Journal club presentation

2. Dr. ABHINAV CHAUDHARY
Junior Resident
Nervous system involvement after infection
with covid-19 and other coronaviruses.
Yeshun
Wu et al

6. INTRODUCTION
On 31st December 2019, 27 cases of pneumonia of unknown aetiology
were identified in Wuhan City, Hubei province in China,
Wuhan is the most populous city in central China with a population
exceeding 11 million.
Centre for Disease Control and Prevention (CCDC) on 7th January
2020, identified the causative agent from throat swab.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
The disease was named COVID-19 by the World Health Organization
(WHO).
Homology (~80%) to SARS-CoV, which caused acute respiratory
distress
syndrome (ARDS) and high mortality during 2002–2003.

7. Majority spontaneously resolved. some have developed various fatal
complications.
On 30th January 2020, the WHO declared the Chinese outbreak of
COVID-19 to be a Public Health Emergency of International Concern.
COVID-19 is caused by SARS-CoV-2, a betacoronavirus.
It is comprised of a single-stranded ribonucleic acid (RNA) structure that
belongs to the Coronavirinae subfamily, part of the Coronaviridae family.

8. CoV have an average diameter of 100 nm, and they are spherical or oval.
There are large spikes of viral membrane glycoproteins on the surface, and,
when observed by electron microscopy, these negatively stained virus
particles show a typical crown-like shape.
Catrin Sohrabi et al

9. Coronaviruses consist of five structural proteins; Spike (S),
membrane
(M), envelop (E) and nucleocapsid (N) .

10. Determines the diversity of coronaviruses and host tropism.
Spike comprises two functional subunits; S1 subunit is responsible for
binding to the host cell receptor and S2 subunit is for the fusion of the
viral and cellular membranes.
Following the binding of SARS-CoV- 2 to the host protein.
The spike protein undergoes protease cleavage.
The coronavirus spike is unusual among viruses because a range of different
proteases can cleave and activate it.
The characteristics unique to SARS-CoV-2 among coronaviruses is the
existence
of furin cleavage site (“RPPA” sequence) at the S1/S2 site

11. The life cycle of the virus within the host consists of the following 5
steps
attachment, penetration, biosynthesis, maturation and release. :
Once viruses bind to host receptors (attachment)
Enter host cells through endocytosis or membrane fusion (penetration)
Contents are released inside the host cells, viral RNA enters the
nucleus
for replication. Viral mRNA is used to make viral proteins (biosynthesis).
Then, new viral particles are made (maturation)
Released by exocytosis.

12. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses
of ~30 kb.
. They infect a wide variety of host species.
Six are HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV,
and MERS-CoV
(Corman et al., 2019).SARS-CoV
Severe acute respiratory syndrome (SARS) is a zoonotic
respiratory disease caused by SARS-CoV that started in Asia and
spread throughout the world in 2003.
.
SARS-CoV could induce neurological diseases such as
polyneuropathy, encephalitis, and aortic ischemic stroke (Tsaiet al.,
2005)
Autopsy studies demonstrated that signs of cerebral edema and
meningeal vasodilation could be detected.

13. MERS-CoV
Middle East Respiratory Syndrome (MERS), caused by MERS-CoV,
originates from bats, and the intermediate host is camel.
Known to be potentially neuroinvasive.
A retrospective study found that 25.7% of patients with MERS can
develop insanity and 8.6%of patients have seizures (Saad et al.,
2014).
Almost 1/5 of patients with MERS-CoV infection show neurological
symptoms during the infection process.
Their neurological complications are not accompanied by
respiratory
symptoms, but delayed by 2–3 weeks (Kim et al)

14. SARS-CoV-2
The genetic similarity between SARS-CoV-2 and SARS-CoV is 79.5%,
Similarity to bat coronavirus is as high as 96% (Wu et al.)
Headache, epilepsy, and disturbed consciousness.
COVID-19 patients report a sudden loss of smell or taste.
Presence of SARS-CoV-2 in cerebrospinal fluid by genome
sequencing supports
theory this new pneumonia virus can also cause nervous system
damage (Xiang et al., 2020).

15. The mechanisms of coronaviruses infections and neurological damage caused by coronaviruses. The coronaviruses can cause nerve damage through direct
infection pathways (blood circulation pathways and neuronal pathways), hypoxia, immune injury, ACE2, and other mechanisms. Meanwhile, the coronaviruses have
detrimental effects to attack the lung tissue, and causes a series of lung lesions such as hypoxia. Furthermore, the coronaviruses can enter the nervous system directly
through the olfactory nerve, and also enter the nervous system through blood circulation and neuronal pathways, resulting in neurological disorders. Ab: antibody;
ACE2: angiotensin-converting enzyme 2; CSF: cerebrospinal fluid; ER: endoplasmic reticulum; TNF: tumor necrosis factor.

17. Blood circulation pathway
A typical virus entering the CNS through the blood circulation is the JE
virus,
which multiplies in the vascular cells of the skin area affected by the
mosquito bite.
It is subsequently released into the blood to reproduce in mononuclear
macrophages throughout the body.
The secondary release into the blood may increase the permeability of the
blood–brain barrier through the produced cytokines, thereby promoting the
virus to enter the brain and causing viral encephalitis.
.
Although there is rare evidence that CoV, especially SARS CoV-2, invade
the nervous system via the blood circulation pathway(Koyuncu et al., 2013;
Desforges et al., 2019).

18. Viral RNA has been measured in the blood of patients infected with
SARSCoV
and MERS-CoV [Hung EC, Chim SS, Chan PK, et al. ]
Detection of SARS coronavirus RNA in the cerebrospinal fluid of a
patient with severe acute respiratory syndrome] and thus, the
dissemination of these two viruses to the CNS may be mediated by
the hematogenous route.
Once crossing the BBB, hCoVs-infected cells could potentially
invade the brain
through perivascular spaces, also known asVirchow-Robin spaces.
Cryptococcal organisms in AIDS patients.
Remains unclear.

19. Neuronal pathway
Neuronal pathway is important vehicle for neurotropic viruses to enter the
CNS. Viruses can migrate by infecting sensory or motor nerve endings,
achieving retrograde or anterograde neuronal transport through the motor
proteins, dynein and kinesins (Swanson and Mc Gavern, 2015).
An example of a neuronal pathway is that of olfactory neuron transport.
The unique anatomical organization of olfactory nerves and the olfactory
bulb in the nasal cavity and forebrain effectively makes it a channel
between the nasal epithelium and the CNS
(Koyuncu et al., 2013).
As a consequence, CoV can enter the brain through the olfactory tract in
the early stages of infection or nasal vaccination (Desforges et al., 2019;
Mori, 2015). For example, after CoV infects nasal cells, it can reach the
entire brain and cerebrospinal fluid.

20. Hypoxia injury
When a virus proliferates in lung tissue cells, it causes diffuse alveolar and
interstitial inflammatory exudation, edema.
.
This, in turn, leads to alveolar gas exchange disorders causing hypoxia in the CNS,
increasing anaerobic metabolism in the mitochondria of brain cells.
The accumulation of acid can cause cerebral vasodilation, swelling of brain cells,
interstitial edema, obstruction of cerebral blood flow, and even headache due to
ischemia and congestion.
If the hypoxia continues unabated, cerebral edema and the cerebral circulation
disorder may worsen sharply. With intracranial hypertension, the brain function
gradually deteriorates, and drowsiness,
bulbar conjunctival edema, and even coma can be observed .(Abdennour et al.,
2012)
In addition, for patients at particular risk of developing cerebrovascular disease,
hypoxia may also induce the occurrence of acute cerebrovascular disease such as

21. Immune injury
Nervous system damage caused by viral infection may be mediated by the
immune system. (Klein et al., 2017).
The pathology of severe viral infections is closely linked to the development of a
systemic inflammatory response syndrome (SIRS).
SARS and COVID-19 have resulted in a large number of fatalities, most of which
have been due to multiple organs failure (MOF) caused by virus-induced SIRS
or SIRS-like immune disorders
The persistence of CoV infections and its ability to infect macrophages,
microglia, and astrocytes
in the CNS are particularly important.
A neurotropic virus can activate glial cells and induce a pro-inflammatory state
(Li et al., 2004).
interleukin (IL)-6, an important member of the cytokine storm, is positively
correlated with the severity of COVID-2019 symptoms (Wanet al., 2020).
Activation of immune cells in the brain will cause chronic inflammation and brain

22. Angiotensin-converting enzyme 2 (ACE2)
Angiotensin-converting enzyme 2 (ACE2) is a cardio-cerebral vascular protection
factor existing in a variety of organs , including the nervous system and skeletal
muscles, playing a major role in regulating nervous system and skeletal muscles,
playing a major role in regulating blood pressure and anti-atherosclerosis
mechanisms. (Miller and Arnold, 2019).
Meanwhile, ACE2 is also an important target for various CoV and influenza
viruses .(Turner et al., 2004; Wrapp et al., 2020; Yanget al., 2014)
Binding to ACE2 receptors, the above-mentioned viruses may cause abnormally
elevated blood pressure and increase the risk of cerebral hemorrhage
.
In addition, given that SARS-CoV-2 spike protein could interact with ACE2
expressed in the capillary endothelium, the virus may also damage the blood–
brain barrier and enter the CNS.

23. Dipeptidyl peptidase-4 (DPP-4)
DPP-4 (also known as CD26) was identified as a cellular receptor for MERS-
CoV
DPP-4 is expressed in human brains , therefore, when the virus gains access
to the brain, cells expressing DPP-4 are potentially available. (Raj VS, Mou H,
Smits SL, et al)
Other potential receptors
Aminopeptidase N (APN, also known as CD13), a cell-surface
metalloprotease,
was proposed as a receptor for hCoV 229E , as well as SARS-CoV .
In addition, the infection of SARS-CoV on ACE2-expressing cells seemed to
be dependent
on a proteolytic enzyme Cathepsin L (CTSL1) in a pH sensitive manner.

24. Neurotransmitter pathway
Neurotransmitter pathways such as serotoninergicdorsal raphe
system.
Lymphatic systems
The intranasal inoculation of rodents with MHV has also revealed a lymphatic
dissemination of coronavirus via cervical and mesenteric lymph nodes in
addition to viremia .
Additional studies are required to determine the role of this potential
dissemination route.
.

25. Antibodies
In addition to known and putative receptors, antibody-dependent
enhancement (ADE) of viral entry using the fusogenic spike protein has
also been reported as a pathway to transfer coronavirus from infected
cells to non-infected cells .
In vitro studies have shown that coronavirus entry could be mediated by
special antibodies that bind the virus surface spike protein and facilitate
subsequence
viral entry of MERS-CoV and SARS-CoV in a receptor-like manner.
The ADE pathway is particularly important for vaccine design and the
development of antibody-based drug therapies.

26. Q. Cheng et al. / EBioMedicine 56 (2020) 102799

27. R. Bridwell, B. Long and M. Gottlieb, Neurologic complications of COVID-19,
American Journal of Emergency Medicine.

28. Acute cerebrovascular disease
Acute cerebrovascular disease remains one of the more common and
serious neurologic
complications seen in COVID-19 population.
SARS-CoV-2 causes a global inflammatory response and a
hypercoagulable state evidenced
by increased D-dimers, prolonged prothrombin time, and disseminated
intravascular coagulation.COVID-19 patients can develop significant hypoxia leading to
decreased cerebral oxygenation
and infarcts, particularly in those with pre-existing cerebrovascular
disease.
Infection, inflammation, and hypercoagulable states can further
increase the risk of ischemic stroke.

29. Encephalitis and encephalopathy
Encephalitis is characterized by acute onset of fever, vomiting, seizures,
and decreased or changed consciousness.
Oedema secondary to inflammatory injury versus direct viral infection.
Acute necrotizing encephalopathy (ANE) is a rare neurologic
complication caused by cytokine storm and damage to the blood-brain
barrier.
The thalamus, brainstem, cerebellum, and cerebral white matter are the
most common areas affected.
Treatment with intravenous immunoglobulin(IVIG) and steroids can be
attempted.

30. Guillain-Barré Syndrome (GBS)
GBS is a symmetric, ascending flaccid paralysis, often preceded by
respiratory or gastrointestinal infections from a virus or bacteria.
This progressive neuropathy has recently been linked to SARS-CoV-2
infection,
with 5 cases reported in Italy and 2 additional cases from Wuhan
,China.
All patients experienced a prodrome of an upper respiratory infection
ranging from 5 to 14 days prior to the development of symmetric
weakness,with 3 patients developing respiratory Failure.
Positive nasopharyngeal polymerase chain reaction (PCR) test and
characteristic chest imaging.
Received IVIG.

31. Hemophagocytic Lymphohistiocytosis (HLH)
Secondary to hematologic malignancy, immunosuppression, or critical
infection, but has also been described in patients with SARS-CoV-2.
HLH is a severe dysregulation of T-lymphocyte, natural killer cell, and
macrophage over-activation causing a massive cytokine storm and multi
organ injury.
Unremitting fevers, pancytopenia, coagulopathy, hepatic dysfunction,
hypertriglyceridemia, and an elevated ferritin.
Treatments include steroids and tocilizumab, both of which are
currently under investigation for treatment of Covid 19.

32. Medication interactions

33. THANK YOU