Neurological Complications of COVID-19: Underlying Mechanisms and Management

Download as pdf or txt
Download as pdf or txt
You are on page 1of 21

International Journal of

Molecular Sciences

Review
Neurological Complications of COVID-19: Underlying
Mechanisms and Management
Ghaydaa A. Shehata 1 , Kevin C. Lord 2 , Michaela C. Grudzinski 3 , Mohamed Elsayed 4 , Ramy Abdelnaby 5
and Hatem A. Elshabrawy 6, *

1 Department of Neurology and Psychiatry, Assiut University Hospitals, Assiut 71511, Egypt;
ghaidaa.abozaid@med.aun.edu.eg
2 Department of Physiology and Pharmacology, College of Osteopathic Medicine, Sam Houston State University,
Conroe, TX 77304, USA; kcl043@shsu.edu
3 College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA; mcg043@shsu.edu
4 Department of Psychiatry and Psychotherapy III, University of Ulm, Leimgrubenweg 12-14, 89075 Ulm, Germany;
mohamed.elsayed@uni-ulm.de
5 Department of Neurology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany;
rabdelnaby@ukaachen.de
6 Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University,
Conroe, TX 77304, USA
* Correspondence: hatem.elshabrawy@shsu.edu; Tel.: +1-(936)-202-5216

Abstract: COVID-19 is a severe respiratory disease caused by the newly identified human coron-
avirus (HCoV) Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The virus was
discovered in December 2019, and in March 2020, the disease was declared a global pandemic by the

 World Health Organization (WHO) due to a high number of cases. Although SARS-CoV-2 primarily
Citation: Shehata, G.A.; Lord, K.C.;
affects the respiratory system, several studies have reported neurological complications in COVID-19
Grudzinski, M.C.; Elsayed, M.; patients. Headache, dizziness, loss of taste and smell, encephalitis, encephalopathy, and cerebrovascu-
Abdelnaby, R.; Elshabrawy, H.A. lar diseases are the most common neurological complications that are associated with COVID-19. In
Neurological Complications of addition, seizures, neuromuscular junctions’ disorders, and Guillain–Barré syndrome were reported
COVID-19: Underlying Mechanisms as complications of COVID-19, as well as neurodegenerative and demyelinating disorders. However,
and Management. Int. J. Mol. Sci. the management of these conditions remains a challenge. In this review, we discuss the prevalence,
2021, 22, 4081. https://doi.org/ pathogenesis, and mechanisms of these neurological sequelae that are secondary to SARS-CoV-
10.3390/ijms22084081 2 infection. We aim to update neurologists and healthcare workers on the possible neurological
complications associated with COVID-19 and the management of these disease conditions.
Academic Editor: Jordi Pérez-Tur

Keywords: SARS-CoV-2; COVID-19; encephalitis; encephalopathy; seizures; neurological; manage-


Received: 26 March 2021
ment; cerebrovascular; stroke; Guillain–Barré syndrome; headache; myalgia; dizziness
Accepted: 13 April 2021
Published: 15 April 2021

Publisher’s Note: MDPI stays neutral


with regard to jurisdictional claims in
1. Introduction
published maps and institutional affil- In December 2019, the novel coronavirus, Severe Acute Respiratory Syndrome
iations. Coronavirus-2 (SARS-CoV-2), was identified as the causative agent of the acute atypi-
cal cluster of pneumonia cases in the city of Wuhan, China [1]. In February 2020, the
World Health Organization (WHO) named the disease COVID-19 [2]. Although initially
identified by respiratory symptoms, there have been increasing reports describing the
Copyright: © 2021 by the authors. copresentation of nonspecific neurological symptoms, including headache, dizziness, fa-
Licensee MDPI, Basel, Switzerland. tigue, and myalgia, impacting greater than 80% of all hospitalized patients [3]. What had
This article is an open access article previously been described only by pulmonary symptoms is now recognized by multiple
distributed under the terms and neurological complications. Current data correlate the acuity of COVID-19 and mortality
conditions of the Creative Commons in critical care patients to the severity of neurological diseases, including acute necrotizing
Attribution (CC BY) license (https:// encephalopathy, encephalitis, epilepsy/seizures, and ataxia, increasing the risk of brain
creativecommons.org/licenses/by/ damage [4]. Additionally, peripheral nervous system (PNS) complications have been re-
4.0/).

Int. J. Mol. Sci. 2021, 22, 4081. https://doi.org/10.3390/ijms22084081 https://www.mdpi.com/journal/ijms


Int. J. Mol. Sci. 2021, 22, 4081 2 of 21

ported, including hypogeusia, hyposmia, Guillain–Barré syndrome, and skeletal muscle


injury [5].
In this review, we aim to provide updates to the most current neurological complica-
tions resulting from COVID-19 and the treatment guidelines for these conditions.

2. Search Strategy and Selection Criteria


We performed a systematic search on PubMed utilizing the search terms “Coronavirus
and Neurological,” “SARS-COV-2 and Neurological,” and “COVID-19 and management
strategies (neurological or stroke or encephalitis or encephalopathy or seizures)” published
between January 2019 and February 2021, yielding 5378 articles. We further filtered for
articles in English, yielding 5212. After duplications and articles not relevant to the purpose
of this review, we evaluated over 750 publications resulting in the 241 we used to support
our review.

3. Coronaviruses and Neurological Complications


The blood–brain and blood–cerebrospinal fluid (CSF) barriers are structured to prevent
the invasion of the brain by pathogens and toxic molecules [6]; however, this is not totally
impermeable. There are multiple mechanisms by which neurotropic viruses are able to
traverse the blood–brain barrier (BBB), but the most common route is the hematogenous
route, which starts by entering the bloodstream causing viremia [7,8]. Once in the blood,
viruses are able to cross the BBB via transcytosis or the infection of endothelial cells [9,10],
infected monocytes (“Trojan Horse” mechanism) [9], and paracellularly via disrupted tight
junctions in the endothelial cells due to inflammation caused by the viremia [7,9]. Another
route not dependent on viremia includes the coordination of dynein and kinesins proteins
in the transport of the virus into the CNS using infected motor or sensory nerves [7].
Viruses can also enter the CNS through olfactory sensory neurons [7]. The latter is a more
common route for respiratory coronaviruses [10].
To date, seven CoVs have been associated with diseases in humans, which include
HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-HKU1, Middle East Respiratory Syndrome-
CoV (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), and
most recently SARS-CoV-2 [11–14]. Only SARS-CoV, MERS-CoV, and SARS-CoV-2 are
recognized as causative agents of severe respiratory diseases, whereas all other human
coronaviruses (HCoVs) typically present as mild diseases [15–17].
Not different from many other viruses [7,18], CoVs are known to cause neurologi-
cal complications [19–23]. However, the neuroinvasive mechanisms have not been well
understood. Murray et al. presented the first evidence of the association of HCoVs with
neurological disease in multiple sclerosis (MS) patients [24,25], with later studies con-
firming HCoV-229E and HCoV-OC43 in patients diagnosed with Parkinson’s disease,
Schizophrenia, Alzheimer’s disease, and meningoencephalitis [26]. A potential mechanism
for CNS infection was suggested in a 2004 case study reporting the presence of HCoV-OC43
in nasopharyngeal and CSF samples of a child who was diagnosed with acute disseminated
encephalomyelitis [19]. These findings were supported by St-Jean et al., who described the
route of HCoV-OC43 infection of mice CNS through the olfactory bulb seven days after
a nasal infection leading to acute encephalitis [20]. Additional murine studies confirmed
the development of acute encephalitis in HCoV-OC43-infected BALB/c mice and HCoV-
OC43-induced apoptosis in mice and rat neuronal cells [27]. These findings highlight the
neurotropic characteristics of HCoVs and their ability to infect the CNS.
Soon after the emergence of SARS-CoV in 2002–2003, neurological complications were
reported in SARS-CoV patients [28]. In addition to regular symptoms, such as fever, chills,
productive cough, and diarrhea, patients developed neurological complications such as
seizures, convulsions, and loss of consciousness during the course of the disease [29]. Tests
later confirmed the presence of SARS-CoV in the CSF. With the new awareness of the
pervasiveness of the disease, the examination of samples from patients who have died
of SARS-CoV has revealed the presence of the SARS-CoV-N protein and viral RNA in
Int. J. Mol. Sci. 2021, 22, 4081 3 of 21

several organs, including the stomach, small intestine, kidney, sweat glands, liver, and
cerebrum [30]. The neurotropic property of SARS-CoV was further confirmed by a study
in C57BL/6 mice, which showed that intranasal infection of mice eventually led to the
infection of mice brain [31]. The previous findings indicate that SARS-CoV is capable of
causing systemic infections, including CNS infections. In 2016, a study showed that some
children who suffered acute encephalitis had a concurrent HCoV infection [32].
Similar to other HCoVs, SARS-CoV-2 has been associated with neurological compli-
cations, which are now recognized as initial symptoms in conjunction with the typical
respiratory manifestations [33]. The most common neurological manifestations include
headache, lethargy, unstable gait, ataxia, and seizures, in addition to PNS manifestations
such as loss of taste and smell, vision impairment, nerve pain, and malaise [34]. The most
serious developing neurological diseases include polyneuritis, Guillain–Barré syndrome
(GBS), meningitis, encephalitis, and encephalopathy, in addition to cerebral hemorrhage
and infarction [34]. Liotta et al., in a study of 509 COVID-19 patients, showed that 82%
of these patients experienced neurological complications, which manifest early in 42% of
patients and in 63% of patients at hospitalization [3]. Adjusting for age and severity of
disease, younger patients and those presenting with severe COVID-19 are more likely to
present with neurological manifestations, while older patients are more likely to develop a
neurological disease (encephalopathies). These findings have been further supported by
another study of 214 patients. In this study, 78 patients (36.4%) suffered from neurological
consequences to COVID-19 [35]. These neurological complications manifest as CNS-related
complications, such as dizziness, headache, impaired consciousness, acute cerebrovascular
disease, ataxia, and seizure, or as PNS manifestations, such as loss of taste and smell,
vision impairment, and nerve pain, as well as skeletal muscular injury. There was a higher
incidence of neurological complications in patients with severe COVID-19 than in mild
COVID-19 patients.
All the previous manifestations depend on the SARS-CoV-2 infection of host target
cells; primarily unciliated bronchial epithelial cells and type II pneumocytes in the lung,
after binding to cell surface receptors; angiotensin-converting enzyme 2 (ACE2), basigin
(BSG; CD147), and neuropilin-1 (NRP-1) [36–38]. Cellular proteases such as TMPRSS2,
furin, and cathepsins are required for priming the viral spike (S) protein, a process that is
essential for viral entry after binding to host cell receptors [36]. Human brain single-nuclear
RNA sequencing (RNA-seq) data suggest low or no expression of ACE2 on different human
brain cells and its microvasculature [39]. However, higher expression of other SARS-CoV-2
receptors, such as BSG and NRP-1, was reported in many brain cell types [39]. Moreover,
host cell proteases are also expressed at different levels in most brain cells [39]. The previous
findings suggest that the brain may be susceptible to SARS-CoV-2 invasion and infection.

4. Mechanisms of SARS-CoV-2 Invasion of the CNS


Studies have reported the presence of SARS-CoV-2 in the CSF and postmortem brain
tissue of COVID-19 patients with encephalitis [40–48]. However, there are contradictory
findings that may indicate that the neurological complications are due to severe systemic
inflammation and not the direct invasion of the brain [49–56].
It has been suggested that SARS-CoV-2 could invade the CNS via the same routes
as other HCoVs [hematogenous route (Figure 1A) or by using retrograde or antegrade
transport mechanisms from peripheral nerves to the CNS (Figure 1B)] [33,40,57–61].
One possible mechanism of the hematogenous route is binding to SARS-CoV-2 recep-
tors on BBB endothelial cells, passing through endothelial cells by transcytosis, and finally
reaching the brain (Figure 1A) [40,62]. The infection of endothelial cells does not involve
any viral replication [33]. Because BSG and NRP1 are more highly expressed than ACE2
in the brain microvasculature, it is more likely that the SARS-CoV-2 would utilize these
receptors to enter the CNS [39]. The other proposed mechanism involves infecting immune
cells that express ACE2, such as monocytes, granulocytes, and lymphocytes, (“Trojan horse”
mechanism) (Figure 1A) [63–67]. The infected immune cells may then carry SARS-CoV-2
Int. J. Mol. Sci. 2021, 22, 4081 4 of 21

to the CNS, where it can infect the brain [68]. SARS-CoV-2 viral RNA was detected in the
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW
lung macrophages of COVID-19 patients; however, viral replication in immune cells and4 of 22
immune infiltration of the brain need to be confirmed [69]. One additional mechanism is
passing through disrupted endothelial cells’ tight junctions (paracellular route) (Figure 1A).

Figure 1. Mechanisms
Figure 1. Mechanisms of SARS-CoV-2
of SARS-CoV-2 invasion
invasionof ofthe
the CNS. (A) Hematogenous
CNS. (A) Hematogenous route:
route: Severe
Severe Acute
Acute Respiratory
Respiratory Syndrome
Syndrome
Coronavirus-2 (SARS-CoV-2) invasion of CNS from the bloodstream is mediated by three mechanisms; 1. Transcellular
Coronavirus-2 (SARS-CoV-2) invasion of CNS from the bloodstream is mediated by three mechanisms; 1. Transcellular
migration which
migration involves
which binding
involves binding ofofthethevirus
virustoto its
its receptors; ACE2,basigin
receptors; ACE2, basigin (BSG),
(BSG), or neuropilin-1
or neuropilin-1 (NRP-1),
(NRP-1), on brain
on brain
microvasculature
microvasculatureendothelial
endothelialcells
cellsthen crossingendothelial
then crossing endothelial cellscells via transcytosis,
via transcytosis, 2. Infecting
2. Infecting immuneimmune cells
cells which thenwhich
carry then
carrythe
thevirus
virusacross
acrossthethe blood–brain
blood–brain barrier
barrier (BBB)(BBB) endothelial
endothelial cells
cells into theinto
CNSthe CNSHorse
(Trojan (Trojan Horse mechanism),
mechanism), and 3. Para-
and 3. Paracellular
cellular route
route by disrupting
by disrupting endothelial
endothelial cells’
cells’ tight tight junctions.
junctions. (B) SARS-CoV-2
(B) SARS-CoV-2 infects
infects olfactory olfactoryand
epithelium epithelium and
reaches the CNSreaches
via the
CNS the
via olfactory
the olfactory neurons.
neurons. This was
This figure figure was with
created created with BioRender.com.
BioRender.com.

OneAs possible
mentionedmechanism
earlier, SARS-CoV-2 may also reach the
of the hematogenous CNS is
route viabinding
peripheral
tonerves, more re-
SARS-CoV-2
specifically the olfactory sensory neurons (Figure 1B) [57,58]. The high expression of ACE2
ceptors on BBB endothelial cells, passing through endothelial cells by transcytosis, and
and the priming protease, transmembrane serine protease 2 (TMPRSS2), in sustentacular
finally reaching the brain (Figure 1A) [40,62]. The infection of endothelial cells does not
cells, stem cells of the olfactory epithelium, and olfactory bulb may allow for retrograde or
involve any transport
antegrade viral replication [33]. [61,70–74].
into the CNS Because BSG and NRP1 are more highly expressed than
ACE2 in the brain microvasculature, it is more likely that the SARS-CoV-2 would utilize
5. Neurological
these receptors toDisorders
enter theandCNS Their
[39].Management in COVID-19
The other proposed Patients involves infecting
mechanism
5.1. Cerebrovascular
immune Diseases ACE2, such as monocytes, granulocytes, and lymphocytes,
cells that express
Cerebrovascular
(“Trojan horse” mechanism) complications
(Figurehave
1A)been documented
[63–67]. in 5% ofimmune
The infected COVID-19 patients,
cells may then
withSARS-CoV-2
carry 60% of these events
to theattributed
CNS, where to an it
acute
canischemic
infect thestroke
brain[35,75,76]. The increasedviral
[68]. SARS-CoV-2 risk RNA
of these events is believed to be due to a hyperinflammatory/hypercoagulable
was detected in the lung macrophages of COVID-19 patients; however, viral replication state, and
altered endothelial cell function resulting from the SARS-CoV-2 infection (Figure 2) [77–81].
in immune cells and immune infiltration of the brain need to be confirmed [69]. One ad-
Several studies have reported a significant increase in neutrophil-to-lymphocyte ratio
ditional
(NLR),mechanism is passing
C-reactive protein (CRP),through
and serum disrupted endothelial
ferritin in COVID-19cells’ tight
patients withjunctions
ischemic(para-
cellular route) (Figure 1A).
stroke, which could predict mortality in these patients [82–87]. Neutrophilia (increase
in As mentioned
neutrophils) earlier,inSARS-CoV-2
described these patientsmay alsoinreach
results the CNS via peripheral
the overproduction of neutrophil nerves,
more specifically
extracellular the
traps olfactory
(NETs), whichsensory
has been neurons
shown to (Figure 1B)thrombi
increase [57,58].formation
The high[88–90].
expression
of Furthermore,
ACE2 and the hypercoagulability
priming protease, andtransmembrane
the increase in thrombi
serine formation
protease 2in(TMPRSS2),
COVID-19 pa- in sus-
tentacular cells, stem cells of the olfactory epithelium, and olfactory bulb may allow for
retrograde or antegrade transport into the CNS [61,70–74].

5. Neurological Disorders and Their Management in COVID-19 Patients


[77–81]. Several studies have reported a significant increase in neutrophil-to-lymphocyte
ratio (NLR), C-reactive protein (CRP), and serum ferritin in COVID-19 patients with is-
chemic stroke, which could predict mortality in these patients [82–87]. Neutrophilia (in-
Int. J. Mol. Sci. 2021, 22, 4081 crease in neutrophils) described in these patients results in the overproduction of5 ofneutro- 21
phil extracellular traps (NETs), which has been shown to increase thrombi formation [88–
90]. Furthermore, hypercoagulability and the increase in thrombi formation in COVID-19
patients could be explained by impaired fibrinolysis, low levels of natural anticoagulants,
tients could be explained by impaired fibrinolysis, low levels of natural anticoagulants,
and highlevels
and high levelsofofcoagulation
coagulation factors
factors andand antiphospholipid
antiphospholipid antibodies
antibodies [91–94].
[91–94]. The for-
The forma-
mation of thrombi is further potentiated by SARS-CoV-2-mediated
tion of thrombi is further potentiated by SARS-CoV-2-mediated damage of the endothe-damage of the endo-
thelium,
lium, whichwhich results
results in nitric
in nitric oxideoxide synthase
synthase (NOS) (NOS) depletion
depletion and subsequent
and subsequent deficiency
deficiency of
of
NO NO [95].
[95]. NONO deficiency
deficiency increases
increases theofrisk
the risk of stroke
stroke becausebecause
NO is aNO is a vasodilator
potent potent vasodilator
and
and an inhibitor
an inhibitor of platelets
of platelets and leukocytes
and leukocytes adhesion adhesion to the endothelium
to the endothelium [95]. [95].

Mechanisms of
Figure2.2.Mechanisms
Figure of COVID-19 neurological
neurologicalcomplications.
complications.Lung Lunginfection
infectionbyby
SARS-CoV-2
SARS-CoV-2 results in severe
results inflam-
in severe inflam-
mation,
mation,acute
acuterespiratory
respiratorydistress
distresssyndrome
syndrome (ARDS),
(ARDS), and hypoxia. This This leads
leads to
to hypoxia-
hypoxia- and inflammation-induced
inflammation-induced en-
cephalopathy
encephalopathy and seizures.
and Brain
seizures. Braindamage
damagedueduetoto viral
viral replication maylead
replication may leadtotoencephalitis.
encephalitis. Severe
Severe systemic
systemic inflammation
inflammation
could
couldresult
resultin
in hypercoagulability
hypercoagulability whichwhichmay
mayeventually
eventuallyleadleadtoto stroke.
stroke. Nonspecific
Nonspecific symptoms
symptoms duedue to nervous
to nervous system
system
affections
affections include headache, dizziness, loss of taste and smell, and myalgia. Usage of ACE2 receptor; by SARS-CoV-2, to to
include headache, dizziness, loss of taste and smell, and myalgia. Usage of ACE2 receptor; by SARS-CoV-2,
infect
infecttarget
targetcells,
cells, including endothelial cells,
including endothelial cells,would
woulddeplete
depletethethereceptor
receptor resulting
resulting in the
in the accumulation
accumulation of angiotensin
of angiotensin II II
(AngII). High levels of AngII promote vasoconstriction, fluid retention, inflammation, and blood coagulation,
(AngII). High levels of AngII promote vasoconstriction, fluid retention, inflammation, and blood coagulation, which could which could
result in ischemic or hemorrhagic stroke. This figure was created with BioRender.com.
result in ischemic or hemorrhagic stroke. This figure was created with BioRender.com.

Moreover,
Moreover, thetheinternalization
internalizationofofACE2,
ACE2, following
following thethe binding
binding of SARS-CoV-2,
of SARS-CoV-2, leadsleads
to
to ACE2
ACE2 depletion
depletion on on the
the surface
surfaceofofendothelial
endothelialcells,
cells,which
whichmaymayincrease
increasethe
theincidence
incidence of
of ischemic
ischemic stroke
stroke [96].
[96]. Data
Data haveshown
have showna asignificant
significantreduction
reduction in in ACE2
ACE2 expression
expression onon en-
endothelial cells of SARS-CoV-2 patients [97]. Lack of ACE2 leaves angiotensin II
dothelial cells of SARS-CoV-2 patients [97]. Lack of ACE2 leaves angiotensin II (Ang II), a (Ang II),
a powerfulvasoconstrictor,
powerful vasoconstrictor,unregulated,
unregulated,thus
thus increasing
increasing the
the risk
risk of
of hypertension,
hypertension,blood
blood co-
coagulation,
agulation, andischemic
and ischemicstroke
stroke(Figure
(Figure 2).
2).
A case
A case study
studyhas hasreported
reportedacute
acutestroke-like
stroke-likesymptoms
symptoms andandintracranial hypertension
intracranial hypertension
in a 75-year-old Australian man due to severe inflammatory response to COVID-19 [98].
in a 75-year-old Australian man due to severe inflammatory response to COVID-19 [98].
The neurological involvement in this case was not discovered until Day 26 postinfection,
which highlights the importance of clinical values, such as NLR, lymphocyte-to-CRP
ratio (LCRPR), and lymphocyte-to-platelet ratio (LPR), as prognostic indicators of severe
inflammation and possible neurological complications. Other studies have shown that
Int. J. Mol. Sci. 2021, 22, 4081 6 of 21

COVID-19-induced severe inflammation and inflammatory infiltrates consisting of T cells,


macrophages, and neutrophils contribute to the rupture of atheromatous plaques in patients
with pre-existing atheromatous disease due to the production of proteolytic enzymes and
endothelial cell disruption [99–101]. Although the use of protease inhibitors in these
patients may be beneficial, they should be carefully used as they may promote SARS-CoV-
2-induced hypercoagulation.
Following the occurrence of ischemic stroke, the production of proinflammatory
mediators from activated immune cells and ischemic brain tissue could further promote
brain injury [102,103]. Therefore, the suppression of inflammation in ischemic stroke could
help ameliorate brain damage following ischemic stroke. However, further studies are
needed to prove the therapeutic utility of this approach.
In addition to ischemic stroke, intracranial hemorrhage was observed in 0.5% of
COVID-19 patients, similar to what was seen in MERS-CoV patients [35,104,105]. Coag-
ulopathies and vascular disorders have been associated with hemorrhage in COVID-19
patients (Figure 2) [106]. It is also possible that reduced levels of ACE2 on endothelial
cells of the brain microvasculature lead to blood coagulation and increased blood pressure,
which may result in the rupture of blood vessels and hemorrhage (Figure 2) [97].
The increased risk of hypercoagulable states has resulted in the suggested addendums
for COVID-19 patients at risk of cerebral vascular incidents. [107–110]. The documented
endothelial injury, changes in circulating prothrombotic factors, and increased stasis re-
sulting from immobilization due to COVID-19 infection have warranted hypervigilance in
the monitoring and prophylactic treatment of these patients. The International Society on
Thrombosis and Hemostasis, American Society of Chest Physicians, and American College
of Cardiology have approved interim guidelines for prophylactic treatment and manage-
ment. However, it is important to note these are interim guidelines until quality evidence,
supporting interventions different from current standard practice, are identified [111–113].
Current recommendations for monitoring hospitalized at-risk patients include baseline
complete blood count, levels of fibrinogen, D-dimer, prothrombin time, activated partial
thromboplastin time, and inflammatory markers such as CRP and IL-6. The frequency of
these tests is determined by the severity of the patient’s clinical presentations [114]. It is
recommended that any abnormal findings in these measures are used for their prognostic
value, and any changes to therapy should be the result of changes in signs or symptoms
associated with stroke. Current treatment and management of patients presenting with
active ischemic or hemorrhagic stroke do not differ from current recommendations, based
on patients’ pre-existing conditions.
The implementation of prophylactic anticoagulant treatment varies depending on
pre-existing conditions. The use of anticoagulants presents with its own adverse effects.
The outpatient recommendations are not different from current guidelines (https://www.
isth.org/page/Published_Guidance, accessed on 14 April 2021). However, as inpatient
recommendations for the treatment and management of ischemic or hemorrhagic stroke
due to COVID-19 are being evaluated, there is a consensus that thromboprophylaxis should
be considered for all COVID-19 patients in intensive care units (ICUs) due to the increased
risk of stasis [79,115].

5.2. Encephalitis, Acute Disseminated Encephalomyelitis, Encephalopathy, and Acute


Necrotizing Encephalopathy
Encephalitis and meningitis are characterized by inflammation of the brain parenchyma
and meninges, respectively [116]. The patient presents with headache, fever, vomiting,
convulsions, and impaired sensations [60]. SARS-CoV-2 was detected in brain tissues
and the CSF of COVID-19 patients who presented with meningitis or encephalitis, which
indicates that the virus itself may cause this complication by infecting and damaging
the brain (Figure 2) [40–42,60,117,118]. However, COVID-19 patients could also present
with acute meningoencephalitis with no detectable SARS-CoV-2 or any other virus in the
CSF [55,56,119]. The previous findings indicate that other mechanisms such as severe
inflammation could be involved in the development of meningoencephalitis in COVID-19
Int. J. Mol. Sci. 2021, 22, 4081 7 of 21

patients. Based on the fatal consequences of encephalitis and meningoencephalitis, it


should be considered as a possible complication in the management of COVID-19 pa-
tients. The early detection and treatment of meningoencephalitis are critical to prevent
hemorrhagic encephalopathy that could be fatal.
Acute disseminated encephalomyelitis (ADEM) is another complication characterized
by demyelination of CNS following viral infections particularly in children; however,
occurrence in adults is reported [120]. MRI images of a 51-year-old woman, who has been
diagnosed with COVID-19, showed several demyelinating lesions that are consistent with
ADEM [121]. Post-COVID-19-ADEM was further confirmed by the CNS axonal damage
and the lesions, in an autopsy of a 71-year-old COVID-19 patient, which are typical of
ADEM [122].
Encephalopathy has also been described in 50% of hospitalized COVID-19
patients [123,124]. A study of several patients who died of COVID-19 showed that a
significant number experienced hypoxic encephalopathy (Figure 2) [123]. Encephalopathy
is more common in COVID-19 patients with coexisting or previous systemic and/or neuro-
logical complications [35,125]. Several cases that presented with altered mental state and
confusion subsequent to COVID-19 did not have any evidence of CNS infection, which is
typical of most cases of encephalopathy [125,126].
Acute necrotizing encephalopathy (ANE) often presents as neurological symptoms
following viral infection, toxemia, and hypoxia [60]. Because SARS-CoV-2 infection results
in viremia and hypoxia, it is not surprising that SARS-CoV-2 is a causative agent of
encephalopathy (Figure 2) [60,97]. ANE was reported in cases with COVID-19, and pre-
existing conditions could increase the risk of ANE [125]. A brain MRI of patients showed
bilateral hemorrhagic rim-enhancing lesions in the thalamic temporal lobes and subinsular
regions [127–129]. The cytokine storm that is associated with SARS-CoV-2 infection is
believed to damage the BBB and cause brain necrosis in patients with severe COVID-19
(Figure 2) [127–129].
Evaluation of the current literature does not indicate any changes or interim recom-
mendations for COVID-19 patients that differ from the current recommended guidelines
for the treatment and management of encephalopathy. However, because encephalopathy
has been identified as a frequent finding among older COVID-19 patients [130] and is
associated with poorer outcomes among this cohort [3,131], there has been hypervigilance
in testing for COVID-19 among these patients. Following the diagnosis of encephalitis,
meningoencephalitis, or ANE, recommendations are to start with CSF PCR analysis for
the presence of SARS-CoV-2 or other potential contributing viral infections such as Herpes
Simplex Virus (HSV) [132]. Furthermore, the combined use of MRI and EEG appears to be
very important in the detection of these cases [132].

5.3. Seizures
It is expected that some COVID-19 patients will develop seizures as a consequence
of hypoxia, metabolic derangements, severe inflammation, organ failure, and cerebral
affection (Figure 2) [41,133]. Indeed, seizures in COVID-19 patients have been reported
due to SARS-CoV-2-induced brain damage, high levels of inflammatory mediators, and
viral-induced encephalitis or meningitis [41,134–136]. Infection with SARS-CoV-2 reduces
the seizures threshold which can worsen the case in epileptic patients or it can lead to
seizures in patients with no history of seizures [137–140]. It is of note that seizures could be
one of the initial symptoms in COVID-19 patients [141]. Focal seizures have been described
in COVID-19 patients in addition to generalized tonic-clonic seizures [134]. Other than
its presentation in adult COVID-19 patients, there were cases of seizures in COVID-19
children who present with fever or no fever (afebrile seizures) [142,143]. Therefore, it is
important to consider seizures in the diagnosis of COVID-19 in children regardless of the
presence or absence of fever [142,143]. The management of seizures could include the use
of antiepileptic drugs and monitoring of seizures by electroencephalography especially
in severe COVID-19 patients [135]. It is critical to diagnose and recognize the typical and
Int. J. Mol. Sci. 2021, 22, 4081 8 of 21

atypical presentation of seizures in COVID-19 patients to better diagnose, treat, and avoid
any long-term complications of seizures [144].
Current recommendations for the treatment and management of seizures and epilepsy
for patients infected with COVID-19 do not differ from current guidelines. However,
awareness of drug–drug interactions with COVID-19 treatment and the treatment for
new or existing seizures must be considered when treating this patient population. The
following discussion excludes the pediatric population because of limited early data that
are reported among this group.
Many of the medications currently used in the treatment and management of COVID-
19 induce, or inhibit, and are metabolized by the hepatic cytochrome P450 enzymes
(CYP450). These enzymes are also altered or involved in the metabolism of many of
the antiepileptic drugs (AEDs) frequently used in the treatment of seizure disorders.
Lopinavir/ritonavir are protease inhibitors used in the treatment of COVID-19 [145].
These drugs are frequently used in combination and have been shown to induce multiple
CYP450 enzymes (CYP2C9, 2C19, 1A2, and 2B6) and glucuronyl transferase [146]. This
activity decreases the plasma concentration of lamotrigine (via glucuronyl transferase)
and possibly phenytoin and valproate (via CYP enzymes), which are frequently used
AEDs [147,148]. Additionally, lopinavir/ritonavir plasma concentration may be reduced
when used concomitantly with carbamazepine, phenytoin, and topiramate due to the ability
of these AEDs to induce the CYP3A4 enzyme which metabolizes lopinavir/ritonavir [148].
Remdesivir is an adenosine analog that targets the RNA-dependent RNA polymerase
and blocks viral RNA synthesis [145]. To date, there is limited information regarding the
metabolism of remdesivir; however, it is partially metabolized via CYP3A4 (10%) [149].
This activity would result in reduced efficacy if used in combination with AEDs that
induce this enzyme. Although there have been no drug interaction trials of remdesivir
and concomitant AEDs it is important to note caution when used in combination with
AEDs [150].
Currently, there is neither experimental nor clinical evidence for any noticeable drug
interactions between AEDs and antivirals such as favipiravir, nitazoxanide, and interferon-
beta which suggests that these antivirals do not require additional dosing considerations
when used with AEDs in the management of COVID-19 patients presenting with seizures.

5.4. Altered Mental State (AMS)


Patients could present with confusion and delirium as early signs of COVID-19
without any of the respiratory symptoms [151]. Accordingly, the early detection of AMS
may help in the proper treatment and prevention of COVID-19 spread. It has been estimated
that 9% of COVID-19 patients have AMS [152]. We believe that AMS could be the result of
direct invasion of the brain or damage resulting from high levels of inflammatory mediators
due to the immune response to SARS-CoV-2 infection. We also believe that individuals
with Alzheimer’s disease (AD) and related dementias are at high risk of COVID-19 and its
associated morbidity and mortality. That could be attributed to the difficulty in applying
disease prevention measures such as washing hands, social distancing, and isolation
at home.
Helms et al. reported that 118 (84.3%) of 140 COVID-19 patients, who were treated in
two intensive care units (ICUs) in France, had mental changes including delirium, agitation,
and corticospinal tract signs [153]. MRI showed bilateral frontotemporal hypoperfusion.
About 33% of the 45 survivors experienced a dysexecutive syndrome suggestive of the
involvement of the frontal lobe, which is responsible for an individual’s mental state [153].
Based on the above findings, we believe that changes in mental status could be an important
diagnostic for COVID-19 because COVID-19 patients may only present with delirium
and confusion.
Patients with pre-existing or developing mental illness due to COVID-19 are expected
to be treated with psychotropic drugs along with the standard treatment for the viral illness.
Benzodiazepines (oxazepam and lorazepam), antidepressants (citalopram and escitalo-
Int. J. Mol. Sci. 2021, 22, 4081 9 of 21

pram), antipsychotics (olanzapine), and the mood stabilizer (valproate) are suggested as
safe considering the tolerability and minimal drug–drug interactions [154–156].

5.5. Guillain–Barré Syndrome (GBS)


GBS can occur following infections such as Campylobacter jejuni, Epstein–Barr virus,
and cytomegalovirus due to molecular mimicry between peripheral nerve antigens and
antigens of these pathogens [157]. Antipathogen antibodies can then cross-react with
peripheral nerve antigens, causing inflammation and neuronal damage [157]. GBS has
been described in several cases of COVID-19 patients, which manifest as weakness in the
lower limbs and paresthesia and may progress to tetraparesis [49,158]. Nerve roots are
typically involved, which is characterized by increased protein concentration in CSF and
normal white blood cell count (cytoalbuminologic dissociation) [159,160]. It is of note
that demyelinating polyradiculoneuropathy and/or axonal damage are characteristics of
GBS in COVID-19 patients [161,162]. GBS may manifest in individuals with COVID-19
even before the appearance of the typical flu-like symptoms [163]. Gupta et al. described
the difference between GBS due to COVID-19 and other types of GBS [164]. COVID-
19 GBS is more prevalent in the elderly and males, and COVID-19 GBS patients may
experience fever, cough, dyspnea, ageusia, hyposmia 5–14 days before the paresthesia,
lower limb weakness, and facial weakness [164]. Unfortunately, COVID-19 GBS has
residual weakness, dysphagia, and extended ICU stay than other GBS types. Variants of
GBS such as Miller Fisher syndrome and polyneuritis cranialis have also been reported in
COVID-19 patients [4,163,165].
Management of GBS is best achieved by intravenous immunoglobulin (IVIG) treat-
ment [166,167]. Lopinavir/ritonavir use in COVID-19 with peripheral neuropathies is
controversial because one study showed that protease inhibitors may increase the risk of
peripheral neuropathy in patients with HIV [168]. However, other studies have found that
lopinavir/ritonavir does not increase the risk of distal sensory polyneuropathy in HIV
patients [169].

5.6. Skeletal Muscle and Neuromuscular Junction Complications


Severe inflammation in critically ill COVID-19 patients could lead to neuromuscular
junction dysfunction and myopathy [170,171]. The invasion of muscle cells, which express
the ACE2 receptor, is also a possible mechanism [170,171]. On the other hand, the risk of
COVID-19 infection increased with the use of immunosuppressive/immunomodulatory
therapies in patients with autoimmune neuromuscular disorders [172–174].
We studied different reports to propose a protocol for the management of myasthenia
gravis (MG) and Lambert–Eaton myasthenic syndrome (LEMS) during COVID-19 [175,176]
and concluded the following.
The MG expert panel suggests that decisions to manage every patient should be
individualized, patients should take more precautions with extraordinary measures, and
MG patients on immunosuppressive therapy should continue taking the medications. Hy-
droxychloroquine should be avoided in COVID-19 patients with MS or LEMS as the drug
is reported to worsen MG [177,178]. The delay in initiation of the B-cell depleting therapy
(rituximab) increases the risk of worsening myasthenia or myasthenia crisis [179,180].

5.7. Neurodegenerative and Demyelinating Disorders


It remains unclear whether SARS-CoV-2 infection is associated with the develop-
ment of neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer’s disease
(AD), and Parkinson’s disease (PD) [181]. There is also no evidence of the acceleration
of these diseases in COVID-19 patients [181]. However, the high expression of ACE2 in
CNS and the brain damage that SARS-CoV-2 causes could lead to long-term neurodegen-
erative diseases/complications [182]. MS is characterized by nerve demyelination and
brain neurodegeneration due to immune-mediated inflammation [181]. The SARS-CoV-
2-mediated neurological damage that results from inflammation or direct invasion of the
Int. J. Mol. Sci. 2021, 22, 4081 10 of 21

brain is similar to that caused by MS [183,184]. However, there is not enough evidence
that SARS-CoV-2 leads to MS or that MS patients are more susceptible to COVID-19, its
CNS involvement, or the reactivation of MS lesions due to SARS-CoV-2-mediated im-
mune dysregulation [185–187]. A case of a 67-year-old woman who had MS and died of
COVID-19 showed that SARS-CoV-2 did not infect neuronal or glial cells and infection
did not result in disease exacerbation or reactivation of MS lesions [187]. The findings of
the previous case are consistent with other studies, which showed that COVID-19 did not
affect the course of autoimmune diseases [185,186].
AD is another neurodegenerative disease that is characterized by neuroinflammation
and neuronal loss and has many risk factors, which include age [188]. Several studies
have shown that AD development could correlate with infections including viral infec-
tions [188]. Because SARS-CoV-2 infects/damages the CNS and induces severe inflamma-
tory responses, it is possible that the long-term effect on cognitive function could develop
in COVID-19 survivors [189]. To date, there is not enough evidence that SARS-CoV-2
causes or increases the risk of developing AD, as long-term studies are needed to draw this
correlation. However, the infection of glutamate-producing and GABA-producing neurons
by SARS-CoV-2 infection is a possible mechanism by which AD could develop secondary
to COVID-19 [182].
Similar to AD, PD patients suffer from cognitive and memory issues in addition to
the impairment of motor function [190]. Although ACE2 is widely expressed in CNS and
SARS-CoV-2 infects and damages several sites in the brain, there is no direct evidence that
SARS-CoV-2 induces or increases the risk of PD development or that PD patients are at
higher risk of contracting SARS-CoV-2 [191,192]. There is not any evidence too that PD
worsens during the course of COVID-19 disease [192]. However, it is highly possible that
SARS-CoV-2 could be linked to PD development or its acceleration once more studies are
conducted and follow-up of COVID-19 survivors is done over the next few years.

5.8. Miscellaneous Complications


The most common neurological symptoms associated with COVID-19 are headache,
dizziness, myalgia, fatigue, hyposmia, hypogeusia, and visual impairment. These symp-
toms are seen in 30 to 45.5% of patients [35,193,194].
Headache is one of the most common neurological symptoms in COVID-19 patients
and could be the first symptom of COVID-19 in a few patients (Figure 2) [35,195–197]. It
occurred in 6-25% of COVID-19 patients depending on the study, and the intensity is often
described as moderate to severe [152,198–204]. It has been noticed that headache as a result
of COVID-19 starts as moderate pain due to systemic spread of the virus, whereas after a
few days, severe inflammation could lead to photophobia and neck stiffness [205].
Past medical histories of several COVID-19 patients indicate that headache has been
a regular complaint [199]. However, there are other cases in which COVID-19 patients
never had any headache in their medical history and only experienced headache after
SARS-CoV-2 infection, which suggests that headache is a complication of COVID-19 [206].
It has been suggested that headache occurs in COVID-19 patients as a result of SARS-CoV-2
infection of the nasal cavity trigeminal nerve endings [198]. Furthermore, headache could
be due to infection of endothelial cells of the vessels in the trigeminovascular system [198].
The high level of proinflammatory cytokines could also irritate the trigeminal nerve end-
ings leading to headache [198]. In our opinion, in addition to all the above-described
mechanisms, headache could also occur due to lack of sleep, isolation, and anxiety in
COVID-19 patients. Despite being a common symptom in COVID-19, headache can be
easily treated by analgesics.
Dizziness is also reported as one of the common neurological symptoms that presents
in 8–9% of COVID-19 patients (Figure 2) [35,207,208]. It is even reported, in some COVID-
19 cases, to be more commonly occurring than headache [35]. A COVID-19 case for a
53-year-old woman was described, and dizziness was reported as an initial symptom
along with dry throat, while fever, cough, and headache were absent [209]. Antiviral and
Int. J. Mol. Sci. 2021, 22, 4081 11 of 21

other drug treatments resulted in case improvement. Therefore, it is important to watch


for dizziness as one of the neurological complications that may help in the diagnosis of
COVID-19 even in absence of respiratory symptoms.
Myalgia and fatigue have been commonly reported in COVID-19 patients (Figure 2) [35,
193,194,207,208]. Depending on the study, fatigue was a complaint in 26–51% of patients,
whereas 3–64% of patients had myalgia [210]. It has been postulated that myalgia in
COVID-19 patients is due to severe inflammation and high levels of proinflammatory
cytokines [211]. However, muscle invasion by SARS-CoV-2 remains a possibility because
muscles express the ACE2 receptor. Some patients showed fatigue, muscle soreness, and
elevated muscle enzyme levels such as creatine kinase all of which may be related to
systemic inflammation and muscle damage [212].
Hyposmia (anosmia) and hypogeusia (ageusia) are loss of smell and taste, respectively,
and they are among the most common early symptoms of COVID-19 (Figure 2) [213–215].
They are reported by up to 88% of COVID-19 patients with mild or moderate disease
and therefore could be used for the diagnosis of COVID-19 [35,216–219]. Anosmia could
appear as an initial symptom and is not accompanied by nasal inflammation [220,221].
Using MRI, an abnormal appearance of the olfactory bulb has been described in COVID-19
patients [220,221]. Infection of the olfactory epithelium and trigeminal nerves by SARS-
CoV-2 may explain the loss of smell and taste in COVID-19 patients [222,223]. Because
anosmia is highly prevalent and an early symptom of COVID-19, it can be used for the
early diagnosis of COVID-19 [224]. This may help in the early isolation and treatment of
COVID-19 patients, which could eventually result in a decline in the number of new cases.
Post-COVID-19 Neurological Syndrome (PCNS) indicates prolonged post-COVID-19
neurological symptoms. Several reports have shown that PCNS could present in the
form of long-term symptoms that persist for months such as muscle pain and weakness,
myopathy, sleep impairment, anxiety, depression, severe post-traumatic stress disorder
(PTSD), dizziness, headaches, and anosmia [225,226]. The previous findings suggest that
COVID-19 patients should be followed up after recovery for possible long-term post-
COVID-19 neurological complications.

6. Mechanisms of SARS-CoV-2-Induced Neurological Complications


The high expression of ACE2 in the brain and peripheral nerves allows SARS-CoV-
2 to infect the nervous system and cause neurological damage, which is manifested as
complications secondary to SARS-CoV-2 infection [57]. Because ACE2 has several physi-
ological functions, including the regulation of blood pressure, its usage by SARS-CoV-2
as an entry receptor may lead to its depletion and the accumulation of Ang II [227–229].
Elevated Ang II would result in increased blood pressure due to vasoconstriction and fluid
retention [229]. Moreover, high levels of Ang II would promote inflammation and blood
coagulation. Complications due to ACE2 depletion could be manifested as cerebrovascular
diseases in COVID-19 patients (Figure 2).
Acute respiratory distress syndrome (ARDS), which occurs as a consequence of severe
SARS-CoV-2 infection, could lead to hypoxia that can have deleterious effects on the
brain, including edema, congestion, and neuronal degeneration (Figure 2) [64,202,230].
This hypoxia-induced brain damage is typically seen in hypoxic encephalopathy and
ischemic stroke secondary to SARS-CoV-2 infection. However, it is important to note
that direct damage of the brain by SARS-CoV-2 could also lead to respiratory failure and
hypoxia [61]. One of the reasons behind ARDS is the severe inflammation due to the
release of an excessive amount of proinflammatory cytokines that could be responsible
for tissue damage in the lungs and other organs including the brain [202,231,232]. Severe
inflammation was also noted locally in the brain after SARS-CoV-2 invasion due to the
production of proinflammatory cytokines by astrocytes and microglia [21]. This also
contributes to brain damage. Accordingly, therapies, such as IL-6 receptor monoclonal
antibodies, which aim to reduce inflammation, have been used to prevent inflammation-
dependent complications in COVID-19 patients [233].
Int. J. Mol. Sci. 2021, 22, 4081 12 of 21

Severe inflammation in COVID-19 patients, the infection of endothelial cells, and the acti-
vation of coagulation cascade could lead to hypercoagulability and disseminated intravascular
coagulation (DIC) that is commonly seen in COVID-19 patients (Figure 2) [77–81]. The severe
systemic inflammation on hospital admission could predict mortality in COVID-19 pa-
tients [87]. Stroke could be a consequence if anticoagulants are not administered [234,235].
A study demonstrated that serial systemic immune inflammation indices (SSIIi), which are
determined based on neutrophil, platelet, and lymphocyte counts, are clinically correlated
with PCNS events [236]. This implies that SSIIi could be used as a biomarker for many
neurological complications including stroke.
Severe immunosuppression could be also implicated in COVID-19 patients with
severe disease [237]. Circulating effector T cells were significantly reduced in COVID-
19 patients [237]. In some patients, IL-6 was elevated but without elevations in other
proinflammatory cytokines. It was noted too that blood mononuclear cells are less activated
and produce lower levels of cytokines. All of the above suggests that immune responses
may be impaired in some COVID-19 patients, which could lead to uncontrolled viral spread
and tissue/organ damage including the CNS. Other studies reported an overproduction of
proinflammatory cytokines in COVID-19 patients [238]. Moreover, another study found
that in severe COVID-19 patients, there is a high level of anti-SARS-CoV-2 spike protein
IgG antibodies [239]. This may indicate that antibody-dependent enhancement (ADE)
of infection could play a role in mediating the infection of immune cells that express
the Fcγ receptor for IgG [240,241]. Antibodies against SARS-CoV-2 can also cross-react
with antigens in the nervous system causing complications such as GBS [158]. Based on
these findings, overactivation of the immune system leads to hyperinflammation, whereas
immunosuppression could result in the dissemination of SARS-CoV-2. Both of these
mechanisms would eventually cause tissue damage.

7. Conclusions
The health care system is posed with a huge challenge of the current COVID-19
pandemic. Several neurological manifestations have been described in COVID-19 patients;
however, more research needs to be performed to understand the pathogenic mechanism
behind each of these disorders to better treat such patients with suitable drugs and in a
timely manner. We believe that some of the available treatment options might potentially
lead to a wave of neurological sequelae. Therefore, treatment of COVID-19 patients should
consider the existing or the unknown neurological complications that may develop.

Author Contributions: Conceptualization, G.A.S. and H.A.E.; writing—original draft preparation,


G.A.S. and H.A.E.; writing—review and editing, K.C.L., M.C.G., M.E., R.A., and H.A.E.; Figures
preparation, M.C.G. and H.A.E. All authors have read and agreed to the published version of
the manuscript.
Funding: This work received no funding.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Zhou, P.; Yang, X.-L.; Wang, X.-G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.-R.; Zhu, Y.; Li, B.; Huang, C.-L.; et al. A pneumonia
outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579, 270–273. [CrossRef]
2. Yang, P.; Wang, X. COVID-19: A new challenge for human beings. Cell. Mol. Immunol. 2020, 17, 555–557. [CrossRef]
3. Liotta, E.M.; Batra, A.; Clark, J.R.; Shlobin, N.A.; Hoffman, S.C.; Orban, Z.S.; Koralnik, I.J. Frequent neurologic manifestations and
encephalopathy-associated morbidity in Covid-19 patients. Ann. Clin. Transl. Neurol. 2020, 7, 2221–2230. [CrossRef]
4. Ahmad, I.; Rathore, F.A. Neurological manifestations and complications of COVID-19: A literature review. J. Clin. Neurosci. 2020,
77, 8–12. [CrossRef] [PubMed]
5. Andalib, S.; Biller, J.; Di Napoli, M.; Moghimi, N.; McCullough, L.D.; Rubinos, C.A.; O’Hana Nobleza, C.; Azarpazhooh, M.R.;
Catanese, L.; Elicer, I.; et al. Peripheral Nervous System Manifestations Associated with COVID-19. Curr. Neurol. Neurosci. Rep.
2021, 21, 9. [CrossRef] [PubMed]
6. McGavern, D.B.; Kang, S.S. Illuminating viral infections in the nervous system. Nat. Rev. Immunol. 2011, 11, 318–329. [CrossRef]
[PubMed]
Int. J. Mol. Sci. 2021, 22, 4081 13 of 21

7. Swanson, P.A., 2nd; McGavern, D.B. Viral diseases of the central nervous system. Curr. Opin. Virol. 2015, 11, 44–54. [CrossRef]
[PubMed]
8. Gonzalez-Scarano, F.; Tyler, K.L. Molecular pathogenesis of neurotropic viral infections. Ann. Neurol. 1987, 22, 565–574. [CrossRef]
[PubMed]
9. Suen, W.W.; Prow, N.A.; Hall, R.A.; Bielefeldt-Ohmann, H. Mechanism of West Nile virus neuroinvasion: A critical appraisal.
Viruses 2014, 6, 2796–2825. [CrossRef]
10. Koyuncu, O.O.; Hogue, I.B.; Enquist, L.W. Virus infections in the nervous system. Cell Host Microbe 2013, 13, 379–393. [CrossRef]
11. Ashour, H.M.; Elkhatib, W.F.; Rahman, M.M.; Elshabrawy, H.A. Insights into the Recent 2019 Novel Coronavirus (SARS-CoV-2)
in Light of Past Human Coronavirus Outbreaks. Pathogens 2020, 9, 186. [CrossRef]
12. Van der Hoek, L. Human coronaviruses: What do they cause? Antivir. Ther. 2007, 12, 651–658.
13. Cabeca, T.K.; Granato, C.; Bellei, N. Epidemiological and clinical features of human coronavirus infections among different
subsets of patients. Influenza Other Respir. Viruses 2013, 7, 1040–1047. [CrossRef] [PubMed]
14. Matoba, Y.; Abiko, C.; Ikeda, T.; Aoki, Y.; Suzuki, Y.; Yahagi, K.; Matsuzaki, Y.; Itagaki, T.; Katsushima, F.; Katsushima, Y.; et al.
Detection of the human coronavirus 229E, HKU1, NL63, and OC43 between 2010 and 2013 in Yamagata, Japan. Jpn. J. Infect. Dis.
2015, 68, 138–141. [CrossRef] [PubMed]
15. Drosten, C.; Gunther, S.; Preiser, W.; van der Werf, S.; Brodt, H.R.; Becker, S.; Rabenau, H.; Panning, M.; Kolesnikova, L.; Fouchier,
R.A.; et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N. Engl. J. Med. 2003,
348, 1967–1976. [CrossRef] [PubMed]
16. Zaki, A.M.; van Boheemen, S.; Bestebroer, T.M.; Osterhaus, A.D.; Fouchier, R.A. Isolation of a novel coronavirus from a man with
pneumonia in Saudi Arabia. N. Engl. J. Med. 2012, 367, 1814–1820. [CrossRef]
17. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. A Novel Coronavirus from
Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727–733. [CrossRef]
18. Zlateva, K.T.; Van Ranst, M. Detection of subgroup B respiratory syncytial virus in the cerebrospinal fluid of a patient with
respiratory syncytial virus pneumonia. Pediatr. Infect. Dis. J. 2004, 23, 1065–1066. [CrossRef]
19. Yeh, E.A.; Collins, A.; Cohen, M.E.; Duffner, P.K.; Faden, H. Detection of coronavirus in the central nervous system of a child with
acute disseminated encephalomyelitis. Pediatrics 2004, 113, e73–e76. [CrossRef]
20. St-Jean, J.R.; Jacomy, H.; Desforges, M.; Vabret, A.; Freymuth, F.; Talbot, P.J. Human respiratory coronavirus OC43: Genetic
stability and neuroinvasion. J. Virol. 2004, 78, 8824–8834. [CrossRef]
21. Li, Y.; Fu, L.; Gonzales, D.M.; Lavi, E. Coronavirus neurovirulence correlates with the ability of the virus to induce proinflamma-
tory cytokine signals from astrocytes and microglia. J. Virol. 2004, 78, 3398–3406. [CrossRef] [PubMed]
22. Rempel, J.D.; Murray, S.J.; Meisner, J.; Buchmeier, M.J. Mouse hepatitis virus neurovirulence: Evidence of a linkage between S
glycoprotein expression and immunopathology. Virology 2004, 318, 45–54. [CrossRef]
23. Almqvist, J.; Granberg, T.; Tzortzakakis, A.; Klironomos, S.; Kollia, E.; Ohberg, C.; Martin, R.; Piehl, F.; Ouellette, R.; Ineichen,
B.V. Neurological manifestations of coronavirus infections—A systematic review. Ann. Clin. Transl. Neurol. 2020, 7, 2057–2071.
[CrossRef] [PubMed]
24. Murray, R.S.; Brown, B.; Brian, D.; Cabirac, G.F. Detection of coronavirus RNA and antigen in multiple sclerosis brain. Ann.
Neurol. 1992, 31, 525–533. [CrossRef]
25. Stewart, J.N.; Mounir, S.; Talbot, P.J. Human coronavirus gene expression in the brains of multiple sclerosis patients. Virology
1992, 191, 502–505. [CrossRef]
26. Arbour, N.; Day, R.; Newcombe, J.; Talbot, P.J. Neuroinvasion by human respiratory coronaviruses. J. Virol. 2000, 74, 8913–8921.
[CrossRef]
27. Jacomy, H.; Fragoso, G.; Almazan, G.; Mushynski, W.E.; Talbot, P.J. Human coronavirus OC43 infection induces chronic
encephalitis leading to disabilities in BALB/C mice. Virology 2006, 349, 335–346. [CrossRef] [PubMed]
28. Hung, E.C.; Chim, S.S.; Chan, P.K.; Tong, Y.K.; Ng, E.K.; Chiu, R.W.; Leung, C.B.; Sung, J.J.; Tam, J.S.; Lo, Y.M. Detection of SARS
coronavirus RNA in the cerebrospinal fluid of a patient with severe acute respiratory syndrome. Clin. Chem. 2003, 49, 2108–2109.
[CrossRef]
29. Lau, K.K.; Yu, W.C.; Chu, C.M.; Lau, S.T.; Sheng, B.; Yuen, K.Y. Possible central nervous system infection by SARS coronavirus.
Emerg. Infect. Dis. 2004, 10, 342–344. [CrossRef] [PubMed]
30. Ding, Y.; He, L.; Zhang, Q.; Huang, Z.; Che, X.; Hou, J.; Wang, H.; Shen, H.; Qiu, L.; Li, Z.; et al. Organ distribution of severe acute
respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: Implications for pathogenesis and virus
transmission pathways. J. Pathol. 2004, 203, 622–630. [CrossRef]
31. Glass, W.G.; Subbarao, K.; Murphy, B.; Murphy, P.M. Mechanisms of host defense following severe acute respiratory syndrome-
coronavirus (SARS-CoV) pulmonary infection of mice. J. Immunol. 2004, 173, 4030–4039. [CrossRef]
32. Li, Y.; Li, H.; Fan, R.; Wen, B.; Zhang, J.; Cao, X.; Wang, C.; Song, Z.; Li, S.; Li, X.; et al. Coronavirus Infections in the Central
Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children. Intervirology 2016, 59, 163–169. [CrossRef]
[PubMed]
33. Baig, A.M.; Khaleeq, A.; Ali, U.; Syeda, H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus
Interaction, and Proposed Neurotropic Mechanisms. ACS Chem. Neurosci. 2020, 11, 995–998. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2021, 22, 4081 14 of 21

34. Wang, H.Y.; Li, X.L.; Yan, Z.R.; Sun, X.P.; Han, J.; Zhang, B.W. Potential neurological symptoms of COVID-19. Ther. Adv. Neurol.
Disord. 2020, 13. [CrossRef] [PubMed]
35. Mao, L.; Jin, H.; Wang, M.; Hu, Y.; Chen, S.; He, Q.; Chang, J.; Hong, C.; Zhou, Y.; Wang, D.; et al. Neurologic Manifestations of
Hospitalized Patients with Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020, 77, 683–690. [CrossRef] [PubMed]
36. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Kruger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche,
A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell
2020, 181, 271–280.e278. [CrossRef] [PubMed]
37. Wang, K.; Chen, W.; Zhang, Z.; Deng, Y.; Lian, J.Q.; Du, P.; Wei, D.; Zhang, Y.; Sun, X.X.; Gong, L.; et al. CD147-spike protein is a
novel route for SARS-CoV-2 infection to host cells. Signal. Transduct. Target. Ther. 2020, 5, 283. [CrossRef]
38. Cantuti-Castelvetri, L.; Ojha, R.; Pedro, L.D.; Djannatian, M.; Franz, J.; Kuivanen, S.; van der Meer, F.; Kallio, K.; Kaya, T.;
Anastasina, M.; et al. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 2020, 370, 856–860. [CrossRef]
[PubMed]
39. Iadecola, C.; Anrather, J.; Kamel, H. Effects of COVID-19 on the Nervous System. Cell 2020, 183, 16–27.e11. [CrossRef] [PubMed]
40. Paniz-Mondolfi, A.; Bryce, C.; Grimes, Z.; Gordon, R.E.; Reidy, J.; Lednicky, J.; Sordillo, E.M.; Fowkes, M. Central nervous system
involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J. Med. Virol. 2020, 92, 699–702. [CrossRef]
[PubMed]
41. Moriguchi, T.; Harii, N.; Goto, J.; Harada, D.; Sugawara, H.; Takamino, J.; Ueno, M.; Sakata, H.; Kondo, K.; Myose, N.; et al. A
first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int. J. Infect. Dis. 2020, 94, 55–58. [CrossRef]
42. Huang, Y.H.; Jiang, D.; Huang, J.T. SARS-CoV-2 Detected in Cerebrospinal Fluid by PCR in a Case of COVID-19 Encephalitis.
Brain Behav. Immun. 2020, 87, 149. [CrossRef]
43. Serrano, G.E.; Walker, J.E.; Arce, R.; Glass, M.J.; Vargas, D.; Sue, L.I.; Intorcia, A.J.; Nelson, C.M.; Oliver, J.; Papa, J.; et al. Mapping
of SARS-CoV-2 Brain Invasion and Histopathology in COVID-19 Disease. medRxiv 2021. [CrossRef]
44. Freij, B.J.; Gebara, B.M.; Tariq, R.; Wang, A.M.; Gibson, J.; El-Wiher, N.; Krasan, G.; Patek, P.M.; Levasseur, K.A.; Amin, M.; et al.
Fatal central nervous system co-infection with SARS-CoV-2 and tuberculosis in a healthy child. BMC Pediatr. 2020, 20, 429.
[CrossRef]
45. Remmelink, M.; De Mendonca, R.; D’Haene, N.; De Clercq, S.; Verocq, C.; Lebrun, L.; Lavis, P.; Racu, M.L.; Trepant, A.L.;
Maris, C.; et al. Unspecific post-mortem findings despite multiorgan viral spread in COVID-19 patients. Crit. Care 2020, 24, 495.
[CrossRef]
46. Song, E.; Zhang, C.; Israelow, B.; Lu-Culligan, A.; Prado, A.V.; Skriabine, S.; Lu, P.; Weizman, O.E.; Liu, F.; Dai, Y.; et al.
Neuroinvasion of SARS-CoV-2 in human and mouse brain. J. Exp. Med. 2021, 218. [CrossRef]
47. Matschke, J.; Lutgehetmann, M.; Hagel, C.; Sperhake, J.P.; Schroder, A.S.; Edler, C.; Mushumba, H.; Fitzek, A.; Allweiss, L.;
Dandri, M.; et al. Neuropathology of patients with COVID-19 in Germany: A post-mortem case series. Lancet Neurol. 2020,
19, 919–929. [CrossRef]
48. Solomon, I.H.; Normandin, E.; Bhattacharyya, S.; Mukerji, S.S.; Keller, K.; Ali, A.S.; Adams, G.; Hornick, J.L.; Padera, R.F., Jr.;
Sabeti, P. Neuropathological Features of Covid-19. N. Engl. J. Med. 2020, 383, 989–992. [CrossRef] [PubMed]
49. Toscano, G.; Palmerini, F.; Ravaglia, S.; Ruiz, L.; Invernizzi, P.; Cuzzoni, M.G.; Franciotta, D.; Baldanti, F.; Daturi, R.; Postorino,
P.; et al. Guillain-Barre Syndrome Associated with SARS-CoV-2. N. Engl. J. Med. 2020, 382, 2574–2576. [CrossRef] [PubMed]
50. Espindola, O.M.; Siqueira, M.; Soares, C.N.; Lima, M.; Leite, A.; Araujo, A.Q.C.; Brandao, C.O.; Silva, M.T.T. Patients with
COVID-19 and neurological manifestations show undetectable SARS-CoV-2 RNA levels in the cerebrospinal fluid. Int. J. Infect.
Dis. 2020, 96, 567–569. [CrossRef]
51. Lee, M.H.; Perl, D.P.; Nair, G.; Li, W.; Maric, D.; Murray, H.; Dodd, S.J.; Koretsky, A.P.; Watts, J.A.; Cheung, V.; et al. Microvascular
Injury in the Brains of Patients with Covid-19. N. Engl. J. Med. 2021, 384, 481–483. [CrossRef]
52. Jensen, M.P.; Le Quesne, J.; Officer-Jones, L.; Teodosio, A.; Thaventhiran, J.; Ficken, C.; Goddard, M.; Smith, C.; Menon, D.;
Allinson, K.S.J. Neuropathological findings in two patients with fatal COVID-19. Neuropathol. Appl. Neurobiol. 2021, 47, 17–25.
[CrossRef]
53. Keller, E.; Brandi, G.; Winklhofer, S.; Imbach, L.L.; Kirschenbaum, D.; Frontzek, K.; Steiger, P.; Dietler, S.; Haeberlin, M.; Willms,
J.; et al. Large and Small Cerebral Vessel Involvement in Severe COVID-19: Detailed Clinical Workup of a Case Series. Stroke 2020,
51, 3719–3722. [CrossRef]
54. Bihlmaier, K.; Coras, R.; Willam, C.; Grampp, S.; Jabari, S.; Eichhorn, P.; Haller, F.; Kuramatsu, J.; Schwab, S.; Castellanos, I.; et al.
Disseminated Multifocal Intracerebral Bleeding Events in Three Coronavirus Disease 2019 Patients on Extracorporeal Membrane
Oxygenation As Rescue Therapy. Crit. Care Explor. 2020, 2, e0218. [CrossRef]
55. Bernard-Valnet, R.; Pizzarotti, B.; Anichini, A.; Demars, Y.; Russo, E.; Schmidhauser, M.; Cerutti-Sola, J.; Rossetti, A.O.; Du
Pasquier, R. Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection. Eur. J. Neurol. 2020,
27, e43–e44. [CrossRef]
56. Ye, M.; Ren, Y.; Lv, T. Encephalitis as a clinical manifestation of COVID-19. Brain Behav. Immun. 2020, 88, 945–946. [CrossRef]
[PubMed]
57. Barrantes, F.J. Central Nervous System Targets and Routes for SARS-CoV-2: Current Views and New Hypotheses. ACS Chem.
Neurosci. 2020, 11, 2793–2803. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 4081 15 of 21

58. Stefano, M.L.; Kream, R.M.; Stefano, G.B. A Novel Vaccine Employing Non-Replicating Rabies Virus Expressing Chimeric
SARS-CoV-2 Spike Protein Domains: Functional Inhibition of Viral/Nicotinic Acetylcholine Receptor Complexes. Med. Sci. Monit.
2020, 26, e926016. [CrossRef] [PubMed]
59. Puccioni-Sohler, M.; Poton, A.R.; Franklin, M.; Silva, S.J.D.; Brindeiro, R.; Tanuri, A. Current evidence of neurological features,
diagnosis, and neuropathogenesis associated with COVID-19. Rev. Soc. Bras. Med. Trop. 2020, 53, e20200477. [CrossRef] [PubMed]
60. Wu, Y.; Xu, X.; Chen, Z.; Duan, J.; Hashimoto, K.; Yang, L.; Liu, C.; Yang, C. Nervous system involvement after infection with
COVID-19 and other coronaviruses. Brain Behav. Immun. 2020, 87, 18–22. [CrossRef]
61. Li, Y.C.; Bai, W.Z.; Hashikawa, T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of
COVID-19 patients. J. Med. Virol. 2020, 92, 552–555. [CrossRef] [PubMed]
62. Pezzini, A.; Padovani, A. Lifting the mask on neurological manifestations of COVID-19. Nat. Rev. Neurol. 2020, 16, 636–644.
[CrossRef]
63. Desforges, M.; Le Coupanec, A.; Brison, E.; Meessen-Pinard, M.; Talbot, P.J. Neuroinvasive and neurotropic human respiratory
coronaviruses: Potential neurovirulent agents in humans. Adv. Exp. Med. Biol. 2014, 807, 75–96. [CrossRef] [PubMed]
64. Gu, J.; Gong, E.; Zhang, B.; Zheng, J.; Gao, Z.; Zhong, Y.; Zou, W.; Zhan, J.; Wang, S.; Xie, Z.; et al. Multiple organ infection and
the pathogenesis of SARS. J. Exp. Med. 2005, 202, 415–424. [CrossRef] [PubMed]
65. Nicholls, J.M.; Butany, J.; Poon, L.L.; Chan, K.H.; Beh, S.L.; Poutanen, S.; Peiris, J.S.; Wong, M. Time course and cellular localization
of SARS-CoV nucleoprotein and RNA in lungs from fatal cases of SARS. PLoS Med. 2006, 3, e27. [CrossRef] [PubMed]
66. Spiegel, M.; Schneider, K.; Weber, F.; Weidmann, M.; Hufert, F.T. Interaction of severe acute respiratory syndrome-associated
coronavirus with dendritic cells. J. Gen. Virol. 2006, 87, 1953–1960. [CrossRef]
67. Trojanowicz, B.; Ulrich, C.; Kohler, F.; Bode, V.; Seibert, E.; Fiedler, R.; Girndt, M. Monocytic angiotensin-converting enzyme 2
relates to atherosclerosis in patients with chronic kidney disease. Nephrol. Dial. Transplant. 2017, 32, 287–298. [CrossRef] [PubMed]
68. Abassi, Z.; Knaney, Y.; Karram, T.; Heyman, S.N. The Lung Macrophage in SARS-CoV-2 Infection: A Friend or a Foe? Front.
Immunol. 2020, 11, 1312. [CrossRef]
69. Bost, P.; Giladi, A.; Liu, Y.; Bendjelal, Y.; Xu, G.; David, E.; Blecher-Gonen, R.; Cohen, M.; Medaglia, C.; Li, H.; et al. Host-Viral
Infection Maps Reveal Signatures of Severe COVID-19 Patients. Cell 2020, 181, 1475–1488.e1412. [CrossRef] [PubMed]
70. Bilinska, K.; Jakubowska, P.; Von Bartheld, C.S.; Butowt, R. Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in
Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age. ACS Chem. Neurosci. 2020, 11, 1555–1562.
[CrossRef]
71. Brann, D.H.; Tsukahara, T.; Weinreb, C.; Lipovsek, M.; Van den Berge, K.; Gong, B.; Chance, R.; Macaulay, I.C.; Chou, H.J.;
Fletcher, R.B.; et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying
COVID-19-associated anosmia. Sci. Adv. 2020, 6. [CrossRef]
72. McCray, P.B., Jr.; Pewe, L.; Wohlford-Lenane, C.; Hickey, M.; Manzel, L.; Shi, L.; Netland, J.; Jia, H.P.; Halabi, C.; Sigmund,
C.D.; et al. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J. Virol. 2007, 81,
813–821. [CrossRef]
73. Li, Y.C.; Bai, W.Z.; Hirano, N.; Hayashida, T.; Hashikawa, T. Coronavirus infection of rat dorsal root ganglia: Ultrastructural
characterization of viral replication, transfer, and the early response of satellite cells. Virus Res. 2012, 163, 628–635. [CrossRef]
[PubMed]
74. Desforges, M.; Le Coupanec, A.; Dubeau, P.; Bourgouin, A.; Lajoie, L.; Dube, M.; Talbot, P.J. Human Coronaviruses and Other
Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? Viruses 2019, 12, 14. [CrossRef]
[PubMed]
75. Yaghi, S.; Ishida, K.; Torres, J.; Mac Grory, B.; Raz, E.; Humbert, K.; Henninger, N.; Trivedi, T.; Lillemoe, K.; Alam, S.; et al.
SARS-CoV-2 and Stroke in a New York Healthcare System. Stroke 2020, 51, 2002–2011. [CrossRef]
76. Lodigiani, C.; Iapichino, G.; Carenzo, L.; Cecconi, M.; Ferrazzi, P.; Sebastian, T.; Kucher, N.; Studt, J.D.; Sacco, C.; Bertuzzi,
A.; et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan,
Italy. Thromb. Res. 2020, 191, 9–14. [CrossRef] [PubMed]
77. Pons, S.; Fodil, S.; Azoulay, E.; Zafrani, L. The vascular endothelium: The cornerstone of organ dysfunction in severe SARS-CoV-2
infection. Crit. Care 2020, 24, 353. [CrossRef]
78. Ranucci, M.; Ballotta, A.; Di Dedda, U.; Bayshnikova, E.; Dei Poli, M.; Resta, M.; Falco, M.; Albano, G.; Menicanti, L. The
procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J. Thromb. Haemost. 2020, 18, 1747–1751.
[CrossRef]
79. Klok, F.A.; Kruip, M.; van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.; Kant, K.M.; Kaptein, F.H.J.; van Paassen, J.; Stals, M.A.M.;
Huisman, M.V.; et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. 2020,
191, 145–147. [CrossRef]
80. Varga, Z.; Flammer, A.J.; Steiger, P.; Haberecker, M.; Andermatt, R.; Zinkernagel, A.S.; Mehra, M.R.; Schuepbach, R.A.; Ruschitzka,
F.; Moch, H. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020, 395, 1417–1418. [CrossRef]
81. Bruggemann, R.; Gietema, H.; Jallah, B.; Ten Cate, H.; Stehouwer, C.; Spaetgens, B. Arterial and venous thromboembolic disease
in a patient with COVID-19: A case report. Thromb. Res. 2020, 191, 153–155. [CrossRef] [PubMed]
82. Liu, Y.; Du, X.; Chen, J.; Jin, Y.; Peng, L.; Wang, H.H.X.; Luo, M.; Chen, L.; Zhao, Y. Neutrophil-to-lymphocyte ratio as an
independent risk factor for mortality in hospitalized patients with COVID-19. J. Infect. 2020, 81, e6–e12. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2021, 22, 4081 16 of 21

83. Liu, J.; Li, S.; Liu, J.; Liang, B.; Wang, X.; Wang, H.; Li, W.; Tong, Q.; Yi, J.; Zhao, L.; et al. Longitudinal characteristics of lymphocyte
responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020, 55, 102763. [CrossRef]
84. Liu, Y.P.; Li, G.M.; He, J.; Liu, Y.; Li, M.; Zhang, R.; Li, Y.L.; Wu, Y.Z.; Diao, B. Combined use of the neutrophil-to-lymphocyte ratio
and CRP to predict 7-day disease severity in 84 hospitalized patients with COVID-19 pneumonia: A retrospective cohort study.
Ann. Transl. Med. 2020, 8, 635. [CrossRef]
85. Shang, W.; Dong, J.; Ren, Y.; Tian, M.; Li, W.; Hu, J.; Li, Y. The value of clinical parameters in predicting the severity of COVID-19.
J. Med. Virol. 2020, 92, 2188–2192. [CrossRef]
86. Wijeratne, T.; Gillard Crewther, S.; Sales, C.; Karimi, L. COVID-19 Pathophysiology Predicts That Ischemic Stroke Occurrence Is
an Expectation, Not an Exception-A Systematic Review. Front. Neurol. 2020, 11, 607221. [CrossRef]
87. Fois, A.G.; Paliogiannis, P.; Scano, V.; Cau, S.; Babudieri, S.; Perra, R.; Ruzzittu, G.; Zinellu, E.; Pirina, P.; Carru, C.; et al. The
Systemic Inflammation Index on Admission Predicts In-Hospital Mortality in COVID-19 Patients. Molecules 2020, 25, 5725.
[CrossRef] [PubMed]
88. Zuo, Y.; Yalavarthi, S.; Shi, H.; Gockman, K.; Zuo, M.; Madison, J.A.; Blair, C.; Weber, A.; Barnes, B.J.; Egeblad, M.; et al. Neutrophil
extracellular traps (NETs) as markers of disease severity in COVID-19. medRxiv 2020. [CrossRef]
89. Tomar, B.; Anders, H.J.; Desai, J.; Mulay, S.R. Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in
COVID-19. Cells 2020, 9, 1383. [CrossRef]
90. Middleton, E.A.; He, X.Y.; Denorme, F.; Campbell, R.A.; Ng, D.; Salvatore, S.P.; Mostyka, M.; Baxter-Stoltzfus, A.; Borczuk, A.C.;
Loda, M.; et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome.
Blood 2020, 136, 1169–1179. [CrossRef]
91. Medcalf, R.L.; Keragala, C.B.; Myles, P.S. Fibrinolysis and COVID-19: A plasmin paradox. J. Thromb. Haemost. 2020, 18, 2118–2122.
[CrossRef]
92. Zhang, Y.; Cao, W.; Jiang, W.; Xiao, M.; Li, Y.; Tang, N.; Liu, Z.; Yan, X.; Zhao, Y.; Li, T.; et al. Profile of natural anticoagulant,
coagulant factor and anti-phospholipid antibody in critically ill COVID-19 patients. J. Thromb. Thrombolysis 2020, 50, 580–586.
[CrossRef] [PubMed]
93. Zhang, Y.; Xiao, M.; Zhang, S.; Xia, P.; Cao, W.; Jiang, W.; Chen, H.; Ding, X.; Zhao, H.; Zhang, H.; et al. Coagulopathy and
Antiphospholipid Antibodies in Patients with Covid-19. N. Engl. J. Med. 2020, 382, e38. [CrossRef] [PubMed]
94. Aubignat, M.; Godefroy, O. COVID-19 and ischemic stroke: Should we systematically look for lupus anticoagulant and
antiphospholipid antibodies? Rev. Neurol. 2020, 176, 505–506. [CrossRef] [PubMed]
95. Akerstrom, S.; Gunalan, V.; Keng, C.T.; Tan, Y.J.; Mirazimi, A. Dual effect of nitric oxide on SARS-CoV replication: Viral RNA
production and palmitoylation of the S protein are affected. Virology 2009, 395, 1–9. [CrossRef]
96. Kochi, A.N.; Tagliari, A.P.; Forleo, G.B.; Fassini, G.M.; Tondo, C. Cardiac and arrhythmic complications in patients with COVID-19.
J. Cardiovasc. Electrophysiol. 2020, 31, 1003–1008. [CrossRef]
97. Sharifian-Dorche, M.; Huot, P.; Osherov, M.; Wen, D.; Saveriano, A.; Giacomini, P.S.; Antel, J.P.; Mowla, A. Neurological
complications of coronavirus infection; a comparative review and lessons learned during the COVID-19 pandemic. J. Neurol. Sci.
2020, 417, 117085. [CrossRef]
98. Wijeratne, T.; Sales, C.A.; Crewther, S.G.; Nguyen, V.; Karimi, L. First Australian Case of Good Recovery of a COVID-19 Patient
with Severe Neurological Symptoms Post Prolonged Hospitalization. Cureus 2020, 12, e10366. [CrossRef]
99. Pereira, M.P.; Lima, E.G.; Serrano, C.V., Jr. Viral infections and atherothrombosis: Another caution in the wake of COVID-19? Rev.
Assoc. Med. Bras. 2020, 66, 366–369. [CrossRef]
100. Hansson, G.K.; Libby, P.; Tabas, I. Inflammation and plaque vulnerability. J. Intern. Med. 2015, 278, 483–493. [CrossRef]
101. Hermus, L.; Lefrandt, J.D.; Tio, R.A.; Breek, J.C.; Zeebregts, C.J. Carotid plaque formation and serum biomarkers. Atherosclerosis
2010, 213, 21–29. [CrossRef]
102. Anrather, J.; Iadecola, C. Inflammation and Stroke: An Overview. Neurotherapeutics 2016, 13, 661–670. [CrossRef]
103. Iadecola, C.; Anrather, J. The immunology of stroke: From mechanisms to translation. Nat. Med. 2011, 17, 796–808. [CrossRef]
104. Algahtani, H.; Subahi, A.; Shirah, B. Neurological Complications of Middle East Respiratory Syndrome Coronavirus: A Report of
Two Cases and Review of the Literature. Case Rep. Neurol. Med. 2016, 2016, 3502683. [CrossRef]
105. Al-Hameed, F.M. Spontaneous intracranial hemorrhage in a patient with Middle East respiratory syndrome corona virus. Saudi
Med. J. 2017, 38, 196–200. [CrossRef] [PubMed]
106. Munakomi, S.; Bharati, K. Letter to the Editor Regarding “Acute Hemorrhage After Intracerebral Biopsy in COVID-19 Patients: A
Report of 3 Cases”. World Neurosurg. 2020, 141, 558. [CrossRef]
107. Phipps, M.S.; Cronin, C.A. Management of acute ischemic stroke. BMJ 2020, 368, l6983. [CrossRef] [PubMed]
108. Salahuddin, H.; Castonguay, A.C.; Zaidi, S.F.; Burgess, R.; Jadhav, A.P.; Jumaa, M.A. Interventional Stroke Care in the Era of
COVID-19. Front. Neurol. 2020, 11, 468. [CrossRef] [PubMed]
109. Al Hashmi, A.M.; Ozdemir, A.O.; Shuaib, A.; Al-Jehani, H.; Mansour, O.Y.; Alhazzani, A.; Aladhem, F.; Farhoudi, M.; John,
S.; Saqqur, M. Current Recommendations for the Management of Stroke Patients in the Middle East in the Era of COVID-19
Pandemic; Statement from the MENA SINO. J. Stroke Cerebrovasc. Dis. 2020, 29, 105181. [CrossRef] [PubMed]
110. Ford, T.; Curiale, G.; Nguyen, T.N.; Aparicio, H.; Hamlyn, E.K.; Gangadhara, S.; Cervantes-Arslanian, A.M.; Greer, D.; Romero,
J.R.; Shulman, J.G. Optimization of resources and modifications in acute ischemic stroke care in response to the global COVID-19
pandemic. J. Stroke Cerebrovasc. Dis. 2020, 29, 104980. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2021, 22, 4081 17 of 21

111. Akima, S.; McLintock, C.; Hunt, B.J. RE: ISTH interim guidance to recognition and management of coagulopathy in COVID-19. J.
Thromb. Haemost. 2020, 18, 2057–2058. [CrossRef] [PubMed]
112. Moores, L.K.; Tritschler, T.; Brosnahan, S.; Carrier, M.; Collen, J.F.; Doerschug, K.; Holley, A.B.; Jimenez, D.; Le Gal, G.; Rali,
P.; et al. Prevention, Diagnosis, and Treatment of VTE in Patients with Coronavirus Disease 2019: CHEST Guideline and Expert
Panel Report. Chest 2020, 158, 1143–1163. [CrossRef]
113. Bikdeli, B.; Madhavan, M.V.; Jimenez, D.; Chuich, T.; Dreyfus, I.; Driggin, E.; Nigoghossian, C.; Ageno, W.; Madjid, M.; Guo,
Y.; et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and
Follow-Up: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2020, 75, 2950–2973. [CrossRef]
114. Valderrama, E.V.; Humbert, K.; Lord, A.; Frontera, J.; Yaghi, S. Severe Acute Respiratory Syndrome Coronavirus 2 Infection and
Ischemic Stroke. Stroke 2020, 51, e124–e127. [CrossRef] [PubMed]
115. Oxley, T.J.; Mocco, J.; Majidi, S.; Kellner, C.P.; Shoirah, H.; Singh, I.P.; De Leacy, R.A.; Shigematsu, T.; Ladner, T.R.; Yaeger,
K.A.; et al. Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young. N. Engl. J. Med. 2020, 382, e60. [CrossRef]
[PubMed]
116. Meyfroidt, G.; Kurtz, P.; Sonneville, R. Critical care management of infectious meningitis and encephalitis. Intensive Care Med.
2020, 46, 192–201. [CrossRef] [PubMed]
117. Pennisi, M.; Lanza, G.; Falzone, L.; Fisicaro, F.; Ferri, R.; Bella, R. SARS-CoV-2 and the Nervous System: From Clinical Features to
Molecular Mechanisms. Int. J. Mol. Sci. 2020, 21, 5475. [CrossRef] [PubMed]
118. Duong, L.; Xu, P.; Liu, A. Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in
Downtown Los Angeles, early April 2020. Brain Behav. Immun. 2020, 87, 33. [CrossRef] [PubMed]
119. Benameur, K.; Agarwal, A.; Auld, S.C.; Butters, M.P.; Webster, A.S.; Ozturk, T.; Howell, J.C.; Bassit, L.C.; Velasquez, A.; Schinazi,
R.F.; et al. Encephalopathy and Encephalitis Associated with Cerebrospinal Fluid Cytokine Alterations and Coronavirus Disease,
Atlanta, Georgia, USA, 2020. Emerg. Infect. Dis. 2020, 26, 2016–2021. [CrossRef] [PubMed]
120. Yu, H.; Sun, T.; Feng, J. Complications and Pathophysiology of COVID-19 in the Nervous System. Front. Neurol. 2020, 11, 573421.
[CrossRef] [PubMed]
121. Parsons, T.; Banks, S.; Bae, C.; Gelber, J.; Alahmadi, H.; Tichauer, M. COVID-19-associated acute disseminated encephalomyelitis
(ADEM). J. Neurol. 2020, 267, 2799–2802. [CrossRef]
122. Reichard, R.R.; Kashani, K.B.; Boire, N.A.; Constantopoulos, E.; Guo, Y.; Lucchinetti, C.F. Neuropathology of COVID-19: A
spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology. Acta Neuropathol. 2020, 140, 1–6.
[CrossRef] [PubMed]
123. Chen, T.; Wu, D.; Chen, H.; Yan, W.; Yang, D.; Chen, G.; Ma, K.; Xu, D.; Yu, H.; Wang, H.; et al. Clinical characteristics of 113
deceased patients with coronavirus disease 2019: Retrospective study. BMJ 2020, 368, m1091. [CrossRef] [PubMed]
124. Nath, A.; Smith, B. Neurological complications of COVID-19: From bridesmaid to bride. Arq. Neuropsiquiatr. 2020, 78, 459–460.
[CrossRef] [PubMed]
125. Filatov, A.; Sharma, P.; Hindi, F.; Espinosa, P.S. Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy.
Cureus 2020, 12, e7352. [CrossRef] [PubMed]
126. Espinosa, P.S.; Rizvi, Z.; Sharma, P.; Hindi, F.; Filatov, A. Neurological Complications of Coronavirus Disease (COVID-19):
Encephalopathy, MRI Brain and Cerebrospinal Fluid Findings: Case 2. Cureus 2020, 12, e7930. [CrossRef]
127. Virhammar, J.; Kumlien, E.; Fallmar, D.; Frithiof, R.; Jackmann, S.; Skold, M.K.; Kadir, M.; Frick, J.; Lindeberg, J.; Olivero-Reinius,
H.; et al. Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid. Neurology 2020, 95, 445–449.
[CrossRef]
128. Radmanesh, A.; Derman, A.; Ishida, K. COVID-19-associated delayed posthypoxic necrotizing leukoencephalopathy. J. Neurol.
Sci. 2020, 415, 116945. [CrossRef] [PubMed]
129. Poyiadji, N.; Shahin, G.; Noujaim, D.; Stone, M.; Patel, S.; Griffith, B. COVID-19-associated Acute Hemorrhagic Necrotizing
Encephalopathy: Imaging Features. Radiology 2020, 296, E119–E120. [CrossRef] [PubMed]
130. Kennedy, M.; Helfand, B.K.I.; Gou, R.Y.; Gartaganis, S.L.; Webb, M.; Moccia, J.M.; Bruursema, S.N.; Dokic, B.; McCulloch, B.;
Ring, H.; et al. Delirium in Older Patients with COVID-19 Presenting to the Emergency Department. JAMA Netw. Open 2020,
3, e2029540. [CrossRef]
131. Pun, B.T.; Badenes, R.; Heras La Calle, G.; Orun, O.M.; Chen, W.; Raman, R.; Simpson, B.K.; Wilson-Linville, S.; Hinojal Olmedillo,
B.; Vallejo de la Cueva, A.; et al. Prevalence and risk factors for delirium in critically ill patients with COVID-19 (COVID-D): A
multicentre cohort study. Lancet Respir. Med. 2021, 9, 239–250. [CrossRef]
132. Cag, Y.; Erdem, H.; Leib, S.; Defres, S.; Kaya, S.; Larsen, L.; Poljak, M.; Ozturk-Engin, D.; Barsic, B.; Argemi, X.; et al. Managing
atypical and typical herpetic central nervous system infections: Results of a multinational study. Clin. Microbiol. Infect. 2016,
22, 568.e9. [CrossRef] [PubMed]
133. Asadi-Pooya, A.A. Seizures associated with coronavirus infections. Seizure 2020, 79, 49–52. [CrossRef] [PubMed]
134. Vollono, C.; Rollo, E.; Romozzi, M.; Frisullo, G.; Servidei, S.; Borghetti, A.; Calabresi, P. Focal status epilepticus as unique clinical
feature of COVID-19: A case report. Seizure 2020, 78, 109–112. [CrossRef]
135. Hepburn, M.; Mullaguri, N.; George, P.; Hantus, S.; Punia, V.; Bhimraj, A.; Newey, C.R. Acute Symptomatic Seizures in Critically
Ill Patients with COVID-19: Is There an Association? Neurocrit. Care 2021, 34, 139–143. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2021, 22, 4081 18 of 21

136. Scullen, T.; Keen, J.; Mathkour, M.; Dumont, A.S.; Kahn, L. Coronavirus 2019 (COVID-19)-Associated Encephalopathies and
Cerebrovascular Disease: The New Orleans Experience. World Neurosurg. 2020, 141, e437–e446. [CrossRef] [PubMed]
137. Lyons, S.; O’Kelly, B.; Woods, S.; Rowan, C.; Brady, D.; Sheehan, G.; Smyth, S. Seizure with CSF lymphocytosis as a presenting
feature of COVID-19 in an otherwise healthy young man. Seizure 2020, 80, 113–114. [CrossRef]
138. Elgamasy, S.; Kamel, M.G.; Ghozy, S.; Khalil, A.; Morra, M.E.; Islam, S.M.S. First case of focal epilepsy associated with SARS-
coronavirus-2. J. Med. Virol. 2020, 92, 2238–2242. [CrossRef] [PubMed]
139. Abdulsalam, M.A.; Abdulsalam, A.J.; Shehab, D. Generalized status epilepticus as a possible manifestation of COVID-19. Acta
Neurol. Scand. 2020, 142, 297–298. [CrossRef] [PubMed]
140. Somani, S.; Pati, S.; Gaston, T.; Chitlangia, A.; Agnihotri, S. De Novo Status Epilepticus in patients with COVID-19. Ann. Clin.
Transl. Neurol. 2020, 7, 1240–1244. [CrossRef]
141. Ashraf, M.; Sajed, S. Seizures Related to Coronavirus Disease (COVID-19): Case Series and Literature Review. Cureus 2020,
12, e9378. [CrossRef] [PubMed]
142. Bhatta, S.; Sayed, A.; Ranabhat, B.; Bhatta, R.K.; Acharya, Y. New-Onset Seizure as the Only Presentation in a Child with
COVID-19. Cureus 2020, 12, e8820. [CrossRef] [PubMed]
143. Saeed, A.; Shorafa, E. Status epilepticus as a first presentation of COVID-19 infection in a 3 years old boy; Case report and review
the literature. IDCases 2020, 22, e00942. [CrossRef] [PubMed]
144. Lu, L.; Xiong, W.; Liu, D.; Liu, J.; Yang, D.; Li, N.; Mu, J.; Guo, J.; Li, W.; Wang, G.; et al. New onset acute symptomatic seizure and
risk factors in coronavirus disease 2019: A retrospective multicenter study. Epilepsia 2020, 61, e49–e53. [CrossRef] [PubMed]
145. von Hentig, N. Repositioning HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors for the treatment of
SARS-CoV-2 infection and COVID-19. Eur. J. Clin. Pharmacol. 2021. [CrossRef] [PubMed]
146. Yeh, R.F.; Gaver, V.E.; Patterson, K.B.; Rezk, N.L.; Baxter-Meheux, F.; Blake, M.J.; Eron, J.J., Jr.; Klein, C.E.; Rublein, J.C.; Kashuba,
A.D. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits
the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J. Acquir. Immune
Defic. Syndr. 2006, 42, 52–60. [CrossRef] [PubMed]
147. Van der Lee, M.J.; Dawood, L.; ter Hofstede, H.J.; de Graaff-Teulen, M.J.; van Ewijk-Beneken Kolmer, E.W.; Caliskan-Yassen, N.;
Koopmans, P.P.; Burger, D.M. Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy subjects. Clin. Pharmacol.
Ther. 2006, 80, 159–168. [CrossRef] [PubMed]
148. Firat, O.; Yalcin, N.; Demirkan, K. COVID-19 & antiepileptic drugs: Should we pay attention? Seizure 2020, 80, 240–241. [CrossRef]
149. Bahcecioglu, O.F.; Gok, S.; Durmus, M. Is it safe to use remdesivir in combination with a combined p-glycoprotein and CYP3A4
inhibitor? Eur. J. Hosp. Pharm. 2021, 28, e6. [CrossRef] [PubMed]
150. Asadi-Pooya, A.A.; Attar, A.; Moghadami, M.; Karimzadeh, I. Management of COVID-19 in people with epilepsy: Drug
considerations. Neurol. Sci. 2020, 41, 2005–2011. [CrossRef]
151. Butt, I.; Sawlani, V.; Geberhiwot, T. Prolonged confusional state as first manifestation of COVID-19. Ann. Clin. Transl. Neurol.
2020, 7, 1450–1452. [CrossRef]
152. Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical
characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513.
[CrossRef]
153. Helms, J.; Kremer, S.; Merdji, H.; Schenck, M.; Severac, F.; Clere-Jehl, R.; Studer, A.; Radosavljevic, M.; Kummerlen, C.; Monnier,
A.; et al. Delirium and encephalopathy in severe COVID-19: A cohort analysis of ICU patients. Crit. Care 2020, 24, 491. [CrossRef]
154. Andrade, G.; Simoes do Couto, F.; Camara-Pestana, L. Recommendations about the Use of Psychotropic Medications during the
COVID-19 Pandemic. Acta Med. Port. 2020, 33, 693–702. [CrossRef]
155. Sabe, M.; Dorsaz, O.; Huguelet, P.; Kaiser, S. Toxicity of psychotropic drugs in patients with COVID-19: A systematic review. Gen.
Hosp. Psychiatry 2021, 70, 1–9. [CrossRef]
156. Plasencia-Garcia, B.O.; Rodriguez-Menendez, G.; Rico-Rangel, M.I.; Rubio-Garcia, A.; Torello-Iserte, J.; Crespo-Facorro, B.
Drug-drug interactions between COVID-19 treatments and antipsychotics drugs: Integrated evidence from 4 databases and a
systematic review. Psychopharmacology 2021, 238, 329–340. [CrossRef]
157. Nguyen, T.P.; Taylor, R.S. Guillain Barre Syndrome. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2021.
158. Rahimi, K. Guillain-Barre syndrome during COVID-19 pandemic: An overview of the reports. Neurol. Sci. 2020, 41, 3149–3156.
[CrossRef] [PubMed]
159. Tiet, M.Y.; AlShaikh, N. Guillain-Barre syndrome associated with COVID-19 infection: A case from the UK. BMJ Case Rep. 2020, 13.
[CrossRef] [PubMed]
160. Sancho-Saldana, A.; Lambea-Gil, A.; Liesa, J.L.C.; Caballo, M.R.B.; Garay, M.H.; Celada, D.R.; Serrano-Ponz, M. Guillain-Barre
syndrome associated with leptomeningeal enhancement following SARS-CoV-2 infection. Clin. Med. 2020, 20, e93–e94. [CrossRef]
[PubMed]
161. Tatu, L.; Nono, S.; Gracio, S.; Kocer, S. Guillain-Barre syndrome in the COVID-19 era: Another occasional cluster? J. Neurol. 2020.
[CrossRef]
162. Caress, J.B.; Castoro, R.J.; Simmons, Z.; Scelsa, S.N.; Lewis, R.A.; Ahlawat, A.; Narayanaswami, P. COVID-19-associated
Guillain-Barre syndrome: The early pandemic experience. Muscle Nerve 2020, 62, 485–491. [CrossRef]
Int. J. Mol. Sci. 2021, 22, 4081 19 of 21

163. Zhao, H.; Shen, D.; Zhou, H.; Liu, J.; Chen, S. Guillain-Barre syndrome associated with SARS-CoV-2 infection: Causality or
coincidence? Lancet Neurol. 2020, 19, 383–384. [CrossRef]
164. Gupta, A.; Paliwal, V.K.; Garg, R.K. Is COVID-19-related Guillain-Barre syndrome different? Brain Behav. Immun. 2020, 87, 177–178.
[CrossRef]
165. Gutierrez-Ortiz, C.; Mendez-Guerrero, A.; Rodrigo-Rey, S.; San Pedro-Murillo, E.; Bermejo-Guerrero, L.; Gordo-Manas, R.; de
Aragon-Gomez, F.; Benito-Leon, J. Miller Fisher syndrome and polyneuritis cranialis in COVID-19. Neurology 2020, 95, e601–e605.
[CrossRef]
166. Lascano, A.M.; Epiney, J.B.; Coen, M.; Serratrice, J.; Bernard-Valnet, R.; Lalive, P.H.; Kuntzer, T.; Hubers, A. SARS-CoV-2 and
Guillain-Barre syndrome: AIDP variant with a favourable outcome. Eur. J. Neurol. 2020, 27, 1751–1753. [CrossRef] [PubMed]
167. Assini, A.; Benedetti, L.; Di Maio, S.; Schirinzi, E.; Del Sette, M. Correction to: New clinical manifestation of COVID-19 related
Guillain-Barre syndrome highly responsive to intravenous immunoglobulins: Two Italian cases. Neurol. Sci. 2020, 41, 2307.
[CrossRef] [PubMed]
168. Khanlou, H.; Valdes-Sueiras, M.; Farthing, C. Peripheral Neuropathy Induced by Lopinavir-Saquinavir-Ritonavir Combination
Therapy in an HIV-Infected Patient. J. Int. Assoc. Physicians AIDS Care 2007, 6, 155. [CrossRef]
169. Ellis, R.J.; Marquie-Beck, J.; Delaney, P.; Alexander, T.; Clifford, D.B.; McArthur, J.C.; Simpson, D.M.; Ake, C.; Collier, A.C.;
Gelman, B.B.; et al. Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Ann. Neurol. 2008,
64, 566–572. [CrossRef]
170. Madia, F.; Merico, B.; Primiano, G.; Cutuli, S.L.; De Pascale, G.; Servidei, S. Acute myopathic quadriplegia in patients with
COVID-19 in the intensive care unit. Neurology 2020, 95, 492–494. [CrossRef] [PubMed]
171. Tankisi, H.; Tankisi, A.; Harbo, T.; Markvardsen, L.K.; Andersen, H.; Pedersen, T.H. Critical illness myopathy as a consequence of
Covid-19 infection. Clin. Neurophysiol. 2020, 131, 1931–1932. [CrossRef] [PubMed]
172. Costamagna, G.; Abati, E.; Bresolin, N.; Comi, G.P.; Corti, S. Management of patients with neuromuscular disorders at the time of
the SARS-CoV-2 pandemic. J. Neurol. 2020. [CrossRef] [PubMed]
173. Sharifian-Dorche, M.; Sahraian, M.A.; Fadda, G.; Osherov, M.; Sharifian-Dorche, A.; Karaminia, M.; Saveriano, A.W.; La Piana, R.;
Antel, J.P.; Giacomini, P.S. COVID-19 and disease-modifying therapies in patients with demyelinating diseases of the central
nervous system: A systematic review. Mult. Scler. Relat. Disord. 2021, 50, 102800. [CrossRef]
174. Guidon, A.C.; Amato, A.A. COVID-19 and neuromuscular disorders. Neurology 2020, 94, 959–969. [CrossRef] [PubMed]
175. Salik, I.; Rodhouse, H.B.; Barst, S. Myasthenic crisis in the setting of Coronavirus Disease 2019 (COVID-19). J. Clin. Anesth. 2020,
67, 110001. [CrossRef] [PubMed]
176. Jacob, S.; Muppidi, S.; Guidon, A.; Guptill, J.; Hehir, M.; Howard, J.F.; Illa, I.; Mantegazza, R.; Murai, H.; Utsugisawa, K.; et al.
Guidance for the management of myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) during the COVID-19
pandemic. J. Neurol. Sci. 2020, 412, 116803. [CrossRef] [PubMed]
177. Koc, G.; Odabasi, Z.; Tan, E. Myasthenic Syndrome Caused by Hydroxychloroquine Used for COVID-19 Prophylaxis. J. Clin.
Neuromuscul. Dis. 2020, 22, 60–62. [CrossRef] [PubMed]
178. Delly, F.; Syed, M.J.; Lisak, R.P.; Zutshi, D. Myasthenic crisis in COVID-19. J. Neurol. Sci. 2020, 414, 116888. [CrossRef] [PubMed]
179. Siddiqi, Z.A.; Khan, W.; Hussain, F.S. Rituximab in Myasthenia Gravis—Where do we stand? Expert Opin. Biol. Ther. 2021.
[CrossRef]
180. Dalakas, M.C. Progress in the therapy of myasthenia gravis: Getting closer to effective targeted immunotherapies. Curr. Opin.
Neurol. 2020, 33, 545–552. [CrossRef]
181. Wang, F.; Kream, R.M.; Stefano, G.B. Long-Term Respiratory and Neurological Sequelae of COVID-19. Med. Sci. Monit. 2020,
26, e928996. [CrossRef]
182. Lukiw, W.J.; Pogue, A.; Hill, J.M. SARS-CoV-2 Infectivity and Neurological Targets in the Brain. Cell. Mol. Neurobiol. 2020.
[CrossRef] [PubMed]
183. Kempuraj, D.; Selvakumar, G.P.; Ahmed, M.E.; Raikwar, S.P.; Thangavel, R.; Khan, A.; Zaheer, S.A.; Iyer, S.S.; Burton, C.; James,
D.; et al. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist 2020, 26, 402–414.
[CrossRef] [PubMed]
184. Zanin, L.; Saraceno, G.; Panciani, P.P.; Renisi, G.; Signorini, L.; Migliorati, K.; Fontanella, M.M. SARS-CoV-2 can induce brain and
spine demyelinating lesions. Acta Neurochir. 2020, 162, 1491–1494. [CrossRef]
185. Peyrin-Biroulet, L.; Danese, S. More on Covid-19 in Immune-Mediated Inflammatory Diseases. N. Engl. J. Med. 2020, 383, 796.
[CrossRef]
186. Sormani, M.P. An Italian programme for COVID-19 infection in multiple sclerosis. Lancet Neurol. 2020, 19, 481–482. [CrossRef]
187. Fuchs, V.; Kutza, M.; Wischnewski, S.; Deigendesch, N.; Lutz, L.; Kulsvehagen, L.; Ricken, G.; Kappos, L.; Tzankov, A.; Hametner,
S.; et al. Presence of SARS-CoV-2 Transcripts in the Choroid Plexus of MS and Non-MS Patients with COVID-19. Neurol.
Neuroimmunol. Neuroinflamm. 2021, 8. [CrossRef]
188. Sochocka, M.; Zwolinska, K.; Leszek, J. The Infectious Etiology of Alzheimer’s Disease. Curr. Neuropharmacol. 2017, 15, 996–1009.
[CrossRef] [PubMed]
189. Chen, X.; Laurent, S.; Onur, O.A.; Kleineberg, N.N.; Fink, G.R.; Schweitzer, F.; Warnke, C. A systematic review of neurological
symptoms and complications of COVID-19. J. Neurol. 2021, 268, 392–402. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2021, 22, 4081 20 of 21

190. Krajcovicova, L.; Klobusiakova, P.; Rektorova, I. Gray Matter Changes in Parkinson’s and Alzheimer’s Disease and Relation to
Cognition. Curr. Neurol. Neurosci. Rep. 2019, 19, 85. [CrossRef]
191. Sulzer, D.; Antonini, A.; Leta, V.; Nordvig, A.; Smeyne, R.J.; Goldman, J.E.; Al-Dalahmah, O.; Zecca, L.; Sette, A.; Bubacco, L.; et al.
COVID-19 and possible links with Parkinson’s disease and parkinsonism: From bench to bedside. NPJ Parkinsons Dis. 2020, 6, 18.
[CrossRef]
192. McAlpine, L.S.; Fesharaki-Zadeh, A.; Spudich, S. Coronavirus disease 2019 and neurodegenerative disease: What will the future
bring? Curr. Opin. Psychiatry 2021, 34, 177–185. [CrossRef]
193. Campiglio, L.; Priori, A. Neurological symptoms in acute COVID-19 infected patients: A survey among Italian physicians. PLoS
ONE 2020, 15, e0238159. [CrossRef] [PubMed]
194. Karadas, O.; Ozturk, B.; Sonkaya, A.R. A prospective clinical study of detailed neurological manifestations in patients with
COVID-19. Neurol. Sci. 2020, 41, 1991–1995. [CrossRef] [PubMed]
195. Lai, C.C.; Ko, W.C.; Lee, P.I.; Jean, S.S.; Hsueh, P.R. Extra-respiratory manifestations of COVID-19. Int. J. Antimicrob. Agents 2020,
56, 106024. [CrossRef] [PubMed]
196. Liu, K.; Pan, M.; Xiao, Z.; Xu, X. Neurological manifestations of the coronavirus (SARS-CoV-2) pandemic 2019-2020. J. Neurol.
Neurosurg. Psychiatry 2020, 91, 669–670. [CrossRef]
197. Singh, J.; Ali, A. Headache as the Presenting Symptom in 2 Patients with COVID-19 and a History of Migraine: 2 Case Reports.
Headache 2020, 60, 1773–1776. [CrossRef]
198. Bolay, H.; Gul, A.; Baykan, B. COVID-19 is a Real Headache! Headache 2020, 60, 1415–1421. [CrossRef]
199. Vacchiano, V.; Riguzzi, P.; Volpi, L.; Tappata, M.; Avoni, P.; Rizzo, G.; Guerra, L.; Zaccaroni, S.; Cortelli, P.; Michelucci, R.; et al.
Early neurological manifestations of hospitalized COVID-19 patients. Neurol. Sci. 2020, 41, 2029–2031. [CrossRef] [PubMed]
200. Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; et al. Clinical course and outcomes of critically
ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir.
Med. 2020, 8, 475–481. [CrossRef]
201. Tian, S.; Hu, N.; Lou, J.; Chen, K.; Kang, X.; Xiang, Z.; Chen, H.; Wang, D.; Liu, N.; Liu, D.; et al. Characteristics of COVID-19
infection in Beijing. J. Infect. 2020, 80, 401–406. [CrossRef]
202. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected
with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [CrossRef]
203. Choi, W.S.; Kang, C.I.; Kim, Y.; Choi, J.P.; Joh, J.S.; Shin, H.S.; Kim, G.; Peck, K.R.; Chung, D.R.; Kim, H.O.; et al. Clinical
Presentation and Outcomes of Middle East Respiratory Syndrome in the Republic of Korea. Infect. Chemother. 2016, 48, 118–126.
[CrossRef] [PubMed]
204. Kim, E.S.; Chin, B.S.; Kang, C.K.; Kim, N.J.; Kang, Y.M.; Choi, J.P.; Oh, D.H.; Kim, J.H.; Koh, B.; Kim, S.E.; et al. Clinical Course
and Outcomes of Patients with Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Preliminary Report of the First 28
Patients from the Korean Cohort Study on COVID-19. J. Korean Med. Sci. 2020, 35, e142. [CrossRef] [PubMed]
205. Belvis, R. Headaches During COVID-19: My Clinical Case and Review of the Literature. Headache 2020, 60, 1422–1426. [CrossRef]
[PubMed]
206. Caronna, E.; Ballve, A.; Llaurado, A.; Gallardo, V.J.; Ariton, D.M.; Lallana, S.; Lopez Maza, S.; Olive Gadea, M.; Quibus, L.;
Restrepo, J.L.; et al. Headache: A striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution.
Cephalalgia 2020, 40, 1410–1421. [CrossRef]
207. Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; et al. Clinical Characteristics
of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020, 323, 1061–1069.
[CrossRef]
208. Sun, L.; Shen, L.; Fan, J.; Gu, F.; Hu, M.; An, Y.; Zhou, Q.; Fan, H.; Bi, J. Clinical features of patients with coronavirus disease 2019
from a designated hospital in Beijing, China. J. Med. Virol. 2020, 92, 2055–2066. [CrossRef] [PubMed]
209. Kong, Z.; Wang, J.; Li, T.; Zhang, Z.; Jian, J. 2019 novel coronavirus pneumonia with onset of dizziness: A case report. Ann. Transl.
Med. 2020, 8, 506. [CrossRef]
210. Tsai, S.T.; Lu, M.K.; San, S.; Tsai, C.H. The Neurologic Manifestations of Coronavirus Disease 2019 Pandemic: A Systemic Review.
Front. Neurol. 2020, 11, 498. [CrossRef]
211. Harapan, B.N.; Yoo, H.J. Neurological symptoms, manifestations, and complications associated with severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19). J. Neurol. 2021. [CrossRef] [PubMed]
212. Pitscheider, L.; Karolyi, M.; Burkert, F.R.; Helbok, R.; Wanschitz, J.V.; Horlings, C.; Pawelka, E.; Omid, S.; Traugott, M.; Seitz,
T.; et al. Muscle involvement in SARS-CoV-2 infection. Eur. J. Neurol. 2020. [CrossRef] [PubMed]
213. Cooper, K.W.; Brann, D.H.; Farruggia, M.C.; Bhutani, S.; Pellegrino, R.; Tsukahara, T.; Weinreb, C.; Joseph, P.V.; Larson, E.D.;
Parma, V.; et al. COVID-19 and the Chemical Senses: Supporting Players Take Center Stage. Neuron 2020, 107, 219–233. [CrossRef]
[PubMed]
214. Giacomelli, A.; Pezzati, L.; Conti, F.; Bernacchia, D.; Siano, M.; Oreni, L.; Rusconi, S.; Gervasoni, C.; Ridolfo, A.L.; Rizzardini,
G.; et al. Self-reported Olfactory and Taste Disorders in Patients with Severe Acute Respiratory Coronavirus 2 Infection: A
Cross-sectional Study. Clin. Infect. Dis. 2020, 71, 889–890. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2021, 22, 4081 21 of 21

215. Beltran-Corbellini, A.; Chico-Garcia, J.L.; Martinez-Poles, J.; Rodriguez-Jorge, F.; Natera-Villalba, E.; Gomez-Corral, J.; Gomez-
Lopez, A.; Monreal, E.; Parra-Diaz, P.; Cortes-Cuevas, J.L.; et al. Acute-onset smell and taste disorders in the context of COVID-19:
A pilot multicentre polymerase chain reaction based case-control study. Eur. J. Neurol. 2020, 27, 1738–1741. [CrossRef]
216. Lechien, J.R.; Chiesa-Estomba, C.M.; Cabaraux, P.; Mat, Q.; Huet, K.; Harmegnies, B.; Horoi, M.; Le Bon, S.D.; Rodriguez, A.;
Dequanter, D.; et al. Features of Mild-to-Moderate COVID-19 Patients with Dysphonia. J. Voice 2020. [CrossRef] [PubMed]
217. Mehraeen, E.; Behnezhad, F.; Salehi, M.A.; Noori, T.; Harandi, H.; SeyedAlinaghi, S. Olfactory and gustatory dysfunctions due to
the coronavirus disease (COVID-19): A review of current evidence. Eur. Arch. Otorhinolaryngol. 2021, 278, 307–312. [CrossRef]
218. Lechien, J.R.; Chiesa-Estomba, C.M.; De Siati, D.R.; Horoi, M.; Le Bon, S.D.; Rodriguez, A.; Dequanter, D.; Blecic, S.; El Afia, F.;
Distinguin, L.; et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus
disease (COVID-19): A multicenter European study. Eur. Arch. Otorhinolaryngol. 2020, 277, 2251–2261. [CrossRef]
219. Benezit, F.; Le Turnier, P.; Declerck, C.; Paille, C.; Revest, M.; Dubee, V.; Tattevin, P.; Group, R.C.S. Utility of hyposmia and
hypogeusia for the diagnosis of COVID-19. Lancet Infect. Dis. 2020, 20, 1014–1015. [CrossRef]
220. Politi, L.S.; Salsano, E.; Grimaldi, M. Magnetic Resonance Imaging Alteration of the Brain in a Patient with Coronavirus Disease
2019 (COVID-19) and Anosmia. JAMA Neurol. 2020, 77, 1028–1029. [CrossRef]
221. Laurendon, T.; Radulesco, T.; Mugnier, J.; Gerault, M.; Chagnaud, C.; El Ahmadi, A.A.; Varoquaux, A. Bilateral transient olfactory
bulb edema during COVID-19-related anosmia. Neurology 2020, 95, 224–225. [CrossRef]
222. Keyhan, S.O.; Fallahi, H.R.; Cheshmi, B. Dysosmia and dysgeusia due to the 2019 Novel Coronavirus; a hypothesis that needs
further investigation. Maxillofac. Plast. Reconstr. Surg. 2020, 42, 9. [CrossRef] [PubMed]
223. Fodoulian, L.; Tuberosa, J.; Rossier, D.; Boillat, M.; Kan, C.; Pauli, V.; Egervari, K.; Lobrinus, J.A.; Landis, B.N.; Carleton, A.; et al.
SARS-CoV-2 Receptors and Entry Genes Are Expressed in the Human Olfactory Neuroepithelium and Brain. iScience 2020,
23, 101839. [CrossRef] [PubMed]
224. Moein, S.T.; Hashemian, S.M.; Mansourafshar, B.; Khorram-Tousi, A.; Tabarsi, P.; Doty, R.L. Smell dysfunction: A biomarker for
COVID-19. Int. Forum Allergy Rhinol. 2020, 10, 944–950. [CrossRef] [PubMed]
225. Wijeratne, T.; Crewther, S. Post-COVID 19 Neurological Syndrome (PCNS); a novel syndrome with challenges for the global
neurology community. J. Neurol. Sci. 2020, 419, 117179. [CrossRef] [PubMed]
226. Wijeratne, T.; Crewther, S. COVID-19 and long-term neurological problems: Challenges ahead with Post-COVID-19 Neurological
Syndrome. Aust. J. Gen. Pract. 2021, 50. [CrossRef] [PubMed]
227. Zou, X.; Chen, K.; Zou, J.; Han, P.; Hao, J.; Han, Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the
potential risk of different human organs vulnerable to 2019-nCoV infection. Front. Med. 2020, 14, 185–192. [CrossRef]
228. Gironacci, M.M.; Cerniello, F.M.; Longo Carbajosa, N.A.; Goldstein, J.; Cerrato, B.D. Protective axis of the renin-angiotensin
system in the brain. Clin. Sci. 2014, 127, 295–306. [CrossRef] [PubMed]
229. Xu, P.; Sriramula, S.; Lazartigues, E. ACE2/ANG-(1-7)/Mas pathway in the brain: The axis of good. Am. J. Physiol. Regul. Integr.
Comp. Physiol. 2011, 300, R804–R817. [CrossRef]
230. Xu, Z.; Shi, L.; Wang, Y.; Zhang, J.; Huang, L.; Zhang, C.; Liu, S.; Zhao, P.; Liu, H.; Zhu, L.; et al. Pathological findings of COVID-19
associated with acute respiratory distress syndrome. Lancet Respir. Med. 2020, 8, 420–422. [CrossRef]
231. Tan, M.; Liu, Y.; Zhou, R.; Deng, X.; Li, F.; Liang, K.; Shi, Y. Immunopathological characteristics of coronavirus disease 2019 cases
in Guangzhou, China. Immunology 2020, 160, 261–268. [CrossRef] [PubMed]
232. Li, X.; Geng, M.; Peng, Y.; Meng, L.; Lu, S. Molecular immune pathogenesis and diagnosis of COVID-19. J. Pharm. Anal. 2020,
10, 102–108. [CrossRef] [PubMed]
233. Zhang, C.; Wu, Z.; Li, J.W.; Zhao, H.; Wang, G.Q. Cytokine release syndrome in severe COVID-19: Interleukin-6 receptor
antagonist tocilizumab may be the key to reduce mortality. Int. J. Antimicrob. Agents 2020, 55, 105954. [CrossRef] [PubMed]
234. Hess, D.C.; Eldahshan, W.; Rutkowski, E. COVID-19-Related Stroke. Transl. Stroke Res. 2020, 11, 322–325. [CrossRef] [PubMed]
235. Tang, N.; Bai, H.; Chen, X.; Gong, J.; Li, D.; Sun, Z. Anticoagulant treatment is associated with decreased mortality in severe
coronavirus disease 2019 patients with coagulopathy. J. Thromb. Haemost. 2020, 18, 1094–1099. [CrossRef] [PubMed]
236. Wijeratne, T.; Wijeratne, C. Clinical utility of serial systemic immune inflammation indices (SSIIi) in the context of post covid-19
neurological syndrome (PCNS). J. Neurol. Sci. 2021, 423, 117356. [CrossRef]
237. Remy, K.E.; Mazer, M.; Striker, D.A.; Ellebedy, A.H.; Walton, A.H.; Unsinger, J.; Blood, T.M.; Mudd, P.A.; Yi, D.J.; Mannion,
D.A.; et al. Severe immunosuppression and not a cytokine storm characterizes COVID-19 infections. JCI Insight 2020, 5. [CrossRef]
238. Coperchini, F.; Chiovato, L.; Croce, L.; Magri, F.; Rotondi, M. The cytokine storm in COVID-19: An overview of the involvement
of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020, 53, 25–32. [CrossRef]
239. Zhang, B.; Zhou, X.; Zhu, C.; Song, Y.; Feng, F.; Qiu, Y.; Feng, J.; Jia, Q.; Song, Q.; Zhu, B.; et al. Immune Phenotyping Based on the
Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients with COVID-19. Front. Mol.
Biosci. 2020, 7, 157. [CrossRef]
240. Fu, Y.; Cheng, Y.; Wu, Y. Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential
Therapeutic Tools. Virol. Sin. 2020, 35, 266–271. [CrossRef]
241. Takada, A.; Kawaoka, Y. Antibody-dependent enhancement of viral infection: Molecular mechanisms and in vivo implications.
Rev. Med. Virol. 2003, 13, 387–398. [CrossRef]

You might also like