL MANIFESTATIONS
INDUCED BY INFECTIONS BY THE NEW CORONAVIRUS: AN INTEGRATIVE REVIEW
COMPREE=
NSÃO
DAS MANIFESTAÇÕES NEUROLÓGICAS INDUZIDAS POR INFECÇÕES PELO NOVO CORONAVÍRU=
S:
UMA REVISÃO INTEGRATIVA
Letícia
Pereira Felipe[1] * Arthur Castro de Lima[2]
* Karina Gonzaga da Costa[3]
* N’ghalna da Silva[4]
* Davide Carlos Joaquim[5]
* Daniel Freire de Sousa[6]
* Ana Caroline Rocha de Melo Leite[7]
ABSTRACT
Objective: To underst=
and
the clinical neurological manifestations of patients with Coronavirus of Se=
vere
Acute Respiratory Syndrome 2 (SARS-CoV-2)/Coronavirus Disease 19 (COVID-19)=
. Methods:
This integrative review was conducted in June 2020, based on the guiding
question “What are the neurological manifestations presented by patients wi=
th
SARS-CoV-2/COVID-19?”, based on the PICO strategy. The combination of words
“SARS-CoV-2” AND “COVID-19” AND “neurologic manifestations” was used in the
search in the databases Cumulative Index to Nursing and Allied Health
Literature (CINAHL), National Library of Medicine (PubMed), Scopus, and Web=
of
Science. Results: Of the six articles included, four were in PubMed,=
and
all had been published in international journals. Among the manifestations
observed, olfactory and gustatory disorders stood out. Other manifestations
observed ranged from myalgia, headache, and dizziness to encephalitis and
Guillain-Barré syndrome. Conclusion: Neurological manifestations are
present in patients with SARS-CoV-2/COVID-19, including those not hospitali=
zed,
highlighting olfactory and taste disorders. These may be associated with ea=
rly
and severe COVID-19, and their recognition in infection is therefore essent=
ial.
Despite the occurrence of these manifestations, it is still necessary to
investigate the pathogenic mechanisms and progression of the disease in the
context of the Central Nervous System (CNS) and Peripheral Nervous System (=
PNS).
Keywords: Neurological Manifestations; Coronavirus Infections; Nursing; Pand=
emics;
Review.
RESUMO=
Objetivo: Compreender
as manifestações clínicas neurológicas apresentadas por pacientes com coronavírus da Síndrome Respiratória Aguda Grave 2
(SARS-CoV-2)/Doença Coronavírus 19 (COVID-19). Métodos: Trata-se de revisão integrativa, conduzida em junho d=
e 2020,
com base na pergunta norteadora “Quais as manifestações neurológicas
apresentadas por pacientes com SARS-CoV-2/COVID-19?”, elaborada a partir da
estratégia PICO. A combinação de palavras “SARS-CoV-2” AND “COVID-19” AND “=
neurologic manifestations=
” foi utilizada
na busca em bases de dados Cumulative Index to
Nursing and Allied Health =
Literature
(CINAHL), National Library of Medicine (PubMed),
Scopus e Web of Science. Resultado=
s: Dos
6 artigos incluídos, 4 constavam na PubMed e todos tinham sido publicados em
periódicos internacionais. Dentre as manifestações observadas, as disfunções
olfativas e gustativas foram as que se destacaram. Outras manifestações
observadas envolveram desde a mialgia, dor de cabeça e tontura à encefalite=
e
Síndrome de Guillain-Barré. Conclu=
são: Manifestações neurológicas es=
tão
presentes em pacientes com SARS-CoV-2/COVID-19, incluindo aqueles não
hospitalizados, destacando as disfunções olfativas e gustativas. Estas podem
estar associadas a um quadro de COVID-19 precoce e severo, sendo, portanto,
importante o seu reconhecimento na infecção. Apesar da ocorrência dessas
manifestações, ainda se faz necessária a investigação dos mecanismos
patogênicos e progressão da doença no contexto do Sistema Nervoso Central (=
SNC)
e Periférico (SNP).
INTRODUCTION
Identified since the 1960s, coronaviru=
ses
are enveloped RNA viruses from the Nidovirales order, Coronavi=
ridae family and Coronavirinae
subfamily, whose appearance in electronic microscopy is similar to a crown =
(Latin
– corona)(1). Able to infect animals, including birds, and human beings, they c=
ause
respiratory, gastroenteric, hepatic, and neurological d=
isturbances(2,3). Seven coronavirus strains are currently recognized as human pathogens(4).
In 2002, humankind expe=
rienced
an outbreak caused by the Severe Acute Respiratory Syndrome coronavirus (SA=
RS-CoV), which has, as primary/definitive host, the bat(5). Beginning in Guandong, in southern Ch=
ina,
the infection spread to Southeast Asia, Europe, South Africa, and North
In epidemiological term=
s,
in July 2003, the World Health Organization (WHO) recorded 8,437
cases of SARS, with 813 deaths(6=
).
Although no other outbreak of the disease has been reported since that year(8), there isn’t adequate
knowledge about the pathology of SARS-CoV, hind=
ering
treatment choices and the development of vaccines(5).
Ten years after SARS-CoV,
a new coronavirus was identified, with the dromedary as definitive host and=
Jeddah,
in Saudi Arabia, as the first site of the disease(=
9).
Since that first report, cases of the disease, named Middle East Respiratory
Syndrome (MERS), have been notified throughout the Arabian Peninsula, Asia,
Europe, Africa, and the United States(9).
Specifically, MERS is a condition
triggered by MERS-CoV, whose manifestation vari=
es
from asymptomatic to severe pneumonia, SARS, multiple organ failure, and
Similarly to SARS-CoV,
MERS-CoV initially infects the lower respirator=
y tract(11) and can be transmitted=
via contact
with an infected person or contaminated surface and object. Its pathology is
unclear, hindering treatment and the development of vac=
cines(5).
In December 2019, in Wuhan, China, began an outbre=
ak
caused by a new type of coronavirus, named SARS-CoV-2 by the International
Committee on Taxonomy of Viruses (ICTV). A few months later, SARS-CoV-2 spr=
ead
across all five continents, leading the WHO, in March 2020, to declare an
international public health emergency due to its high capacity for asymptom=
atic
dissemination and transmission(1=
2).
Currently, there is =
strong
evidence that the virus or=
iginated
from bats(13).
According to WHO data(14),
until April 25th, 2021, were reported 146,054,107 cases of
Coronavirus Disease 19 (COVID-19), infection caused by SARS-CoV-2, and
3,092,410 deaths, with greater incidence in America. According to the WHO, =
the
United States, India, and Brazil are among the most affected countries, with
31,656,636, 16,960,172 and 14,237,078 confirmed cases of the disease,
respectively.
Regarding
SARS-CoV-2, this virus, although it has many genetic characteristics simila=
r to
MERS-CoV, shows elevated homology with bat SARS=
and
SARS-CoV(15-16).
Like SARS-CoV and MERS, it=
can
be highly fatal, initially affecting the upper and lower respiratory tract<=
sup>(11).
Its transmiss=
ion
occurs via droplets from the nostrils or oral cavity of infected people,
externalized while speaking, exhaling, coughing, or sneezing. The virus can=
be
transmitted indirectly, through contact with contaminated objects(17)
and through the placenta(18).
Concerning its mechanism of action, SARS-CoV-2 bin=
ds
to the angiotensin converter enzyme 2 (ACE-2) (expressed in epithelial tiss=
ue
of the respiratory tract, endothelium, kidney, pulmonary parenchyma and sma=
ll
bowel cells)(18–20), throu=
gh its
Spike protein (S), a phenomenon followed by endocytosis and activation of t=
his
protein by the transmembrane serine protease 2 (TMPRSS2) (enzyme bound to t=
he
cell membrane located in the vicinity of ACE-2)(21).
Proteolytic
cleavage of protein S by TMPRSS2 can also occur directly, fostering the fus=
ion
between the viral membrane and plasmatic membrane, releasing RNA from the v=
irus
into the cytoplasm. The RNA in the cytoplasm or endosome will activate nucl=
eic
acid detection systems, such as Toll-like receptors, triggering the activat=
ion
of nuclear factor – κβ (NF-κβ) and the production of inflammatory mediators(21).
In cases of SARS-CoV-2 infection, its symptoms have
varied from mild to severe manifestations(11),
having, as typical presentation, fever, cough, myalgia, fatigue, and pneumo=
nia(22).
Mild symptoms range from fever, cough, and shortness of breath to headache,
loss of smell and taste, and sore throat. Severe symptoms include pneumonia,
SARS, and sepsis(11). Epid=
emiological
data indicate that 80% of the contaminated population has mild to moderate =
atypical
pneumonia, 15% progresses to severe pneumonia, and 5% may develop SARS(23).
Regarding neurological symptoms and si=
gns,
due to the similarity between SARS-CoV-2 and other beta coronaviruses, this
type of manifestation and possible complications are not expected(24).
However, reports of these manifestations have been increasingly frequent(25), seeming to occur in
approximately 36% of patients(26). These include headache,
dizziness, cerebrovascular events, anosmia, ageusia, and encephalopathy(25,27).
Despite these occurrences, studies related to SARS-CoV-2 infection of the
Central Nervous System (CNS) and Peripheral Nervous System (PNS) are limited(26).
In this sense, the literature has
suggested the action of immune dysregulation induced by SARS-CoV-2, marked =
by
T-cell depletion and overproduction of cytokines, in the origin of neurolog=
ical
symptoms(25,28). Although =
neuroinvasivity has not yet been confirmed, hematogen=
ous
and neuronal retrograde dissemination are suggested as access routes of the
virus to the CNS(28).
Thus, regardless of the means used by SARS-CoV-2 in the induct=
ion
of possible neurological signs and symptoms, it is necessary to raise aware=
ness
of this reality as an attempt to recognize, treat and manage potentially fa=
tal
neurological complications(27).
In this perspective, Nursing stands out
for the relevant role it plays in combatting COVID-19, providing assistance=
at the
different levels of health care for the individual, family, and community(27). In addition, this
professional category more easily establishes a bond with the patient and
offers them 24-hour assistance(2=
7),
allowing the detection of the most diverse presentations of the disease,
including within the CNS and PNS. =
In view of the above, the study aimed =
to
understand the neurological manifestations presented by patients with
SARS-CoV-2/COVID-19.
METHODS
This is an integrative review, an
Evidence-Based Practice (EBP) method that contributes to the deepening of
knowledge on a given subject. This method enables gathering and synthesizing
results of primary studies, in a systematic and orderly manner, facilitating
the incorporation of evidence for decision making and indicating possible g=
aps
to be clarified in new research in the field(29).
The conduction of this review followed=
six
stages, namely: - identification of the theme and elaboration of the resear=
ch
question; - establishment of criteria for inclusion and exclusion of studie=
s; -
categorization of studies; - evaluation of the studies included in the
integrative review; - interpretation of the results; - synthesis of the kno=
wledge
of the main results evidenced in the analysis of the included articles(29,30).
The
guiding question was elaborated based on the PICO strategy, an acronym whic=
h means
“patient, intervention, comparison and outcome”. Based on this strategy, se=
en
as a relevant resource for the formulation of research questions and search=
for
evidence in the literature(30,31=
),
the review attributed to the letter “P” patient with SARS-CoV-2/COVID-19, “=
I”
and “C” were not applied and “O” was associated with neurological
manifestations. Thus, the following guiding question was obtained: What are=
the
neurological manifestations presented by patients with SARS-CoV-2/COVID-19?=
The search for and analysis of the
articles took place in June 2020, through consultation at the Journal Porta=
l of
the Coordination for the Improvement of Higher Education Personnel (CAPES)/=
Ministry
of Education (MEC), in the following databases: Cumulative Index to Nursing=
and
Allied Health Literature (CINAHL), National Library of Medicine (PubMed),
Scopus, and Web of Science.
For the article search, we used the
controlled descriptor “Neurologic manifestations”, indexed in the Health
Sciences descriptors (DeCS), and the keywords “SARS-CoV-2” and “COVID-19”.
These terms were combined as follows: “SARS-CoV-2” AND “COVID-19” AND “neur=
ologic
manifestations”.
As inclusion criteria, we considered a=
rticles
available in full, in Portuguese, English and Spanish, which answered the g=
uiding
question. The exclusion criteria adopted comprised: repeated publications,
dissertations, case studies and articles that were not related to the objec=
tive
of the review. Study selection followed the recommendations of the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses method – PRISMA(32).
For the data collection and analysis f=
rom
the selected articles, a tool was created based on the study by Ursi
The evidences of the articles were cat=
egorized,
based on the quality or strength of the evidence, which can be characterize=
d in
the following levels: level I - systematic review or meta-analysis; level I=
I -
randomized controlled study; level III - controlled study without
randomization; level IV - case-control study or cohort study; level V -
systematic review of qualitative or descriptive studies; level VI - qualita=
tive
or descriptive study; level VII - opinion or consensus<=
sup>(34).
RESULTS
Through the application of the search
strategy, 1,679 papers were found, of which 986 had been published in 2020.=
Of
these, 481 were in English, Spanish, or Portuguese. After reading the title=
and
abstract, 460 publications were excluded because they were not related to t=
he
objective of the review and 7 were excluded due to duplicity. Of the 14
articles read in full, 5 were excluded because they were case studies and
dissertations and 3 were excluded for not answering the guiding question. T=
hus,
the review consisted of 6 articles (Figure 1).
Figure 1 – Flowcha=
rt
identifying the study selection process to make up the integrative review. =
Redenção - CE, Brazil, 2020
=
Source: =
The
authors
Among the publications included, most =
were
in the PubMed database (n =3D 4) and had been developed in Italy (n =3D 4).=
All
articles were in English and had been published in international journals,
especially in the journal European Archives of Oto-Rhino-Laryngology (n =3D=
3)
(Table 1).
Table 1 -=
Characterization of the publications includ=
ed
in the review, according to the number, database, title, country, and journ=
al. Redenção
- CE, Brazil, 2020.
|
N. |
Database |
Publication
title |
Publication
country |
Journal |
|
1 |
PubMed |
Neurol=
ogic
manifestations in hospitalized patients with COVID-19: the ALBACOVID regi=
stry |
Spain |
Neurol=
ogy |
|
2 |
PubMed |
New
onset of loss of smell or taste in household contacts of home-isolated
SARS-CoV-2-positive subjects |
Italy |
Europe=
an
Archives of Oto-Rhino-Laryngology |
|
3 |
PubMed |
Olfactory and
gustatory dysfunctions in 100 patients hospitalized for COVID-19: sex
differences and recovery time in real-life |
Italy |
Europe=
an
Archives of Oto-Rhino-Laryngology |
|
4 |
PubMed |
Subjective
neurological symptoms frequently occur in patients with SARS-CoV-2 infect=
ion |
Italy |
Brain,=
Behavior,
and Immunity |
|
5 |
Web
of Science |
Olfactory and
gustatory dysfunctions as a clinical presentation of mild-to-moderate for=
ms
of the coronavirus disease (COVID-19): a multicenter European study |
Italy,
Belgium, and Spain |
Europe=
an
Archives of Oto-Rhino-Laryngology |
|
6 |
Web
of Science |
Olfactory dysfunct=
ion
and sinonasal symptomatology in COVID-19:
prevalence, severity, timing, and associated characteristics |
Switzerland |
Otolar=
yngology–
Head and Neck Surgery |
Source: The authors
Regar=
ding
the objectives of the studies, they aimed to identify, quantify and
characterize neurological manifestations related to SARS-CoV-2 infection, as
well as to establish the recovery time and severity of these manifestations=
and
associate them with classic symptoms of COVID-19. Regarding the type of stu=
dy
and level of evidence, most publications were descriptive studies (n =3D 4)=
, and
all had level VI of evidence (Table 2).
Table 2 - Characterization of the
publications included in the review, according to the number, objective, ty=
pe of
study and evidence level. Redenção - CE, Brazil,
2020.
|
N. |
Object=
ive |
Type of
study |
Eviden=
ce
level |
|
1 |
To det=
ermine
the common neurological manifestations in hospitalized patients with SARS=
-CoV-2
and describe their main characteristics. |
Observ=
ational
and retrospective |
VI |
|
2 |
To est=
imate
the prevalence of impaired smell or taste in slightly symptomatic SARS-Co=
V-2 patients
isolated at home. |
Cross-=
sectional |
VI |
|
3 |
To
investigate the recovery time for olfactory and gustatory dysfunctions in=
a
cohort of patients with SARS-CoV-2 hospitalized at non-intensive care war=
ds
one month before the research. |
Descri=
ptive |
VI |
|
4 |
To ide=
ntify
and quantify the occurrence of subjective neurological symptoms in
hospitalized patients with SARS-CoV-2 infection. |
Observ=
ational
and descriptive |
VI |
|
5 |
To inv=
estigate
and characterize the occurrence of olfactory and gustatory dysfunctions in
patients with SARS-CoV-2 infection confirmed by a laboratory. |
Descri=
ptive |
VI |
|
6 |
To characterize the prevalence, timing and
severity of olfactory dysfunction reported by the patient, as well as oth=
er sinonasal symptoms and their association with class=
ic
symptoms of SARS-CoV-2, such as fever, cough, and shortness of breath. |
Descri=
ptive |
VI |
Source: =
The
authors
Through detailed reading of the results presented =
by
the articles, it was possible to identify neurological manifestations in
patients with SARS-CoV-2, with the most reported being olfactory and gustat=
ory
dysfunctions. Other manifestations observed ranged from myalgia, headache, =
and
dizziness to encephalitis and Guillain-Barré syndrome (Table 3).
Table 3 - Characterization of the
publications included in the review, according to the number and main resul=
ts. Redenção - CE, Brazil, 2020.
|
Main results |
|
|
1 |
Out of 841 patients, 57.4%
developed at least one neurological symptom. The most frequent symptoms w=
ere
myalgia (17.2%), headache (14.1%), and dizziness (6.1%).
Symptoms associated with cranial nerves were anosmia (4.9%) and dysgeusia
(6.2%). Consci=
ousness
disorders were the most repeatedly observed neurological symptoms (19.6%).
Other symptoms described were myopathy (1.3%), dysautonomia (2.5%),
cerebrovascular diseases (1.7%), seizures (0.7%), movement disorders (0.7=
%),
encephalitis (0.1%), Guillain-Barré syndrome (0.1%), and optic neuritis (=
0.1%). |
|
2 |
Out of 296 interviewees who had
home contact with patients infected with SARS-CoV-2, 74 reported loss of smell or taste. Among 121 submitted to serol=
ogical
test, 54 had a positive result for COVID-19 and 34 presented loss of smell and taste. Among the 175 who did not u=
ndergo
the test, 67 had common symptoms of SARS-CoV-2 infection and 39 had loss =
of
smell and taste. |
|
3 |
Among 100 patients included in=
the
study, 42 reported subjective chemosensory dysfunctions. Of these, 41 cit=
ed
gustatory dysfunction, 29 olfactory and 28 both. All reported the occurre=
nce
of these symptoms in the first week or considered them as the first sympt=
oms
observed. The mean duration of olfactory and gustatory dysfunction was 18=
and
16 days, respectively. |
|
4 |
Of the 103 patients with confi=
rmed
SARS-CoV-2 infection included in the analysis, 94 reported at least one
neurological symptom. Sleep impairment was the most frequent (49.51%),
followed by dysgeusia (46.60%), headache (38.83%), and hyposmia (37.86%).=
|
|
5 |
Among 417 patients, 85.6% and
88.0% reported the presence of olfactory and gustatory dysfunctions,
respectively. There was a significant positive association between olfact=
ory
and gustatory dysfunctions. In 11.8% of cases, olfactory dysfunction appe=
ared
before other symptoms. The scores of the Questionnaire of Olfactory Disor=
ders
– Negative Statements were significantly lower in patients with anosmia
compared to individuals with normosmia or hyp=
osmia. |
|
6 |
The prevalence of olfactory
dysfunction was 61.2% and its severity was significantly correlated with =
the
severity of the loss of taste experienced by the patient. In 8.7% of the participants,
olfactory dysfunction was experienced on the first day of SARS-CoV-2,
becoming generalized on the third day of infection. Among patients with
olfactory dysfunction, 95.2% had at least one of the following symptoms:
fever, cough, or shortness of breath. |
Source: =
The authors
DISCUSSION
This integrative review evidenced the
neurological manifestations related to COVID-19, whose importance is ground=
ed,
in addition to the associated consequences, on the possibility of correspon=
ding
to the first signs of infection in so-called asymptomatic patients or patie=
nts with
mild symptoms and occurring in individuals in the process of recovery from =
non-neurological
manifestations a few weeks prior(
After evaluating the number of studies
included in this research, according to database, the highlight of PubMed e=
mphasizes
the fact that it is the largest database available since 1996, consisting of
more than 26 million citations of Medline, life sciences journals, and onli=
ne
books. In addition, it displays access links to full texts in the citations=
of
PubMed Central(39).
As for the journal of publication, the
fact that all the articles included have been published in international
journals can be justified based on the fact that COVID-19 did not begin in
Brazil and became a global pandemic(<=
sup>40).
We can also propose, as possible reasons for that, the distribution range a=
nd the
impact that a paper achieves when published in this type of journal.
In particular, for the largest number =
of
productions included here that were published in the journal European Archi=
ves
of Oto-Rhino-Laryngology, this finding can be explained if it is understood
that it represents the Official Journal of the European Confederation of
Otorhinolaryngology and Head and Neck Surgery, in addition to its agility in
disseminating information related to basic sciences and diagnosis and treat=
ment
of head and neck diseases internationally(38).
It is also possible that this phenomen=
on
occurred, considering that all the studies included in this review were
developed in European countries, due to Europe having been the epicenter of
SARS-CoV-2(41). In this sense, it should be mentioned that the
spread of the virus in Europe was marked by an atypical presentation of the
disease, especially in patients with olfactory and gustatory dysfunction(42).
Concerning the country of publication,=
the
emphasis on Italy can be based on the fact that it was the most affected Eu=
ropean
country at the beginning of the pandemic(14).
For the predominance of the English language among the articles of this res=
earch,
this data can be understood considering that these journals publish their w=
orks
in that language and because this is one of the strategies used for scienti=
fic internationalization(43).
Regarding the objectives, although the
studies present different focuses, such as determining<=
sup>(44)
(article n. 1), estimating the prevalence(42) (article n. 2),
identifying(45) (article n. 4), characterizing(38) (a=
rticle
n. 5) and establishing the recovery time and severity of these manifestatio=
ns
and associating them to the classic symptoms of COVID-19(35)
(article n. 6), we perceive the real need to understand the relationship
between these manifestations and SARS-CoV-2 infection. Furthermore, it was
noticeable that olfactory and gustatory dysfunction stood out among the stu=
dies’
objectives(35,36,38,42).
Concerning the type of study, there wa=
s a
predominance of descriptive studies. This result can be justified by the
current and emerging nature of the disease, since descriptive studies aim to
determine the distribution of health-related conditions, in order to descri=
be a
certain phenomenon based on its characteristics(46).
Despite its importance, this type of study does not aim to evaluate a possi=
ble
relationship between the cause of the disease and its e=
ffect(47).
As for the evidence level, all studies
were classified with low evidence level, signaling the need for further res=
earch
with greater methodological rigor on neurological manifestations related to
SARS-CoV-2 infection.
Through the analysis of the main resul=
ts
of the studies, it was observed that patients infected with SARS-CoV-2
presented, as more recurrent neurological manifestations, olfactory and
gustatory dysfunction (articles n. 2-6). In this context, it is worth
mentioning that olfactory dysfunction is a pathological alteration characte=
rized
by the partial or total inability to detect or distinguish volatile chemicals(48). It is multifactor=
ial
and may be related to obstructive nasal and sinus diseases, upper respirato=
ry
tract infections, traumatic brain injury, aging, exposure to toxics and some
medications, nasal or intracranial neoplasia, psychiatric pathologies,
iatrogenic, and idiopathic or congenital causes(49).
On gustatory dysfunction, it is
characterized by loss or decrease in gustation, through the interaction bet=
ween
multicausative factors and sensory receptors of=
the
oral cavity(49). In additi=
on to
taste buds, gustatory dysfunction is directly related to chemical receptors,
mechanoreceptors, thermoreceptors and nociceptors(=
50).
Regarding the mechanisms through which
SARS-CoV-2 acts interfering in the neurological system of infected patients,
two main routes of transmission are suggested: hematogenous dissemination a=
nd
neuronal retrograde dissemination. The first is secondary to a viremia, whi=
ch
triggers Systemic Inflammatory Response Syndrome (SIRS). This fosters
mechanisms of intracellular, paracellular and transcellular penetration thr=
ough
the blood-brain barrier. In the second, the invasion of the CNS occurs via
transport of peripheral neurons invaded by the virus
Specifically, for olfactory and gustat=
ory
dysfunction, the literature is unclear regarding pathophysiological mechani=
sms.
According to Meini et al.
It is also speculated that the infecti=
on
of support cells and regenerative stem cells of olfactory neurons inhibits =
the
function of the latter, triggering anosmia. Another hypothesis would be
infection of the CNS by coronavirus, via cribriform plate, causing an
inflammatory response capable of reducing sensitivity to smell(52).
For dysgeusia, it is speculated that h=
igh
levels of pro-inflammatory cytokines, such as tumor necrosis factor – α
(TNF-α), interferon – γ (INF-γ) and interleukin – 6 (IL-6),
induced by COVID-19, may inhibit the proliferation of stem cells and decrea=
se
the half-life of mature cells of taste buds(=
52).
Thus, olfactory and gustatory dysfunct=
ion
can be considered a marker of SARS-CoV-2 infection, especially in situations
where the test capacity is limited(
In addition to these manifestations, t=
he
included studies revealed that patients infected with SARS-CoV-2 could pres=
ent recurrent
headache (articles n. 1 and 4), sleep impairment (article n. 4), myalgia and
dizziness (article n. 1). As for headache, this symptom may be related to
increased permeability of the blood-brain barrier due to cytokine productio=
n,
triggering a neuronal disorder of inflammatory nature
Regarding myalgia, this can be caused =
by
the intense inflammatory response induced by SARS-CoV-2, which increases the
levels of cytokines, including IL-6, whose positive regulation causes muscle
and joint pain(55). Another
hypothesis associated with myalgia is based on the elevation of lactate
dehydrogenase, due to the damage caused by the virus in muscle tissue, and
lactate and decreased cytoplasmic pH and oxygen levels<=
sup>(56).
For dizziness, the literature points out, as possible mechanisms, direct in=
vasion
of the nervous system, hypoxia, hypercoagulopathy and
immune-mediated insults(57).
Among other neurological manifestations
presented in the articles, dysautonomia, conceptualized as the failure or
hyperactivity of the Autonomic Nervous System (ANS)
On cerebrovascular diseases, ischemic =
cerebrovascular
accident, although the mechanisms involved are not yet clear, has been
associated with a state of hypercoagulability(59).
As for intracranial hemorrhage, this has been related to the elevation of b=
lood
pressure as a consequence of the binding of SARS-CoV-2 to ACE-2(53).
As for convulsion, it can result from
hypoxia, metabolic disorders, organ failure, and brain =
damage(60).
On encephalitis, characterized by inflammatory lesions in the brain(61), although its mechanis=
m is
not clear, it is suggested that it originates from an inflammatory response=
to SARS-CoV-2,
capable of raising the levels of interleukins and ACE in the cerebrospinal
fluid(62).
Concerning optic neuritis, it can occu=
r if
we consider that SARS-CoV-2 can be transported by the optic nerve(63).
As for Guillain-Barré Syndrome, considered as an autoimmune process that
affects peripheral nerves and induces a demyelinating n=
europathy(64),
Morsy’s hypothesis(65) suggests that=
the
NCAM protein (neuronal cell adhesion molecule) is responsible for the devel=
opment
of the syndrome in patients with SARS-CoV-2, in the presence of HLA-A*68 and
HLA-DQA1/HLA-DQB1.
Regarding myopathy, observed in patien=
ts
with the severe form of COVID-19, its development has been attributed to the
injury of peripheral nerves and striated muscle by the virus, as well as the
presence of vascular events, both thrombotic and ischem=
ic(66).
Concerning movement disorders, when
sitting (twisted movements of the lower limb), walking (ataxic gait) or at =
rest
(spasmodic movements in supine position), they may express an involvement of
the CNS and PNS. As for sleep impairment, it may be associated with
hospitalization, a phenomenon capable of triggering insomnia symptoms(67-68).
Regarding the limitations of the study=
, we
can mention the small number of publications included in this review, despi=
te a
comprehensive search in four databases of international relevance. This
phenomenon suggests the need to conduct more research on the theme addresse=
d.
CONCLUSIONS
It can be concluded that neurological
manifestations are present in patients with SARS-CoV-2/COVID-19, including
those who are not hospitalized, with emphasis on olfactory and gustatory
dysfunctions. These may be associated with early and severe COVID-19 condit=
ions,
and therefore their recognition in infection is important.
In addition to these dysfunctions, oth=
er
neurological signs and symptoms, such as myalgia, headache, dizziness, and
cerebrovascular diseases, are observed in patients with COVID-19. Regardles=
s of
this form of disease presentation, it should be considered, since it is cap=
able
of compromising the well-being and life of human beings.
Despite the occurrence of neurological
manifestations induced by SARS-CoV-2, it is still necessary to investigate =
the
pathogenic mechanisms and progression of the disease in the context of the =
CNS
and PNS.
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Corresponding author: Ana Caroline Rocha de Melo Leite, Un=
iversidade
da Integração Internacional da Lusofonia Afro-Brasilie=
ra
– Campus das Auroras – Rua José Franco de Oliveira, s/n, CEP – 62.790-970 –
Redenção – Ceará, fone (85) 99168-0679 e e-mail acarolmelo@unilab.edu.br
Submission: 2021-05-08
Approval: 2021-06-10
[1]=
Universidade da Integração
Internacional da Lusofonia Afro-Brasileira (UNILAB), Redenção, Brasil. ORCI=
D https://orcid.org/0000-0003-2551=
-9143
[2]=
Universidade da Integração
Internacional da Lusofonia Afro-Brasileira (UNILAB), Redenção, Brasil. ORCI=
D https://orcid.org/0000-0003-1826=
-2247
[3]=
Universidade da Integração
Internacional da Lusofonia Afro-Brasileira (UNILAB), Redenção, Brasil. ORCI=
D https://orcid.org/0000-0002-4127=
-0424
[4]=
Universidade da Integração
Internacional da Lusofonia Afro-Brasileira (UNILAB), Redenção, Brasil. ORCI=
D https://orcid.org/0000-0003-2937=
-6960
[5]=
Universidade Federal do Ceará (UFC),
Fortaleza, Brasil. ORCID https://orcid.org/0000-0003-0245-3110
[6]=
Universidade da Integração
Internacional da Lusofonia Afro-Brasileira (UNILAB), Redenção, Brasil. ORCI=
D https://orcid.org/0000-0002-2333-5343
[7]=
Universidade da Integração In=
ternacional
da Lusofonia Afro-Brasileira (UNILAB), Redenção, Brasil ORCID https://orcid.org/0000-0002-9007-7970