This document discusses the neuropsychiatric manifestations of COVID-19. It notes that SARS-CoV-2 can invade the brain through direct routes like hematogenous spread or neural pathways, or indirectly through immune activation and cytokine release. Common neuropsychiatric symptoms reported in COVID-19 patients include headaches, dizziness, impaired consciousness, strokes, and psychiatric conditions like depression and psychosis. The document explores several mechanisms by which the virus may cause neuroinflammation and neuroinvasion, resulting in neuropsychiatric complications.
2. • The COVID-19 pandemic is caused by the novel coronavirus (CoV), SARS-CoV-2, that
predominantly affects the respiratory system
• there is increasing evidence that SARS-CoV-2 can be Neuro invasive, resulting in
neuropsychiatric complications. [Troyer et al. 2020]
• Psychological stress associated with the fear of illness and the uncertainty of the future can result
in direct and vicarious traumatization. [Li et al. 2020]
• Historically, past influenza pandemics have been associated with a post-infection increase in
anxiety, insomnia, fatigue, depression, suicidality, and delirium [Honigsbaum 2013]
• There are several viruses with neurotropic potential; influenza virus, human metapneumovirus,
members of the Enterovirus/rhinovirus genus, echoviruses, coxsackieviruses, respiratory syncytial
virus, Hendra and Nipah viruses.
• in the case of SARS-COV, autopsy studies showed cerebral oedema and meningeal vasodilation.
Microscopically, infiltration of monocytes and lymphocytes in the vessel wall, ischaemic neuron
changes, demyelination and detection of SARS COV viral particles and genome sequences in the
brain were detected. [Wu Y et al., 2020]
3. • The MERS-CoV outbreak in 2012, also precipitated neuropsychiatric symptoms as a
result of an immunological reaction. [Tsai et al. 2004], [Kim et al. 2017]
• A systematic review and meta-analysis [Rogers J et al., 2020] of the neuropsychiatric
manifestations of SARS and MERS CoV revealed that during the acute illness,
common
• symptoms included confusion (27.9%), depressed mood (32.6%), anxiety (35.7%),
impaired memory (34.1%) and insomnia 41.9%.
• In the post-illness stage, depressed mood (10.5%), insomnia (12.1%), anxiety
(12.3%), irritability (12.8%), memory impairment 18.9%, fatigue 19.3%, traumatic
memories (30.4%) and sleep disorder (100%) were frequently reported.
• post- traumatic stress disorder was 32•2%, depression 14•9% and anxiety disorders
was 14•8%.
4. MECHANISMS OF VIRUS ENTRY
There are 6 stages in a virus life cycle
• 1. Attachment
• 2. Penetration
• 3. Uncoating
• 4. Replication
• 5. Assembly
• 6. Release.
5. Once inside the cell, viruses will go through a process of uncoating by which the viral capsid is removed, and the
viral genome is released.
The viral genome will then replicate in the nucleus or cytosol. The viral mRNA ‘hijacks’ the host cell machinery to
make new virus particles
These viral particles are then released by a process of budding (blebbing) or lysis of the cell and go on to infect
new cells
6. STRUCTURE OF SARS-COV-2
SARS-CoV-2 belongs to the β-coronavirus family and exists in the form of RNA. It has nearly 30000
nucleotide base pairs that hold the genetic code for viral production, diameter of 100 nm and is
spherical or oval. The virus has large spikes of viral membrane glycoproteins on the surface
8. VIRAL REPLICATION
Once inside the host cell, the foreign viral RNA ‘hijacks’ the host cell machinery inducing it to
produce RNA and proteins that produce new viral particles, These viral particles will then exit the
cell to infect new cells.
9. CLINICAL PRESENTATION
• The symptoms of COVID-19 infection usually appear after an incubation period of about five days
• Fever, cough, dyspnea, and fatigue; other symptoms include headache, hemoptysis, among others
• Fever (80.4%), fatigue (46%), cough (63.1%) and expectoration (41.8%) were the most common clinical
manifestations. Other common symptoms included muscle soreness (33%), anorexia (38.8%), chest
tightness (35.7%), shortness of breath (35%), dyspnea (33.9%).
• Minor symptoms included nausea and vomiting (10.2%), diarrhea (12.9%), headache (15.4%), pharyngalgia
(13.1%), shivering (10.9%) and abdominal pain (4.4%).
•
• Normal leukocytes count (69.7%), lymphopenia (56.5%), elevated C‐reactive protein levels (73.6%),
elevated ESR (65.6%) and oxygenation index decreased (63.6%) were observed in most patients.
• About 37.2% of patients with elevated D‐dimer, 25.9% of patients with leukopenia, along with abnormal
levels of liver function (29%) and renal function (25.5%).
• Other findings included leukocytosis (12.6%) and elevated procalcitonin (17.5%). Only 25.8% of patients had
lesions involving single lung and 75.7% of patients had lesions involving bilateral lungs.
10. PATHOPHYSIOLOGY OF CNS INVOLVEMENT
SARS‐CoV‐2 can take two pathways to involve the brain; direct and indirect pathways.[Wu Y et
al., 2020]
12. POSTULATED DIRECT PATHWAYS
The haematogenous route
• The virus gains access by infecting endothelial cells of the blood-brain-barrier,
epithelial cells of the blood-cerebrospinal fluid barrier in the choroid plexus or
using inflammatory cells as Trojan horses to gain access to CNS (myeloid cell
trafficking).
• Observation of viral-like particles in brain capillary endothelium and actively
budding across endothelial cells strongly suggests the hematogenous route
as a highly likely pathway for SARS-CoV-2 to the brain
Neuronal transport
• The virus can use retrograde axonal transport (travel from axon terminals across
the axon) to reach the neuron cell bodies in the central nervous system.
• Retrograde axonal transport may occur through the olfactory, respiratory, and
enteric nervous system networks.
13. Olfactory network
• Retrograde neuronal transport via the olfactory pathway (across the cribriform plate of the ethmoid bone to
the olfactory bulb situated in the forebrain) is a likely route given the proximity to the brain but also due to the
presence of ACE2 receptors on olfactory cilial cells.
•
• The virus can reach the CSF and brain through olfactory nerve and bulb within 7 days and can cause
inflammation and a demyelinating reaction. Removal of the olfactory bulb in mice resulted in the restricted
entry of COV-2 into CNS. [Bohmwald K et al., 2018]
14. The gut is postulated as a key entry point due to the following factors:
The higher relative expression of ACE-2 receptor in enterocytes than lungs
Evidence that SARS-CoV-2 can directly infect and replicate in intestinal cells
The worse clinical outcome of COVID-19 patients with concomitant GI symptoms with increased acute respiratory distress and need for
mechanical ventilation.
The enterocytes are connected to the enteric nervous stem and may provide a source of entry to the brain. Once inside the brain, the virus can
activate the immune cells of the brain to start a cascade of neuroinflammation
16. Peripheral immune cell transmigration
Human coronaviruses may play a possible role in
the development of psychiatric symptoms via the
opportunistic infection of peripheral myeloid cells
(Trojan Horse mechanism), which are then
trafficked to the brain causing neuroinflammation
and virus-induced neuropathology. [Desforges et
al 2019]
17. CYTOKINES RELEASED THROUGH PERIPHERAL INFLAMMATION MAY INCREASE THE PERMEABILITY
OF THE BBB PROVIDING A PATHWAY FOR THE VIRUS TO ENTER THE BRAIN. ONCE IN THE CNS, IT
CAN INFECT OF ASTROCYTES AND MICROGLIA ACTIVATING THE CASCADE OF
NEUROINFLAMMATION AND NEURODEGENERATION THROUGH THE RELEASE OF TNF, CYTOKINES,
ROS AND OTHER INFLAMMATORY MEDIATORS.
Neuroinflammation
18. POST-INFECTIOUS AUTOIMMUNITY
• Molecular mimicry:Potential for T-cell receptors (TCRs) specific for certain
microbial epitopes to potentially cross-react with self-antigens that have
similar molecular patterns or mimics
• Bystander activation of immune cells:Overactive response to virus results in the
release of self-antigens that trigger off the immune response by processing antigens
by inflammatory monocyte-derived APCs to autoreactive T cells
• Epitope spreading:In the context of antiviral immunity, activation of a broad
set of viral-specific T cells is potentially a helpful event. However,
destruction of host tissue and autoimmunity may result should the spread
happen to include epitopes expressed by host tissues
19. HYPOXIC INJURY
• Hypoxia in the brain may occur via direct infection of the lung tissue but
may also occur due to the neuroinvasive potential of the virus directly
affecting the medullary cardiorespiratory centre. [Li Y et al., 2020]
• Hypoxia of the brain increases anaerobic metabolism in the mitochondria
of the brain cells, and the resultant lactic acid leads to cerebral oedema,
reduced blood flow, raised intracranial pressure, which can clinically
present with a range of neuropsychiatric symptoms.
20. IMMUNOMODULATORY
TREATMENTS
• There is evidence that some patients have been treated with high dose
corticosteroids during the acute phase.
• Unfortunately, this type of therapy is linked to acute neuropsychiatric
effects such as sleep disturbances, delirium, mania, depression, and
psychosis. [Warrington and Bostwick 2006]
21. GUT MICROBIOME TRANSLOCATION [GAO Q ET
AL., 2020]
• Inflammation disrupts the intestinal barrier resulting in ‘gut leak’ causing
bacterial translocation into circulation and secondary systemic infection.
• Increased intestinal permeability leads to the influx of large amounts of
lipopolysaccharides which in turn causes the release of TNFα, IL-1β, and
IL-6, further exacerbating systemic inflammation
• It will be of interest to determine whether the infection causes any
change to microbial composition in the gut which may be linked to
psychiatric disorder
22. ANGIOTENSIN-CONVERTING ENZYME 2 (ACE-2) RECEPTOR
INVOLVEMENT [VADUGANATHAN M ET AL., 2020]
The virus uses the ACE2 receptor for entry into cells and results in the destruction of ACE2 producing tissues.
ACE2 is thought to be an essential regulator of the renin-angiotensin system (RAS) essential for cardiac function and blood
pressure control. ACE-2 is a negative regulator of the RAS.ACE2 cleaves Ang I and Ang II into the inactive Ang 1-9 and Ang
1-7, respectively preventing hypertension. Loss of ACE2 can be detrimental, as it leads to the functional deterioration of the
heart and progression of cardiac, renal, and vascular pathologies
23. HYPERCOAGULABILITY
• Certain cytokines, including IL-6, could activate the coagulation system and
suppress the fibrinolytic system.
• Pulmonary and peripheral endothelial injury due to direct viral attack.
• Endothelial cell injury can strongly activate the coagulation system via exposure of
tissue factor and other pathways.
• Dysfunctional coagulation may exacerbate an aggressive immune response
setting up a vicious cycle
•
Production of anti-cardiolipin and anti-β2GP1 antibodies (Zhang Y et al. 2020]
• The pathogenesis of neuropsychiatric involvement via antiphospholipid
• antibodies [Rege S & Mackworth-Young C, 2015] may provide some clues
towards the pathogenesis of brain involvement in COVID-19
26. NEUROPSYCHIATRIC MANIFESTATIONS
• A study of 214 hospitalized patients in Wuhan, China showed that 36.4% had
neurologic manifestations. Patients with more severe infection were more likely to
have neurological involvement, such as acute cerebrovascular diseases, impaired
consciousness, and skeletal muscle injury. [Mao L et al.,2020]
• The most common symptoms at onset of illness were fever (61.7%), cough (50.0%),
and anorexia (31.8%).
• Seventy-eight patients (36.4%) had nervous system manifestations: CNS (24.8%),
PNS (8.9%), and skeletal muscle injury (10.7%).
• In patients with CNS manifestations, the most common reported symptoms were
dizziness (16.8%) and headache (13.1%).
• In patients with PNS symptoms, the most common reported symptoms were taste
impairment (5.6%) and smell impairment (5.1%).
• Most neurologic manifestations occurred early in the illness (the median time to
hospital admission was 1-2 days).
27. NEUROPSYCHIATRIC MANIFESTATIONS
• In the first 3 weeks of UK-wide surveillance system, 153 cases were notified with a median
(range) age 71 (23-94) years. 77 (62%) had a cerebrovascular event: 57 (74%) ischemic strokes,
nine (12%) intracerebral haemorrhages, and one CNS vasculitis.
• The second most common group were 39 (31%) who had altered mental status, including 16
(41%) with encephalopathy of whom seven (44%) had encephalitis.
•
• The remaining 23 (59%) had a psychiatric diagnosis of whom 21 (92%) were new diagnoses;
including ten (43%) with psychosis, six (26%) neurocognitive (dementia-like) syndrome, and 4
(17%) an affective disorder. [Varatharaj A et al., 2020]
• A systematic review and meta-analysis of neuropsychiatric manifestations of COVID-19 revealed
there was evidence for delirium (confusion) in 65% of intensive care unit patients and altered
consciousness in 21% of patients who subsequently died in another study. [Rogers J et al., 2020]
•
Immunologic test results from COVID-19 patients show that CNS symptoms such as headache,
dizziness, and ataxia are linked to significantly lower blood lymphocyte counts, platelet counts,
and higher blood urea nitrogen levels compared to those without CNS symptoms [Mao et al.
2020]. Lymphopenia has been suggested to be indicative of immunosuppression in patients with
CNS symptoms
29. CLINICAL PRESENTATIONS
• Headache:The incidence of headache as a symptom has been variable with
studies showing rates from 8-70% [Lechien J et al., 2020]
• A meta-analysis showed the prevalence of headache at 12% [Borges do
Nascimento I et al., 2020]
• Acute cerebrovascular disease:Both ischaemic and haemorrhagic strokes
have been described.
• Hypercoagulability is associated with stroke in younger individuals. [Oxley T
et al. 2020]
• A case series of 221 patients with COVID-19 showed 11 (5%) developed
acute ischemic stroke, 1 (0·5%) cerebral venous sinus thrombosis (CVST),
and 1 (0·5%) cerebral haemorrhage [Li Y et al. 2020 ]
31. PSYCHIATRIC DISORDERS
• The psychological effects of SARS-CoV-1 and MERS-CoV on healthcare workers have
been linked to an increase in psychiatric diagnoses, especially mood disorders [Lin et al.
2007], [Lee et al. 2018]. However, it is unknown whether this is due to exposure to the virus or
is linked to the host immune response.
• Increased prevalence of depression has been identified in patients who experienced COVID-
19 infection, while the prevalence of anxiety was not statistically different. [Zhang J et al. 2020]
• Prevalence of depression in COVID-19 is associated with low health literacy.[Nguyen HC et
al., 2020]
Seropositivity for a Human CoV strain (HCOV-NL63) has been associated with mood disorder
but not its polarity. [Okusaga O et al., 2011]
• for the treatment of depression triggered by a state of hyperinflammation resulting from the
infection, immune modulation therapies, such as interleukin-6 inhibitors and melatonin, are
under investigation, and other therapies such as cytokine blocking drugs and Janus kinase
inhibitors (JAK) have also been suggested (Ferrando et al., 2020).
• Depending on the circumstances and symptoms of each patient, alternative
medications such as gabapentin, buspirone, hydroxyzine or a low dose of selective
serotonin reuptake inhibitors (SSRIs) can be used in Anxiety
Depression and anxiety
32. PSYCHOTIC DISORDERS
• Immunoreactivity to the human coronavirus, HCoV-NL63, has been
reported in patients that have had a recent psychotic episode.
[Severance et al. 2011]
• Furthermore, some patients that were confirmed to have been exposed
to MERS-CoV have reported hallucinations and psychotic features. [Kim
et al. 2018]
• COVID-19 has been linked to an increase in the incidence of first-
episode presentations of schizophrenia with a shift towards late age
onset. [Hu W et al., 2020]
• Patients may present with delusional themes related to the pandemic.
•
33. PTSD
• A cross-sectional study of 714 recovered and clinically stable COVID-19
inpatients showed that 96% had significant posttraumatic stress
symptoms. [Bo H et al., 2020]
• Evidence from previous pandemics points towards higher rates of
PTSD in health care workers. See mental health challenges for
health care workers in COVID-19
34. NEUROMUSCULAR COMPLICATIONS
• Peripheral neuropathy, myopathy, Bickerstaff brainstem encephalitis, and Guillain-Barre
syndrome are rare nerve diseases linked to demyelination that have previously been
observed in some patients after both SARS-CoV-1 and MERS-CoV [Tsai et al.2004], [Kim
et al. 2017].
• Neuralgia has been described in COVID-19.
• Several cases of Guillain–Barré Syndrome (GBS) have been associated with SARS- COV-2.
[Toscano G et al., 2020]
• It is still unclear if GBS is a typical presentation of COVID-19. However, GBS is known to
occur post-infection as in the case of Zika virus.
• Other neuromuscular complications described are Myasthenia gravis, transient cortical
blindness and acute disseminated encephalomyelitis.
• Muscular complications include soreness, fatigue and raised muscle enzymes
35. NEURODEGENERATIVE DISORDERS
• There is no current clear evidence of neurodegenerative considerations
associated with SARS-COV-2. However, experience from past
pandemics show that the lag period may be months to years for the
onset of neurodegenerative illnesses when associated.
• Anti-CoV Abs have been identified in cerebrospinal fluid (CSF) of
individuals with Parkinson’s disease. [Fazzini et al., 1992]
• The Braak hypothesis of Parkinson’s disease (PD) proposes that a
neurotropic virus invading neural tissue through the nasal cavity and the
gastrointestinal tract causes α- synuclein to turn into a promiscuous
binder and be transmitted, prion-like, to key areas such as the substantia
nigra. [Santos S et al., 2019]
• Given that neural and immune cells can serve as reservoirs of latent
CoV, it is plausible that this could contribute to delayed
neurodegenerative processes, but this also remains to be seen in
COVID-19. [Desforges M et al., 2019]
36.
37. MENTAL HEALTH ASPECTS OF THE
PANDEMIC
• Mental health burden in health care workers
• Psychological effects of quarantine
• Neuropsychiatric sequelae in survivors
• Managing concerns, fears, and misconceptions at the local
community and broader public level
38. ROLE OF THE PSYCHIATRIST
• The psychiatrist will play an essential role in differentiating between organic and functional
psychiatric illness.
• Previous experience from other forms of encephalitis highlights the important role of the psychiatrist
Diagnostic
Psychosocial perspective
Providing important tips to manage the consequences of isolation in the short term
Early identification, prevention, and treatment of mental health conditions
Psychological first aid can be administered to patients by public health and public behavioural health
workers.
Identification and management of relapses or exacerbation of illness due to the pandemic in a vulnerable
population and
In the long term, manage the consequences of losses e.g. employment, financial distress, bereavement,
etc).
Acting as an important part of the multidisciplinary team to manage exacerbation of psychiatric and
behavioural disturbances arising from neuropsychiatric complications
In the aftermath of pandemics, increased psychiatric screening and surveillance is recommended to
address acute stress disorder, posttraumatic stress disorder, depressive disorders, and substance abuse.
Working with key decision-makers at a systemic level to devise a meaningful mental health response to an
impending potential mental health catastrophe.
At a systemic level, the psychiatrist can assist in prevention and data collection to design services to
combat pandemics in the future.
39. DIAGNOSTIC AND BIOCHEMICAL MARKERS OF SEVERITY
• Elevated levels of IL-6, CRP and procalcitonin
• Lymphopenia appears to predict morbidity and mortality even at early stages. [Fei et al.,
2020]
• Elevation in lactic acid levels
• Imaging results showing bilateral or multilobar infiltration, pleural effusion, or short-term
increase in lesions
• Thrombocytopenia and elevated D-dimer levels may be indicative of coagulopathies.
[Fogarty et al., 2020]
• Neutrophil-to-lymphocyte ratio (NLR). Patients aged ≥50 years and with NLR ≥3.13 tend to
develop severe COVID-19 and should be admitted to the ICU immediately [Xie P et al.,
2020]
•
PCR testing of SARS-CoV-2 in CSF. Many cases described in the literature have
known to be N-P swab positive and CSF negative although cases of N-P swab
negative and CSF positivity have also been described
40. FINDINGS ON MRI AND PERFUSION IMAGING DESCRIBED IN
THE LITERATURE
• Cortical signal abnormalities on FLAIR images
• Leptomeningeal
• Bilateral frontotemporal hypoperfusion
• Focal hyperintensities indicative of acute and sub ischaemic
strokes
• Hemorrhagic and posterior reversible encephalopathy syndrome
(PRES) -related brain lesions in non-survivors of COVID-19 that
might be triggered by the virus-induced endothelial disturbances.
45. • Cytotoxic medications
• Neutralising Antibodies and Convalescent Plasma Therapy
• Vaccine development
• Routine use with corticosteroids to be avoided as evidence from previous
coronavirus outbreaks suggests that viral shedding may be prolonged.
• Second-line treatments like IVIg or Plasma exchange (PLEX) are less likely to
delay viral clearance and may be beneficial in sepsis. IVIg may be associated with
an increased risk of thromboembolism.
• Third line immunotherapies such as cyclophosphamide and rituximab are high-
risk treatments and are only considered if other treatments fail.
• Due to the high rates of thromboembolism, prophylactic anticoagulation is
being considered as it is associated with decreased mortality in high-risk patients.
[Tang N et al., 2020]
• Prophylaxis with Enoxaparin
46. GENERAL PRINCIPLES OF PSYCHIATRIC MANAGEMENT IN COVID-19
• Recognising neuropsychiatric manifestations of COVID -19 and liaising with relevant medical
professionals
• Managing acute behavioural disturbance using bio-psychosocial strategies. Judicious use of
medications as patients with organic brain illness may be more susceptible to side effects
• Differentiating between ‘normal’ and pathological responses to the pandemic
• Treatment for grief and loss
• Treatment of PTSD
• Diagnosis and treatment of clinical depression
• Mirtazapine 7.5–45 mg may be a good choice in patients with postinfectious cachexia and exhaustion as
it promotes weight gain. Its sedative properties may help patients suffering from insomnia.
• Tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors are useful if
there is also concurrent neuropathic pain or a lingering inflammatory process that persists
following some viral infections (amitriptyline 10–400 mg at bedtime, duloxetine 60–120mg/day).
47. SIDE EFFECTS OF MEDICATIONS USED IN THE TREATMENT OF
COVID-19
• Drug-Drug and Cytochrome P450 interactions
• Interactions between SSRIs and Anti-Retrovirals
• Decreased levels of sertraline and citalopram by ritonavir (metabolised by CYP3A4 and CYP2D6; inhibits CYP2D6 and
CYP2C19)
• Decreased levels of fluvoxamine and fluoxetine by nevirapine (potent inducer of CYP3A4).
• Fluoxetine (CYP2D6 inhibitor) and fluvoxamine (CYP1A2 inhibitor) can both increase the levels of amprenavir, delavirdine,
efavirenz, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, and saquinavir.
• Increased levels of all TCAs by ritonavir except desipramine which is decreased.
• Increased levels of trazodone by ritonavir and darunavir
• Antivirals such as amantadine have been associated with psychosis and delirium and interferon treatment are frequently
associated with depression.
• Antimalarials have been shown to increase the levels of phenothiazine neuroleptics
• Clarithromycin and erythromycin (CYP3A4 inhibitors) can increase carbamazepine, buspirone, clozapine, alprazolam,
and midazolam levels
• Quinolones may increase clozapine and benzodiazepine levels but reduce benzodiazepine effect via the GABA receptor
• Risk of QTc prolongation with erythromycin, azithromycin, hydroxychloroquine or with combinations. SSRIs such as
escitalopram and citalopram can be associated with QTc prolongation and if used with the above antibiotics can increase
the risk of Torsades de Pointes.
• Fluvoxamine may be used early in the course of the COVID-19 infection to prevent more severe complications like
cytokine storm by activating the sigma -1 receptor
48. CONCLUSION
• The current pandemic is unprecedented in modern medicine, and its effects on
human mental health are likely to be heterogenous, extensive, and long term
• The causality and etiopathogenic mechanisms of CNS involvement in SARS-CoV-2
are still being studied
• a neurotropic and neuroinvasive property of the SARS-COV-2 suggesting a possible
substantial global neuropsychiatric burden from COVID-19.
• Psychiatrists will play an important role in bridging the gap by addressing the short
and long term biological, psychological and social consequences of the condition.
• The main psychiatric and neuropsychiatric repercussions were depression, anxiety,
post-traumatic stress disorder, psychosis, nonspecific neurological symptoms,
delirium, cerebrovascular complications, encephalopathies, neuromuscular disorders,
anosmia and ageusia.
49. REFERENCES
• Troyer E et al., Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms
and potential immunologic mechanisms. Brain Behav Immun. 2020.
• Li Z et al., Vicarious traumatization in the general public, members, and non- members of medical teams aiding in
COVID-19 control. Brain Behav Immun. 2020.
• Honigsbaum M. The art of medicine: “an inexpressible dread”: Psychoses of influenza at fin-de-siècle. Lancet.
2013;381:988–989.
• Hoffman, L. A., & Vilensky, J. A. (2017). Encephalitis lethargica: 100 years after the epidemic. Brain, 140(8), 2246-2251.
• McCall, S., Vilensky, J. A., Gilman, S., & Taubenberger, J. K. (2008). The relationship between encephalitis lethargica
and influenza: a critical analysis. Journal of neurovirology, 14(3), 177-185.
•
Wu, Y., Xu, X., Chen, Z., Duan, J., Hashimoto, K., Yang, L., … & Yang, C. (2020). Nervous system involvement after
infection with COVID-19 and other coronaviruses. Brain, Behavior, and Immunity.
• Tsai L et al., Neuromuscular disorders in severe acute respiratory syndrome. Arch. Neurol. 2004;61:1669–1673.
• Kim J et al., Neurological complications during treatment of middle east respiratory syndrome. J. Clin. Neurol.
2017;13:227–233.
• Rogers, J., Edward, C., Dominic, O., Thomas, P., Philip, M., Paolo, F. P., … & Anthony, D. (2020). Psychiatric and
neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta- analysis
with comparison to the COVID-19 pandemic. The Lancet Psychiatry.
• Viral Pathogenesis, Third Edition, 2016
50. REFERENCES
• Zhou, P., Yang, X. L., Wang, X. G., Hu, B., Zhang, L., Zhang, W., … & Chen, H. D. (2020). A pneumonia outbreak associated with a
new coronavirus of probable bat origin. nature, 579(7798), 270-273
• Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C. L., Abiona, O., … & McLellan, J. S. (2020). Cryo-EM structure of the
2019-nCoV spike in the prefusion conformation. Science, 367(6483), 1260-1263.
• Sungnak, Waradon, et al. “SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune
genes.” Nature
• medicine (2020): 1-7.
• Zhu, J., Ji, P., Pang, J., Zhong, Z., Li, H., He, C., … & Zhao, C. (2020). Clinical characteristics of 3,062 COVID‐19 patients: a
meta‐analysis. Journal of Medical Virology.
• Xiang, P., Xu, X. M., Gao, L. L., Wang, H. Z., Xiong, H. F., & Li, R. H. (2020). First case of 2019 novel coronavirus disease with
• Encephalitis. ChinaXiv, 202003, 00015.
• Moriguchi, T., Harii, N., Goto, J., Harada, D., Sugawara, H., Takamino, J., … & Nakao, A. (2020). A first Case of
Meningitis/Encephalitis associated with SARS-Coronavirus-2. International Journal of Infectious Diseases.
• Paniz‐Mondolfi, A., et al., (2020). Central Nervous System Involvement by Severe Acute Respiratory Syndrome Coronavirus‐2
(SARS‐CoV‐2). Journal of medical virology.
• Bohmwald, K., Galvez, N., Ríos, M., & Kalergis, A. M. (2018). Neurologic alterations due to respiratory virus infections. Frontiers in
cellular neuroscience, 12, 386.
• Li Y et al., The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19
patients. J. Med. Virol. 2020;24–27.
• Wu Y et al., Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol 2020;5:434-435.
• Esposito G et al., 2020 Can the enteric nervous system be an alternative entrance door in SARS-CoV2 neuroinvasion? Brain,
Behavior, and Immunity.
• Huang K et al., An interferon-γ-related cytokine storm in SARS patients. J. Med. Virol. 2005;75:185–194.
• Desforges M et al., Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central
Nervous System? Viruses 2019;12:14.