REVIEW
Pathophysiological
mechanisms of covid-19 cerebrovascular accident in young adults
Jacqueline Stephanie Fernandes do Nascimento*, Nicolle dos Santos Moraes Nunes*, Janie Fernandes do Nascimento*, Marco Antônio Alves Azizi**, Carlos Henrique Melo Reis**, Marco Antônio Orsini Neves***, Mauricio de Sant Anna Jr****, Renata Rodrigues Teixeira Castro*****
*Graduate
student at the Iguaçu University Medical School, Universidade
Iguaçu - UNIG-RJ, Nova Iguaçu/RJ, **Iguaçu University – UNIG, Faculty of
Medicine, Nova Iguaçu/RJ, **Iguaçu University - UNIG and Nova Iguaçu General
Hospital, Nova Iguaçu/RJ,, ***MD, Post Doctor at the Federal University
of Rio de Janeiro, Full Professor at the Iguaçu University, Neurology Service,
Iguaçu University - UNIG, Nova Iguaçu/RJ, Brazil, ****FT,
Professor Instituto Federal do Rio de Janeiro (IFRJ), *****MD,
Professor University Iguaçu University - UNIG-RJ, Nova
Iguaçu/RJ, Brazil
Received
on: July 13, 2020; accepted on: August 15, 2020.
Corresponding author:
Jacqueline Stephanie Fernandes do Nascimento, Rua Av. Dr. Mário Guimarães
863/1603 Centro 26255-230 Nova Iguaçu RJ
Jacqueline Stephanie
Fernandes do Nascimento: jac.fn@hotmail.com
Nicolle dos Santos
Moraes Nunes: nicolle.nunes_@hotmail.com.br
Janie Fernandes do
Nascimento: janiekelly@hotmail.com
Marco Antônio Alves Azizi: marcoazizimed@gmail.com
Carlos Henrique Melo
Reis: chmeloreis@hotmail.com
Marco Antônio Orsini Neves: orsinimarco@hotmail.com
Mauricio de Sant Anna Jr: mauricio.junior@ifrj.edu.br
Renata Rodrigues Teixeira Castro: castrorrt@gmail.com
Abstract
Introduction: COVID-19 is an infection caused by the SARS-CoV-2 virus, which was
originated in the city of Wuhan (China) and spread rapidly to other countries
and continents until the World Health Organization (WHO) declared a pandemic
situation. Among the serious conditions resulting from the pathology, it was
observed that certain patients had systemic neurological symptoms, such as
cerebrovascular accident (CVA). Objective: The objective of this study
is to propose a discussion about the current knowledge about the
pathophysiology of CVA in young adults with COVID-19. Methods: A search
was carried out in the main databases: Lilacs, Bireme, Pubmed
in Portuguese and English, for articles of the current year. The choice had
taken place at random, obviously, following a line of reasoning of the authors
involved. The keywords searched were: COVID-19, Cerebrovascular accident,
Pathophysiology, Coagulopathy. Results: It is conjectured countless
possibilities that would explain the connection of the virus to the
cerebrovascular disease. SARS-CoV-2 is considered to instigate an inflammatory
process in the arterial wall and this is responsible
for the CVA. Although the correlation between these two clinical conditions is
notorious, there are still no studies that clearly determine the
pathophysiological mechanism involved in the process. Conclusion:
Neurological manifestations in the COVID-19 are reported, including
cerebrovascular accident. The state of hypercoagulability generated by the
cytokine storm seems to be related to the pathophysiological mechanism of this
condition. Still, there is no clear evidence in this regard and studies are
needed in order to elucidate its physiopathogeny.
Keywords: coronavirus infections, stroke, pathophysiology, coagulopathy.
Resumo
Mecanismos
fisiopatológicos do acidente vascular encefálico por COVID-19 em adultos jovens
Introdução: A COVID-19 é uma
infecção causada pelo vírus SARS-CoV-2, que se originou na cidade de Wuhan
(China) e se propagou rapidamente para outros países e continentes até que a
Organização Mundial da Saúde (OMS) declarasse situação de pandemia. Dentre as
condições graves decorrentes da patologia, observou-se que determinados
pacientes apresentaram sintomatologias neurológicas sistêmicas, como acidente
vascular encefálico (AVE). Objetivo: O objetivo do presente trabalho é
propor uma discussão acerca dos conhecimentos atuais sobre a fisiopatologia do
AVE em adultos jovens com COVID-19. Métodos: Foi realizada uma busca nas
principais bases de dados: Lilacs, Bireme e Pubmed nos idiomas português e inglês, de artigos
publicados no ano vigente. A escolha ocorreu de forma aleatória, obviamente, seguindo
uma linha de raciocínio dos autores envolvidos. As palavras-chave pesquisadas
foram: COVID-19, Acidente Vascular Encefálico, Fisiopatologia, Coagulopatia. Discussão: Conjectura-se inúmeras
possibilidades que explicariam a ligação do vírus à doença cerebrovascular. É
considerado que o SARS-CoV-2 instiga um processo inflamatório na parede
arterial e isso seja responsável pelo AVE. Embora a correlação entre essas duas
condições clínicas seja notória, ainda não existem estudos que determinem
claramente o mecanismo fisiopatológico implicado no processo. Conclusão:
Manifestações neurológicas na COVID-19 são relatadas, incluindo o acidente
vascular encefálico. O estado de hipercoagulabilidade
gerado pela tempestade de citocinas parece estar relacionado ao mecanismo
fisiopatológico desta condição. Ainda assim, não existem evidências claras
quanto a isso e estudos são necessários a fim de elucidar sua fisiopatogenia.
Palavras-chave: infecção por coronavírus, acidente vascular encefálico, fisiopatologia, coagulopatia.
Resumen
Mecanismos
fisiopatológicos del accidente
cerebrovascular por COVID-19 en adultos jóvenes
Introducción: El COVID-19 es una infección desencadenada por el virus SARS-CoV-2, que se originó en la
ciudad de Wuhan (China) y se extendió
rápidamente a otros países
y continentes hasta que la Organización
Mundial de la Salud (OMS) ha declarado pandemia. De entre las
condiciones graves decurrentes de la
patología, se observó que ciertos pacientes presentaban síntomas neurológicos sistémicos, como el
Accidente cerebrovascular (ACV). Objetivo: El
objetivo del presente trabajo
es proponer una discusión acerca los conocimientos
actuales sobre la fisiopatología del ACV en adultos jóvenes con COVID-19. Métodos: Se hizo
una búsqueda en las principales bases de datos: Lilacs, Bireme, Pubmed en los
idiomas portugués e inglés,
de artículos comprendidos en
el año actual.
La elección se había
realizado al azar, obviamente, siguiendo una línea de
razonamiento de los
investigadores involucrados. Las palabras
clave buscadas fueron: COVID-19, Accidente
cerebrovascular, Fisiopatología, Coagulopatía.
Discusión: Se conjeturan
innumerables posibilidades
que explicarían la conexión del virus
con la enfermedad
cerebrovascular. Es considerado que el SARS-CoV-2
incita un proceso de inflamación en la pared arterial y eso sea responsable
por el ACV. Aunque la correlación entre las dos condiciones clínicas sea notoria, aún no hay estudios que determinen claramente el
mecanismo fisiopatológico involucrado en el proceso. Conclusión:
Manifestaciones neurológicas en
la COVID-19 son relatadas, incluyendo el accidente
cerebrovascular. La condición de hipercoagulabilidad
generado por la gran cantidad de citocinas puede estar relacionada con el mecanismo fisiopatológico de esta condición.
Sin embargo, no existen evidencias claras sobre eso y estudios son necesarios
a fin de aclarar su fisiopatogenia.
Palabras-clave: infecciones por coronavirus, accidente
cerebrovascular, fisiopatología, coagulopatia.
COVID-19 is an infection caused by the SARS-CoV-2 virus, which was
originated in the city of Wuhan (China) and spread rapidly to other countries
and continents until the World Health Organization (WHO) declared a pandemic.
The clinical condition of the pathology varies from asymptomatic individuals to
severe conditions that culminate in death. Among the serious conditions
resulting from the pathology, it was observed that certain patients had
systemic neurological symptoms, such as cerebrovascular accident (CVA)
[1].
Although little is known about the new Coronavirus, there is evidence of
tropism by the Nervous System (neurotropism). The inflammatory process and the
vascular lesions generated by it can increase the permeability of the
blood-brain barrier, promoting adverse effects on the Central Nervous System
(CNS). Many are the ways of transporting the virus against the blood-brain
barrier, highlighting the transcellular, retrograde and paracellular axonal
transport along the entire length of the olfactory and sensory nerves [1,2].
The axonal transport of SARS-CoV-2 is pointed out, through the cribiform plate adjacent to the olfactory bulb to the
brain, as a possible cause of the loss of smell. The anosmia, which appears
early in most cases, can be associated with this mechanism [1,2]. The slowed
microcirculation in the capillary compartment can contribute to the binding of
the peak glycoprotein of the virus with the Angiotensin-Converting Enzyme 2
(ACE2) in the cell membranes, which favors the penetration of SARS-CoV-2. The
ACE2 is expressed on the surface of several cells in the body such as:
gastrointestinal tissue, epithelium of the respiratory system and brain [3].
SARS-CoV-2 can deregulate the Angiotensin-Converting Enzyme 2, which
leads to the over activation of the Renin-Angiotensin-Aldosterone System
(RAAS). In addition, it reduces the activation of the alternative RAAS pathway
in the brain. The RAAS imbalance associated with disharmony in vasodilation,
oxidative stress, thrombotic response and neuroinflammation may be fundamental
factors in the pathophysiology of Cerebrovascular accident throughout the
SARS-CoV-2 infection [1]. The aim of the present study is to propose a
discussion about the pathophysiological mechanisms involved in the genesis of
cerebrovascular accident caused by COVID-19 in young adults, based on a brief
review of the current literature.
The purpose of this article is, based on current literature, to produce
and update reflections about the ongoing pandemic context. To this end, a
search was carried out in the main databases: Lilacs, Bireme, Pubmed in Portuguese and English, for articles included in
the current year. The choice had taken place at random, obviously, following a
line of reasoning from the authors involved. The keywords searched were:
COVID-19, cerebrovascular accident, pathophysiology, coagulopathy.
The ischemic cerebrovascular accident (ICVA) is reported as a
complication of COVID-19, however, the mechanisms that govern this pathology
have not yet been elucidated. It is known that the ICVA associated with the
clinical entity is usually a late complication, however, it can happen both in
the beginning and in the final course of the disease. Cerebral venous sinus
thrombosis, ischemic cerebrovascular accident and intraparenchymal hemorrhage
were some of the clinical conditions described in individuals affected by the
virus [4]. In addition, it was found that the involvement of smell and taste
predicts COVID-19 infection.
The SARS-CoV-2 infectious process is linked to a pro-thrombotic state,
which generates venous lesions and arterial thromboembolism, in addition to an
increase in D-Dimer levels. In addition, the disease releases pro-inflammatory
cytokines that incite cell activation mononuclear and endothelial cells with
tissue factor expression, carrying the activation of the coagulation cascade
and generation of thrombin. The lack of control of circulating thrombin by
anticoagulants can activate platelets and promote thrombogenesis [5,6].
Countless possibilities are conjectured that would explain the
connection of the virus to cerebrovascular disease. SARS-CoV-2 is considered to
instigate an inflammatory process in the vessel wall, and this is responsible
for the occurrence of a cerebrovascular accident. It is also believed that
SARS-CoV-2 has a function analogous to the herpes simplex virus, which has been
shown to minimize the binding to anti-thrombin III, heparan sulfate,
thrombomodulin, prostacyclin and ultimately potentiate the formation of
thrombin, expression of tissue factor and platelet bonding [7,8].
Recently, The New England Journal of Medicine published an informative
study, reporting five cases of cerebral vascular accident in young adults, all
younger than 50 years of age. Symptoms such as headache, coughing and chills
lasting for a week have been mentioned. Among the participants in this study, a
33-year-old woman reported not having previous pathologies [9]. This study suggested
as explanations for the possible cases of cerebral vascular accident from
COVID-19, endothelial dysfunction and coagulopathy [10].
The cells of the epithelium of the respiratory and gastrointestinal
systems are the focus of infection of SARS-CoV-2, however, their impact is not
limited to just the afore mentioned cells and the nervous system can also be
compromised. Considerably, the presence of the virus was found in the
cerebrospinal fluid [7], and pathologies such as seizures, leukoencephalopathy,
refractory mal-epileptic status, encephalitis, Guillain-Barré syndrome (GBS)
and myopathy were found in patients with COVID-19 [8]. Neurological signs such
as dizziness, headache and altered level of consciousness have been documented
in 8%, 11%, 9% of infected patients, respectively [11,12].
A study, carried out in Singapore, described 5 patients who had
cerebrovascular accident of major vessels after infection by SARS-CoV-2. In
this study, it was proposed that embolisms located proximally, such as in the
heart and severe hypotension, could have been precursors to CVA. The supposed
relation between COVID-19 and CVA can be simultaneous, however, about one third
of the cases had pulmonary thromboembolism [13-15]. It is also worth noting
that some studies suggest that COVID-19 stimulates the production of
antiphospholipid antibodies (aPL), as a mechanism of
ischemic cerebral vascular accident, even though the post-infection aPL are generally transient and not related to thrombosis
[16].
Certain patients with the severe form of COVID-19 have Disseminated
Intravascular Coagulation (DIC) or total consumption of coagulation factors and
activation of the coagulation cascade. Current literature indicates that
patients infected with SARS-CoV-2 are subject to developing coagulopathy due to
acute systemic inflammatory response. The COVID-19-induced coagulopathy is
determined by an increase in blood clotting markers, such as: D-dimer and
fibrin or fibrinogen breakdown products, in addition to an increase in
peripheral inflammatory markers, such as C-Reactive Protein, and mild
thrombocytopenia [17,18]. Furthermore, the virus can bind to Toll-like
receptors and trigger the synthesis and release of interleukin 1 [19].
It is a fact that COVID-19 inflammatory mechanisms generate a state of
hypercoagulability, and the number of CVA cases in young adults associated with
the pathology tends to increase as it spreads. Although the correlation between
these two clinical conditions is notorious, there are still no studies that
clearly determine the pathophysiological mechanism involved in the process.
Therefore, research related to the damage caused by the virus in the Cerebral
Vascular System is necessary in order to elucidate the pathophysiology of the
CVA in these patients.
The clinical conditions of patients infected with COVID-19 range from
asymptomatic to severe conditions. Among these, neurological manifestations are
reported, including cerebral vascular accidents. Epidemiological statistics on
the incidence of CVA cases during the COVID-19 pandemic have not yet been
published, however, informal observations suggest an increase in the number of
cases of thromboembolic CVA among young adults. The state of hypercoagulability
generated by the cytokine storm seems to be related to the pathophysiological
mechanism of this condition. Still, there is no clear evidence for this. Thus,
research related to the damage caused by the virus in the cerebral vascular
system is necessary in order to elucidate its pathophysiology.
Conflicts
of interest: The authors declare no conflict of
interest.