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COVID-19
Neuroinvasion, neurotropic, and neuroinflammatory events
of SARS-CoV-2: understanding the neurological manifestations
in COVID-19 patients
Yassine Yachou
1
&Abdeslem El Idrissi
2
&Vladimir Belapasov
1
&Said Ait Benali
3
Received: 12 May 2020 /Accepted: 2 July 2020
#Fondazione Società Italiana di Neurologia 2020
Abstract
Respiratory viruses are opportunistic pathogens that infect the upper respiratory tract in humans and cause severe illnesses,
especially in vulnerable populations. Some viruses have neuroinvasive properties and activate the immune response in the brain.
These immune events may be neuroprotective or they may cause long-term damage similar to what is seen in some neurode-
generative diseases. The new “Severe Acute Respiratory Syndrome Coronavirus 2”(SARS-CoV-2) is one of the Respiratory
viruses causing highly acute lethal pneumonia coronavirus disease 2019 (COVID-19) with clinical similarities to those reported
in “Severe Acute Respiratory Syndrome Coronavirus”(SARS-CoV) and the “Middle East Respiratory Syndrome
Coronavirus”(MERS-CoV) including neurological manifestation. To examine the possible neurological damage induced by
SARS-CoV-2, it is necessary to understand the immune reactions to viral infection in the brain, and their short- and long-term
consequences. Considering the similarities between SARS-CoV and SARS-CoV-2, which will be discussed, cooperative ho-
mological and phylogenetical studies lead us to question if SARS-CoV-2 can have similar neuroinvasive capacities and
neuroinflammatiory events that may lead to the same short- and long-term neuropathologies that SARS-CoV had shown in
human and animal models. To explain the neurological manifestation caused by SARS-CoV-2, we will present a literature review
of 765 COVID-19 patients, inwhich 18% had neurological symptoms and complications, including encephalopathy, encephalitis
and cerebrovascular pathologies, acute myelitis,and Guillain-Barré syndrome. Clinical studies describe anosmia or partial loss of
the sense of smell as the most frequent symptom in COVID19 patients, suggesting that olfactory dysfunction and the initial
ultrarapid immune responses could be a prognostic factor.
Keywords COVID-19 .Human respiratory virus .Human coronavirus .Respiratory viral infection .Neuroinvasion .CNS
infection .Acute and chronic neurological diseases .Encephalitis .Encephalopathy
Introduction
In a review on the central nervous system (CNS) viral infec-
tion, Koyuncu et al. concluded that all viruses can reach the
CNS under the right conditions depending on viral factors
(mutations in specific virulence genes) and host factors
(immunodepression, age, and comorbidities) [1]. Respiratory
illnesses caused by viral agents, characterized by high rates of
morbidity and mortality, are considered problems of critical
importance in public health [2–4]. Several human respiratory
viruses (including coronavirus CoV) are neuroinvasive and
neurotropic with potential neuropathological consequences
in vulnerable populations. The neurological manifestation
seen in patients with viral infection are caused by what is
known as the “cytokine storm”including pro-inflammatory
and anti-inflammatory cytokines as an immune reaction to
*Yassine Yachou
Yassine.yachou@gmail.com
Abdeslem El Idrissi
abdeslem.elidrissi@csi.cuny.edu
Vladimir Belapasov
belopasov@yandex.ru
Said Ait Benali
aitbenalis@yahoo.fr
1
Neurology Department, Astrakhan State Medical University,
Astrakhan, Russia
2
Center for Developmental Neuroscience, City University of New
York, College of Staten Island, New York, USA
3
Neurosurgery Department, Mohammed VI University Hospital
Center, Cadi Ayyad University, Marrakech, Morocco
Neurological Sciences
https://doi.org/10.1007/s10072-020-04575-3
the viral infection of the CNS. Such an exaggerated response
to the infection can lead to meningitis, encephalitis, meningo-
encephalitis, or death. The CoVID-19 pandemic, caused by
SARS-CoV 2, is a human respiratory virus that causes infec-
tion of the respiratory tract and may lead to pneumonia and
respiratory failure similar to SARS-CoV, which shows a
neuroinvasive and neurotropic capabilities (Fig. 1).
Neuroinvasion, neuroinflammation,
and microglia activation
The central nervous system is a highly protected organ from
most viral infections by virtue of external multilayer barriers,
the blood-brain barrier, and effective immune responses.
However, some viruses can still enter the CNS through the
hematogenous or neuronal retrograde routes resulting in de-
bilitating direct immune-mediated pathologies, although inva-
sion of the nervous system has no selective advantage for the
host or the pathogen. The virus can infect the PNS or CNS
either by direct infection of nerve endings in the tissues and
using axonal transport machinery to gain access to the CNS
(Figs. 2and 3)[1], or by infecting cells of the circulatory
system that ultimately carry the infection through the blood-
brain barrier (BBB) into the CNS. In the hematogenous route,
several viruses infect endothelial cells of the BBB or epithelial
cells in the choroid plexi and therefore invading neuronal tis-
sue by breaking the blood-cerebrospinal fluid barrier or using
leukocytes as a vector for dissemination within the CNS [1].
Once the virus escapes these physical barriers and invades the
CNS, the first line of defense is the activation of microglia.
Microglia are the residing mononuclear phagocytes of the
brain, highly heterogeneous cells within the healthy CNS [5],
with multiple morphological and functional profiles depend-
ing on their environment. They account for about 10% of the
total cell population of the brain [6,7]. The presence of
activated glial cells is indicative of neuropathology and con-
sidered a marker of brain injury and neuroinflammatory
events [8]. However, neuroinflammation has been considered
a mediator of secondary damage by secretion of cytokines,
neurotrophic factors, and activation of proteases for extracel-
lular matrix remodeling. We now know that molecules of the
systemic innate immune system or directly impacted neuronal
populations can activatethe microglia in the brain and start the
neuroinflammatory events. While microglia are not the only
cells responsible for the inflammatory or immune-mediated
responses in the brain, nevertheless, they can rapidly respond
to environmental changes. Recently, there is increasing evi-
dence showing that brain resident glial cells can be trans-
formed into an aggressive effector cells causing neuronal
damage [9].
Therefore, microglia may confer short-term neuroprotec-
tion or trigger long-term neurodegeneration depending on
the interplay between pro- and anti-inflammatory cytokines
released in response to viral infection.
Viral infection and neuroinflammation are triggers of
neurodegenerative diseases
Viruses can lead to brain dysfunction and neuronal damage by
direct cytolytic effects or secondary inflammatory reactions
(indirect effect) [10]. Neurotropic viruses have developed
mechanisms to escape host immune surveillance to gain ac-
cess to the CNS. The systemic and local inflammatory re-
sponses to viruses are potential causes of neuronal damage.
Primary infection of neurons leads to acute cell dysfunction
that can result in lethal encephalomyelitis [11]. Activated mi-
croglia have been considered to be the main contributors to
released cytokine and chemokine. However, recently, there is
evidence showing that neuronal cells express specific mole-
cules that can play the role of immune receptors to the immune
system to modulating the innate immune response in the brain
Fig. 1 Immune control of viral infections
Neurol Sci
[12]. These molecules also have a major function in the
neuroplasticity and organization of neuronal networks and
synapses. Such autonomous activation of neuronal cells using
the innate receptors during viral infections could compromise
neuroplasticity and the trigger subsequent neuronal dysfunc-
tion. Furthermore, viral infection-induced inflammatory
events show similarities to those observed in early neurode-
generative conditions, including altered expression of proteins
relevant to axonal transport and synaptic transmission ([13].
[14]). In animal models of autoimmune encephalomyelitis
(multiple sclerosis), the inflammation targets dendritic spines
and leads to synaptic degeneration [15]. Additionally,
Fig. 2 Several viruses spread to the CNS by infecting the neuron receptor in the nasal olfactory epithelium to reach the brain by axonal transport along
the olfactory nerve
Fig. 3 Some respiratory viruses spread from the lungs to the CNS through the vagus nerve
Neurol Sci
synaptic dysfunction also occurs typically in the early stages
of Alzheimer’s disease pathogenesis [16].
Therefore, inflammatory reactions triggered by viral infec-
tions could initiate neurodegeneration, especially in individ-
uals who are already at risk for neurodegenerative disorders as
a result of the epigenetic differences that modulate the im-
mune response or the individual’s genetic makeup or suscep-
tibility to infectious diseases [17].
The particularity of respiratory viruses in infected
nervous system
Respiratory viruses such as respiratory syncytial virus (RSV)
[18,19], henipaviruses ([20,21]), influenza A and B ([22]),
and enterovirus D68 [23] are also sometimes found in the
blood and, being neuroinvasive, they may use the hematoge-
nous route to reach the CNS. These respiratory viruses can
also use the olfactory nerve (Fig. 3) to reach the brain [1,24,
25]. Furthermore, some of these viruses can use other periph-
eral nerves by targeting nociceptive neuronal cells in the nasal
cavity and use the trigeminal nerve [26,27], or in other cases,
the sensory fibers of the vagus nerve in different organs of the
respiratory tract [18,28].
Several viruses spread to the CNS by infecting the neuron
receptor in the nasal olfactory epithelium to reach the brain via
axonal transport along the olfactory nerve.
Some viruses can spread by infecting the pseudounipolar
sensory neurons of the PNS then anterograde axonal transport
to CNS.
Influenza Virus (IV) is the most relevant viral etiology
agent in respiratory tract infections. Several studies have
shown that influenza A can be associated with neurological
complications in both children and adults [29–31]. Several
neurological pathologies related to influenza A infection have
been described in the literature, including encephalitis [32],
Guillain-Barre syndrome [33,34], febrile seizure [35], acute
necrotizing encephalopathy, and possibly acute disseminated
encephalomyelitis (ADEM) [36]. In animal models, studies
have shown that the routes of invasion used by IV are either
the olfactory route in the nasal cavity or the sensory neurons of
the vagus nerve in the lungs (Fig. 4). Thus, influenza A virus
can affect cognition and behavior as long-term sequelae by
altering the hippocampus and the regulation of neurotransmis-
sion [18,37–40]. Other studies related to the influenza A virus
show the risk of developing neurodegenerative diseases such
as Parkinson’s disease (PD) [41].
Coronavirus CoV is a group of non-segmented positive-
sense RNA viruses belonging to the Coronaviridae family
and the Nidovirales with four subfamilies: AlphaCoV
(ACoV), BetaCoV (BCoV), DeltaCoV (DCoV), and
GammaCoV [42]. CoV-OC-43 and CoV-229E are described
as pathogenic in humans and are responsible for two beta
coronaviruses (BCoVs) epidemics: the Middle East
respiratory syndrome (MERS-CoV) [43,44], and Severe
Acute Respiratory Syndrome (SARS-CoV) [45,46].
The WHO declared that in December 2019, a series of viral
pneumonia cases of unknown cause has erupted in Wuhan,
Hubei, China (WHO Novel coronavirus report January 19,
2020) [47]. A sequencing analysis from respiratory tract sam-
ples showed a novel coronavirus, named 2019 novel corona-
virus (COVID-19).
The last endemics of SARS-CoV and MERS-CoV showed
that CoV could cause extra-pulmonary pathologies most com-
monly in children as myocarditis, severe diarrhea, and multi-
organ failure ([48–53]). Several studies described the neuro-
tropic and neuroinvasive capabilities of CoV, through the he-
matogenous or neuronal retrograde route, leading to neurolog-
ical pathologies such as multiple sclerosis and encephalomy-
elitis ([3,54–56]); nevertheless, the capacity of CoV to infect
the CNS is not well known ([57,58]) .
In 1980, Burks was the first to detect CoV in the CNS in an
autopsy of patients with MS ([59]). In 2000, Arbour et al.
reported a 67% case positive for CoV in a series of autopsy
samples from patients with different neurological diseases,
especially MS. In 2003, Hung et al. reported the first case of
SARS-CoV infection with neurological manifestations [60]; a
Fig. 4 aSeveral viruses spread to the CNS by infecting the neuron
receptor in the nasal olfactory epithelium to reach the brain by axonal
transport along the olfactory nerve. bSome respiratory viruses spread
from the lungs to the CNS through the vagus nerve
Neurol Sci
59-year-old woman was first admitted with severe respiratory
failure and seizures; in addition, the detection was also posi-
tive in both tracheal aspirates and CSF samples [60]. Lau et al.
reported that viral genetic material was found in CSF samples
of a 32-year-old woman with SARS-CoV infection [54].
SARS-CoV organ dissemination was reported in autopsy
samples from patients that died of SARS-CoV. The autopsy
showed the existence of viral RNA and SARS-CoV-N protein
in the small intestine, liver, sweat glands, parathyroid, stom-
ach, kidney, pituitary gland, and cerebrum, confirming the
capacity of SARS-CoV to induce a systemic infection [61].
Furthermore, experimental studies show that transgenic
mice infected intranasally with SARS-CoV-34 or MERS-
CoV-13 had the virus detected in some specific brain areas
(thalamus and brainstem) [62]. Some studies detected MERS-
CoV virus only in the brain and not in the lungs with a high
mortality rate [62]. Interestingly, the brainstem was the most
heavily infected area of the brain either by SARS-CoV-34, 35
or MERS-CoV [62].
CoV are respiratory viruses with neurotropic capacities,
which allow them to avoid the immune response and cause
neurological complications associated with their infection.
The mechanisms and routes to reach the CNS have not been
well elucidated; the olfactory route and cranial nerves are the
most plausible explanation for their invasion of CNS.
SARS-CoV-2 infected nervous system in COVID-19
patients
SARS-CoV and MERS-CoV cause lethal acute pneumonia
with similar clinical signs and symptoms reported in pneumo-
niacausedbySARS-CoV-2inCOVID-19patients[60].
However, the literature suggests that the target of SARS-
CoV-2 is the upper airway tract while SARS-CoV targets
the lower airway tract, which is the main difference between
these two viruses. The common symptoms of COVID-19 re-
ported in a Wuhan local hospitals were fever, dry cough, and
respiratory distress, most of which are the characteristic symp-
toms of COVID-19 ([60,63,76]).
As discussed above, the BCoV (SARS-CoV, MERS-CoV,
CoV-229E, CoV-OC43) have neuroinvasive capabilities, and
neurological manifestations have been documented ([62,64,
65]). Although the routes of neuroinvasion is not well
established, the invasion of peripheral nerve terminals, espe-
cially the olfactory and vagus nerve are most likely the rea-
sonable routes that lead to CNS infection ([62,65]).
Thus far, several studies provide direct evidence for the
neurotropism of SARS-CoV-2 [66,67]. Both SARS-CoV-2
and SARS-CoV bind to the ACE2 receptor to access human
cells [68]. Because of the structural similarities and their target
receptor, many SARS-CoV-mediated pathologies could also
apply to SARS-CoV-2. A multiple number of studies have
provided strong evidence for the neurovirulence and
neurotropism of SARS-CoV [69]. Several case report studies
showed that CSF samples of a SARS patient who presented
with tonic–clonic seizures tested positive for SARS-CoV,
suggesting possible infection of the CNS by SARS-CoV
[54]. Furthermore, Jun et al.isolated SARS-CoV from a spec-
imen of brain tissue of a patient with SARS in which the
pathological examination of the brain tissue indicated neuro-
nal necrosis and glial cell hyperplasia [70]. In an autopsy
study of eight cases with SARS, the viral particles and their
genomic sequence were detected in the brain tissue of all
cases. Six of them presented with edema and scattered red
degeneration of the neurons [53]. Consistent with this, animal
models suggest that the brain was the principal target organ for
SARS-CoV in transgenic mice for human ACE2 receptor
(hACE2 mice) [71]. These findings of neurovirulence and
neuroinvasion in SARS-CoV could provide strong circum-
stantial evidence of the neurotropic characteristics of SARS-
CoV-2.
Similarity between SARS-CoV and SARS-CoV-2
The similarity in the pathologies between SARS-CoV and
SARS-CoV-2 is becoming more and more evident. Recent
studies showed a 79.5% genomic sequence homology be-
tween SARS-CoV and SARS-CoV-2 [131] and genetic sim-
ilarities to bat coronavirus as high as 96% [72]. In a study
based on the Homology and Phylogenetic Analysis of
SARS-CoV and SARS-CoV-2 for a comparative purpose,
the protein sequence using Blast showed that most of
SARS-CoV-2 proteins are highly homologous (95–100%) to
the proteins of SARS-CoV virus, in the comparative genomic
analyses of SARS-CoV-2 and SARS-CoV using zpicture. The
genomic sequences of SARS-CoV-2 and SARS-CoV have a
high homology at the nucleotide level, with only six regions of
difference (RD) in the genome sequence between SARS-CoV
and SARS-CoV-2 [73]. The nucleocapsid protein in SARS-
CoV-2 shares ~90% amino acid identity with that in SARS-
CoV [74]. In addition, spike stalk S2 in SARS-CoV-2 are 99%
identical to those of the two bat SARS-like CoVs (bat-SL-
CoVZXC21 and bat-SL-CoVZC45) and human SARS-CoV
[127].
The neuroinvasive capabilities in SARS-CoV are reported
as a common feature of coronaviruses. This leads us to con-
clude that it is most likely that SARS-CoV-2 has a similar
neuropathogenic potential, theoretically. The chronology of
SARS-CoV-2 infection process includes manifestation of
symptoms after 5 days of infection. Older patients and patients
with immunodeficiency may develop respiratory failure in 8
to 15 days [76]. Consistent with this, SARS-CoV-2 has a long
enough latency period for the invasion of peripheral nerve
terminals which subsequently results in the invasion of the
CNS.
Neurol Sci
Neurological manifestations of SARS-CoV-2 in pa-
tients with COVID-19
To date, there are only six reports describing the neuro-
logical manifestations of SARS-CoV-2 in patients with
COVID-19 (Table 1), in which 173 of 756 patients had
neurological manifestation. In a case report of 214 pa-
tients with COVID-19 in WHAN, China, neurological
manifestation as acute cerebrovascular diseases and im-
paired consciousness were seen in 36.4% of all patients,
and about 88% (78/88) of patients with serious compli-
cations ([125]). Moriguchi et al. reported a 24-year-old
man admitted to hospital with transient generalized sei-
zures with a Glasgow coma scale of 6 with hemodynamic
stability. Before 9 days, the patient felt headaches, gen-
eralized fatigue, and fever. The RT-PCR test for SARS-
CoV-2 was performed using a nasopharyngeal swab and
CSF. Viral nucleic acids were detected in the CSF but
not from nasopharyngeal swabs. This patient was diag-
nosed with meningoencephalitis due to SARS-CoV-2 in-
fection [125].
In Beijing Ditan Hospital, Xiang et al. confirmed the pres-
ence of SARS-CoV-2 in the CSF of patients with COVID-19
clinically presented with viral encephalitis [78].
Similarly, Mingxiang et al. reported the same observation
in a patient with SARS-CoV-2 presented with a viral menin-
goencephalitis in which SARS-CoV-2 was detected in the
CSF.
SARS-CoV-2 can also damage the spinal cord and lead to
acute myelitis [75]. Zahra et al. reports a caseof a 65-years-old
male admitted with acute progressive symmetric ascending
quadriparesis that began with acute progressive weakness of
distal lower extremities. The patient had also facial paresis
bilaterally 5 days before hospital admission. Two weeks later,
the patient suffered from cough, fever, and sometimes dys-
pnea. RT-PCR for COVID-19 was positive. In this study,
Guillain-Barre syndrome in a patient infected with COVID-
19 was reported 2020) [128].
Hua et al. reported a case of a 61-years-old woman admit-
ted with progressive weakness in both legs and severe fatigue.
Four days before she returned from Wuhan, without fever,
cough, chest pain, or diarrhea. The patient was diagnosed with
Guillain-Barre syndrome associated with SARS-CoV-2 infec-
tion [129].
The olfactory epithelium and olfactory dysfunction in
COVID 19 patients
SARS-CoV-2 is characterized by the high infectivity due to
glycoprotein spike considered as the important factor acceler-
ating the spread of COVID-19. The spike leads the virus to
bind to the host receptor with much higher affinity as com-
pared to related SARS-CoV virus. Recentreports indicate that
the early marker of SARS-CoV-2 infection is anosmia or par-
tial loss of the sense of smell (hyposmic). In a study of 357
patients, 85.6% had olfactory dysfunction related to the
SARS-CoV-2 infection, 284 (79.6%) patients were anosmic,
and 73 (20.4%) were hyposmic [79]. This manifestation may
be considered as direct damage to the olfactory receptor neu-
rons located in the olfactory epithelium. Additionally, cells
located in the olfactory epithelium (neuronal and nonneuronal
cells) express both ACE2 and TMPRSS2 protein receptors
required for efficient SARS-CoV-2 infection in humans
([80]. [81]). Some studies showed that TMPRS2 protein
Table 1 Literature review of 765 COVID-19 patients, in which 18% had neurological symptoms and complications, including encephalopathy,
encephalitis and cerebrovascular pathologies, acute myelitis, and Guillain-Barré syndrome
Author and year Serie type Patients
(n)
Patients with
Neurological
manifestations
(%)
Type of neurological manifestations (%)
Mao et al.; [75] Retrospective case
serie
214 36 Headache (13%); dizziness (17%); impaired consciousness (8%);
acute
cerebrovascular problems (3%); ataxia (0.5); seizures (0.5%)
Wang et al. [76] Retrospective case
serie
138 16 Dizziness in 9%; headache in 7%
Chen et al. [63] Retrospective case
serie
99 17 Confusion in 9%; Headache in 8%
Huang et al.; 2020
[133]
Retrospective case
serie
41 8 Headache in 8%
Yang et al.; [77] Retrospective case
serie
52 6 Headache in 6%
[134] Retrospective case
serie
221 6 5% developed acute ischemic stroke; 0.5%had cerebral venous sinus
thrombosis; 0.5% had cerebral hemorrhage
Total 765 18 Headache in 42%
Neurol Sci
receptors is expressed on neuronal cells and likely facilitate
SARS-CoV-2 brain infection through the anterograde axonal
transport along the olfactory nerve (Fig. 2)[81,82]. SARS-
CoV-2 can reach the brain if the virus first invades high ACE2
expressing, yet unidentified nonneuronal, cells in the olfactory
epithelium and then pass to low ACE2 expressing mature
neuronal cells to be transported along olfactory axons to the
brain.
In animal models, some studies showed that the expression
of murine ACE2 and TMPRSS2 have the tendency to increase
with age as determined by microarray analysis [82]. If this is
the case for humans, then in elderly people, the olfactory ep-
ithelium may be more sensitive to SARS-CoV-2
accumulation.
To understand the antiviral protective immune responses of
neuronal cells in the olfactory epithelium, a recent study in
fish shows that neuronal cells initiate ultrarapid immune re-
sponses in the olfactory epithelium after binding rhabdovirus
surface glycoprotein [83]. Additionally, the activation of the
pro-inflammatory effects inhibits the uptake of the virus into
ciliated dendrites/soma and subsequent anterograde axonal
transport along the olfactory nerve to reach the brain. As a
result, infected neurons undergo apoptosis, which may elimi-
nate initiation of olfactory stimuli and anosmia.
Based on the above observation, infected people with
SARS-CoV-2 who show signs of olfactory dysfunctions
may actually represent those individuals with faster and stron-
ger initiate immune response against the SARS-CoV-2 infec-
tion. Noteworthy that older patients who are much more sen-
sitive to SARS-CoV-2 infection also have degenerative dys-
functions in their neuronal cells in the olfactory epithelium.
This is consistent with the observation that elderly patients
have more severe COVID-19 symptoms most likely due to
the attenuated early immune response.
The anatomical perspective in COVID-19 infection
In experimental studies using transgenic mice, SARS-CoV-
34, 35 or MERS-CoV was found inthe brain and very heavily
in the brainstem [62]. It is known that some respiratory viruses
can reach the brain by the retrograde route via infecting the
sensory fibers of the vagus nerve in different organs of the
respiratory tract [18,28]. The vagal nucleus consists of four
nuclei, including the ambiguous nucleus located in the medul-
la oblongata in the brainstem [84]. Additionally, the basic
respiratory rhythm is generated in the central respiratory neu-
ron network located in various sites in the lower brainstem,
more specifically, ventral to the ambiguous nucleus and the
dorsal motor nucleus of the vagus, and the area postrema,
which are then output as motor activitiesgenerated to regulate
the respiratory rhythm [85]. Therefore, it is plausible to hy-
pothesize that if SARS-CoV-2 reach the brain through the
vagus nerve, the virus will invade the brainstem starting with
the vagal nucleus and surrounding sites including the respira-
tory control center which can lead to more respiratory dys-
function that further exacerbate the damage caused by the
primary infection in the lungs.
Neuropathologies and sequelae related to SARS-CoV-
2 infections
Some studies describe the persistence of CoV RNA in the
human CNS [86]. In experimental studies, mice who survived
acute encephalitis caused by CoV showed a long-term sequel-
ae, including the hypo-activity in an open field test, decreased
hippocampus excitability with concomitant neuronal loss in
the CA1 and CA3[87]. Similar results in studies with infection
by the influenza A virus and RSV [88–90] infection by West
Nile virus (WNV) showed the same neuronal loss in the CA3
[91].
A patient with COVID-19 was diagnosed with necrotizing
hemorrhagic encephalitis after presenting with altered mental
status. CT images showed a symmetric hypo-attenuation in
medial thalami bilaterally and MRI confirmed a hemorrhagic
lesions in the bilateral thalami, subinsular regions and medial
temporal lobes [92]. In a case report of a 24-year-old man, he
presented headaches, generalized fatigue, fever, with general-
ized seizures, and altered mental status that progressed and led
to impaired consciousness. Clinical and laboratory diagnosis
was viral meningoencephalitis and RT-PCR analysis of the
CSF confirm the SARS-CoV-2 infection. Brain MRI showed
changes in the right mesial temporal lobe, the right wall of the
lateral ventricle, and the hippocampus. Interestingly, the na-
sopharyngeal swab specimen for RT-PCR was found to be
negative for SARS-CoV-2, which means that COVID-19
may have independent mechanisms of neuropathogenesis
[125].
Xu et al. reported in an autopsy study that edema has been
detected in the brain tissue of COVID-19 patients due to the
hypoxia caused by SARS-CoV-2 [73]. This means COVID-
19 patients have the potential to develop infectious toxic en-
cephalopathy due to the hypoxia and viremia. The essential
pathological changes in this disease are cerebral edema, with
no evidence of inflammation from CSF analysis [130].
A significant amount of evidence shows that respiratory
infection is an independent risk factor for acute cerebrovascu-
lar disease [94,95]. Experimental mouse models suggest that
some respiratory viruses as influenza can aggravate ischemic
brain injury and increase the risk of cerebral hemorrhage by
triggering a cytokine storm [96]. As previously discussed,
SARS-CoV-2 causes cytokine storm syndromes, which may
be one of the factors that patients with COVID-19 can develop
acute cerebrovascular disease [63,97]. Furthermore, SARS-
CoV-2 infections often show elevated levels of D-dimer and
severe platelet reduction in patients with critical conditions,
Neurol Sci
which may increase the chance of acute cerebrovascular
events [76].
Cerebrovascular diseases and SARS-CoV-2 infections
A meta-analysis of 46,248 infected patients in 8 studies from
China showed that the most prevalent comorbidities were hy-
pertension (17%) and diabetes mellitus (8%), then cardiovas-
cular diseases (5%) [77,98]. This indicates that COVID-19
and stroke share similar risk factors. There is strong evidence
that the severity of COVID-19 infection is directly linked to
the presence of cardiovascular comorbidities [99]. In a case
series from Wuhan of 214 patients with COVID-19, 14 pa-
tients developed strokes. The study concluded that patients
with cardiovascular risk factors were more likely to developed
acute cerebrovascular diseases [75]. Similarly, 4 COVID-19
patients with cardiovascular risk developed stroke. The mech-
anism of vascular damage in all these patients was the large
vessel disease [100]. An observational study showed that in
221 COVID-19 patients, 5% developed acute ischemic stroke,
0.5% cerebral hemorrhage, and 0.5% cerebral venous sinus.
The incidence was higher in older patients with cardiovascular
risk factors [101].
COVID-19 and multiple sclerosis
The etiology of several long-term neuropathologies is still
not well known, such as multiple sclerosis (MS), in which
a viral infection may play a role in the pathogenesis in
genetically predisposed individuals [102–106]. Over the
last decades, several viruses have been associated with
MS, based on detection of viral nucleic acids, virions, or
viral proteins in the CNS or the presence of antiviral an-
tibodies in the serum and/or cerebrospinal fluid. In 1980,
for the first time, the association of coronaviruses with
MS was suggested for by their isolation from the CNS
of two patients [59].
Since then, multiple studies have linked human
coronaviruses (including CoV-OC-43 and CoV-229E) with
MS. In several autopsy studies, the coronavirus-like particles
were detected in brain material obtained from MS patients
[107] and in other studies, viruses molecularly related to mu-
rine neurotropic coronaviruses were detected in the brain tis-
sue from MS patients [59]. Additionally, anti-HCoV intrathe-
cal antibody synthesis, indicative of a CNS infection, was
reported in MS patients [108]. Furthermore, HCoV RNA
was detected in the brain [109–111] and in the cerebrospinal
fluid of MS and other neurological disease (OND) patients
[112]. Coronavirus antigens were also detected in MS patient
brains [109,110].
Interestingly, in an autopsy studies of 90 patients with
MS, viral RNA was present in a large number of samples;
48% (44 of 90) of all donors were positive for one or both
viral strains (CoV-OC-43 and CoV-229E). HCoV-OC43
RNA was widely detected in normal white and gray mat-
ter as well as in plaques of MS patient brains. This study
also suggested that HCoV-OC43 has the capacity to per-
sistently infect cells in the human CNS and that such
infections could lead in some cases to specific molecular
adaptation of this virus to the CNS environment [57].
Consistent with this, in animal model studies, a persistent
coronavirus infection provoked a chronic demyelination
in genetically predisposed mice through immune
reaction-mediated mechanisms [113].
There are multiple possible mechanisms by which a viral
infection could induce a demyelinating disease such as MS-
like lesions. It could be induced as a direct consequence of
viral infection such as lytic infection of oligodendrocytes
[114]. Alternatively, it could be indirectly mediated through
the expression of cytotoxic molecules by glial cells such as
MHV-induced chronic demyelination in the CNS. In the lat-
ter, several inflammatory molecules, such as IL-6, tumor ne-
crosis factor, interleukin 1β(IL-1β), type 2 nitric oxide syn-
thase [115], RANTES, cytokine response gene 2, and
macrophage-inflammatory protein 1β, or their mRNAs, were
detected [116].
The HCoV-OC43 virus was detected in the CNS of a child
with acute disseminated encephalomyelitis (ADEM) [55]
which is another demyelinating neurological disorder charac-
terized by neuroinflammation after nonspecific upper respira-
tory tract infections. Even though the etiological agent re-
mains unknown, several studies suggest that human
coronviruses can lead to ADEM. Subacute panencephalitis
sclerosis (SSPE), a progressive fatal neurological disease, is
also clearly linked to a viral infection as the persistence of
measles virus within the CNS [117].
Viral infection of oligodendrocytes could lead to demye-
linating disease through the alteration of their normal function
or cytolysis as is the case for reactivated human polyomavirus,
which induces the progressive lysis of oligodendrocytes dur-
ing progressive multifocal leukoencephalopathy [118,119].
The release of myelin components could also trigger an auto-
immune attack. Infection or activation of astrocytes and mi-
croglia could lead to release of inflammatory mediators that
could damage oligodendrocytes, therefore exacerbating the
pathology [120–123].
It has been shown that CoV-OC-43 is responsible for
encephalitis with a T cell response to the infection
[124]. This underlines the possibility that the trigger
for long-term demyelinating neuropathologies such as
MS-like lesions in patients with respiratory viruses is
the immune response. Considering the phylogenetic
studies and the similarities between SARS-CoV-2 and
all beta coronaviruses, including the lineage A groups
prototypical coronaviruses, we can conclude that even if
the genotype of the virus itself can play a role in the
Neurol Sci
pathogenesis of MS-like lesions associated to viral in-
fection and CoV-OC-43 and CoV-229E may be consid-
ered as a risk factor to develop MS. Taking into ac-
count the similarities between SARS-CoV-2 and CoV-
OC-43 and CoV-229E as well as the characteristics of
theimmuneresponsetoSARS-CoV-2infectioninclud-
ing to the cytokine storm and the surge of IL-6, tumor
necrosis factor, interleukin 1β(IL-1β), and type 2 nitric
oxide synthase, it is almost certainly that SARS-CoV-2
may be responsible for MS-like demyelinating lesions as
a long-term consequences of COVID-19.
Conclusion
Based on the available data, it is highly likely that respiratory
distress is not only the result of pulmonary inflammatory
structural damage, but also due to the damage caused by the
virus in the respiratory centers of the brain, making it more
difficult to manage these patients.
Several human respiratory viruses can have neuroinvasive
and neurotropic capabilities, leading to neuropathological
consequences in vulnerable populations. Understanding the
consequences of neuroinvasion and the underlining mecha-
nisms of respiratory viruses (including coronaviruses) and
their interactions with the central nervous system is essential
as it can be used to better understand the potential pathological
relevance of the infection, in addition to the design of novel
diagnosis and intervention strategies that will helpuncover the
potential draggability of molecular virus-host interfaces high-
ly relevant to symptoms of various neurological diseases with
a viral involvement.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval Ethical approval was waived by the local Ethics
Committee of Cadi Ayyad University, Faculty of Medicine and
Pharmacy Marrakech in view of the retrospective nature of the study
and all the procedures being performed were part of the routine care.
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