Neurological Complications of COVID-19: Underlying Mechanisms and Management
Neurological Complications of COVID-19: Underlying Mechanisms and Management
Neurological Complications of COVID-19: Underlying Mechanisms and Management
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
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.
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].
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
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.
pram), antipsychotics (olanzapine), and the mood stabilizer (valproate) are suggested as
safe considering the tolerability and minimal drug–drug interactions [154–156].
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.
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.
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