Key-words:
Coronavirus - neuroinvasive - neurology - pandemic
Introduction
Coronavirus disease 2019 (COVID-19) was first described in December 2019 in Wuhan,
China, and rapidly spread widely and became a global concern. In this outbreak, a
new beta coronavirus from the order Nidovirales, which has a positive sense and single-stranded
RNA genome, was identified with a mortality rate of approximately 3%–4%.[[1]] The angiotensin-converting enzyme receptors are possibly responsible for the entry
of this virus to the human cells, and these receptors are present on lung cells, renal
tubular cells, arteries, gastric cells, and other tissues, including the central nervous
system (CNS).[[2]] [[Figure 1]] shows the importance of the COVID-19 to the public health-seeking behavior. It
is noteworthy that for the first time since 2004, a disease was more popular than
the most commonly searched words on Google (Facebook, YouTube, and Google) or a medicine
topic (health).[[3]]
Figure 1: Google trends searching behavior of the terms “Coronavirus (COVID), Facebook (FB),
and Health” from January to March 2020. To evaluate how often people search the Google
to look for online information related to coronavirus disease, FB, and Health, we
entered a set of keywords: “coronavirus,” “Facebook,” and “health” at the “Google
Trends” main page, which was selected worldwide in the last 90 days (available at
https://trends.google.com/, accessed on 03/31/2020). The number represents the search
interest relative to the highest point on the chart for the given region and time,
where higher values are associated with higher popularity of the term
Herein, we would like to highlight the neurological complications of the COVID-19
and the neuroinvasive potential of this virus. It is worthy of mentioning that COVID-19
mainly causes acute respiratory distress syndrome, which is one of the most common
causes of death. However, the latest studies demonstrated that, in severe cases, neurological
manifestation can occur.
Summary of Recent Studies
It is already known that human coronaviruses can spread from the respiratory tract
to the CNS through transneuronal and hematogenous routes.[[4]] Even though these theories are feasible, other explanations for the neuronal damage
could be direct damage to the lung tissue, leading to global hypoxia or an exacerbated
inflammatory response [[Figure 2]].[[2]],[[5]],[[6]] In this context, Mehta et al. observed that patients infected by COVID-19 may have
a cytokine storm syndrome leading to multiorgan failure, which is characterized by
increased interleukin (IL)-2, IL-7, granulocyte-colony-stimulating factor, interferon-γ
inducible protein 10, monocyte chemo-attractant protein 1, macrophage inflammatory
protein 1-α, and tumor necrosis factor-α.[[7]],[[8]] Thus, they stated that “We recommend identification and treatment of hyperinflammation
using existing, approved therapies with proven safety profiles to address the immediate
need to reduce the rising mortality.”[[7]]
Figure 2: Pathogenesis of the central nervous system caused by coronavirus disease 2019. The
indirect injury can be caused by a hypoxic mechanism or a systemic inflammatory response.
SARS: severe acute respiratory syndrome
The transneuronal route is by the invasion of the virus throughout the olfactory mucosa
[[Figure 3]].[[9]],[[10]] One supporting finding of this hypothesis is the presence of anosmia in a high
percentage of COVID-19 patients.[[11]] Furthermore, studies with other types of coronavirus showed that about 30% of the
anosmias is caused by a coronavirus.[[12]] The majority of the individuals affected by COVID-19 only have mild symptoms, such
as anosmia, cough, dyspnea, fever, headache, and myalgia, some develop acute respiratory
distress syndrome after a week. Hence, one important question that arises is if this
headache could be an earlier symptom of the occurrence of viral meningitis.
Figure 3: Schematic diagram of transneuronal invasion by HCoV-OC43, a coronavirus type. The
virus (1, stars) invades the olfactory mucosa going by the olfactory sensory neurons
(2) to the olfactory bulb (3). From the bulb, the virus invades the olfactory tract
(4) which directly connects with the central nervous system
Another interesting point of discussion is the fact that some patients have developed
encephalopathy. To be more specific, this is supported by three reports in the literature.[[13]],[[14]],[[15]] The increasing number of individuals diagnosed with coronavirus worldwide would
possibly turn the occurrence of rare clinical manifestations such as these more common.
Therefore, physicians should be aware of these presentations among patients presenting
with altered mental status and with or without respiratory symptoms.
A recent article by Mao et al. elucidated the nervous system complications observed
in hospitalized patients with COVID-19. They classified these findings into skeletal
muscular, CNS, and peripheral nervous system (PNS) symptoms. The CNS symptoms include
dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia,
and epilepsy. The PNS were hypogeusia, hyposmia, hypopsia, and neuralgia. The skeletal
muscle system was only evaluated by the general-term muscle injury. Mao et al. found
that patients with severe infection, when compared to those without a severe coronavirus
infection, were more likely to have neurological manifestations (45.5% vs. 30.2%).
From all those symptoms, only impaired consciousness, acute cerebrovascular disease,
and muscle injury were statistically significant. Furthermore, the patients with severe
CNS involvement when compared to those without a severe state demonstrated higher
blood urea nitrogen levels, lower lymphocyte, and platelet counts. However, No laboratory
findings were helpful for the prediction of PNS symptoms.[[16]]
It is worthy of mentioning that the majority of the patients with COVID-19 do not
test positive for the virus in the cerebrospinal fluid (CSF). However, the report
of the first patient with CSF positive for COVID-19 suggests considering direct neuroinfection
when these individuals present with neurological symptoms. Furthermore, this report
could partially explain why patients with a history of neurological illnesses are
more susceptible to coronavirus infection.[[17]]
Immunocompromised patients are possibly particularly vulnerable to the infection by
COVID-19. Other types of coronavirus have already been shown to be associated with
severe neurological complications in this group of individuals.[[18]] Many neurological patients have autoimmune diseases (multiple sclerosis, myasthenia
gravis, and neuromyelitis optica), and are on immunosuppressive therapies, which can
cause systemic immune suppression and predispose them to severe infections.[[19]] In such patients is prudent to recheck dosages of the medications as well as reinforcing
precautions. Furthermore, these drugs should not be withdrawn due to the risk of severe
complications of underlying neurological diseases and the increased necessity of go
to emergency centers and be more able to be infected by COVID-19. We believe that
these last recommendations should also be followed by patients affected by headaches
that are using Botox, and need to have their appointment, to avoid them go to the
emergency department.[[20]]
[[Table 1]] provides a summary of the information on neurological studies with COVID-19.[[2]],[[9]],[[12]],[[13]],[[14]],[[15]],[[16]],[[17]],[[19]],[[21]],[[22]],[[23]],[[24]],[[25]],[[26]],[[27]],[[28]],[[29]],[[30]]
Table 1: Neurological symptoms and other important features already reported in association
with severe acute respiratory syndrome-coronavirus 2
Conclusion
In summary, we believe that awareness of physicians about neurological clinical manifestation
could prompt the diagnosis and reduce the mortality rate in individuals infected with
COVID-19. Future studies need to determine the risk factors and pathological explanations
related to these neurological symptoms to help establishing specific management and
reducing complications.
Authors' contribution
Equal.
Compliance with ethical principles
Not applicable.
Reviewers:
Ashraf Elghul (Abu Dhabi, UAE)
Ahmed Elhassi (Benghazi, Libya)
Editors:
Salem A Beshyah (Abu Dhabi, UAE)
Elmahdi A Elkhammas (Columbus OH, USA)
