Neurological manifestations of sars cov 2

THE NEUROLOGICAL MANIFESTATIONS OF
SARS-COV-2
SERGE EDDY MBA, MBChB, DHA, MMed

Worldwide caseload: 18,585,774 Total fatalities: 701,665
05 August 2020

COVID-19 SITUATION IN ZIMBABWE (05 AUGUST 2020)
• Number of confirmed cases : 4339 ( added 118 cases yesterday)
• Number of deaths due to covid-19: 84
Source: Situation report, Ministry oh health and Child Care, Zimbabwe, 2020

WHAT IS COVID-19
• Originated in Wuhan province, China
• Declared a global pandemic by WHO on 11 March 2020.
• Corona virus disease (COVID-19)
• Causative organism: RNA virus called Novel Corona virus or Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
• The novel corona virus has been isolated in CSF, Tears,blood, Saliva,
Stool and Urine
• Mode of transmission: mainly respiratory droplets

SARS-CoV-2 AND THE CNS
•Related to SARS-Cov(79%), MERS-Cov(50%), Pangolin
Cov(90%), Bat Cov(96%) (Zhou P et al., 2020)
•Goblet and ciliated cells in the nose express ACE-2
receptors; likely point of infection of SARS-Cov-2 (Waradon S et
al., 2020)
•Neuroinvasion, neurotropism can be attributable to any
virus (Wrapp D et al., 2020)

STAGES OF SARS-COV-2 REPLICATION

WHAT IS THE EVIDENCE OF CNS INVOLVEMENT
BY SARS-COV-2?
• index case of viral encephalitis , March 2020, China (Xiang P et al., 2020)
• SARS-CoV-2 encephalitis reported in Japan the CSF in the absence of
nasopharyngeal positivity. ?direct infection or haematogenous route.
(Moriguchi T et al., 2020)
• Electron microscopy of the brain tissue of a 74-year-old male with
indicated the neuroinvasive nature of the virus and the likely routes of
transmission to the CNS. (Paniz-Mondolfi A et al., 2020)
• Viral particles found in frontal lobe sections
• Viral particles found in endothelial cells
• Blebbing observed in/out endothelial cells
• Vacuoles containing whole viral particles found in neuronal cell bodies

PATHOPHYSIOLOGY OF
CNS INVOLVEMENT
SARS‐CoV‐2 can take two pathways to involve the brain;
direct and indirect pathways. (Wu Y et al., 2020)

PATHWAYS OF CNS INVOLVEMENT
• DIRECT PATHWAYS
• Haematogenous route
• Neuronal transport : retrograde axonal transport
o Olfactory network
o Respiratory network
o Enteric nervous system (gut-brain barrier)
• INDIRECT PATHWAYS
• Cytokine dysregulation (cytokine storm)
• Peripheral immune cell transmigration
• Neuroinflammation
• Post infectious autoimmunity
o Molecular mimicry
o Bystander activation of immune cells
o Epitope spreading
• Hypoxic injury
• hypercoagulability

DIRECT PATHWAYS OF CNS INVOLVEMENT
•HAEMATOGENOUS
• Endothelial cells of the blood-brain barrier
• Epithelial cells of the blood-csf barrier
• Myeloid cells (Trojan horse mechanism)
•RETROGRADE NEURONAL TRANSPORT
• Olfactory network
• Respiratory network
• Gut-brain pathway

DIRECT PATHWAYS OF CNS INVOLVEMENT
(Desforges et al 2019)
(Bohmwald K et al., 2018)

CYTOKINE STORM
• 1993: Graft vs Host disease (Ferrara et al, 1993)
• 2002/2003: First used in reference to an infection, Influenza
encephalopathy (Yokota, 2003)
• The 1918 Influenza pandemic (Spanish flu), SARS epidemic
in 2003, the H5N1 bird flu epidemic : cytokine storm is
thought to have contributed to the high combined mortality of
17-50M

Neurological manifestations of sars cov 2

Cytokine profile associated with COVID-19
• Increased in the following:
• Interleukin (IL)-2
• Granulocyte colony stimulating factor
• Interferon γ
• Inducible protein 10
• Monocyte chemoattractant protein 1
• Macrophage inflammatory protein 1α
• Tumour necrosis factor α
• Serum ferritin
? Virally driven hyperinflammation

Cytokine storm
• Patients with severe disease may have a cytokine storm syndrome2
• Same subset of patients are likely to present with severe neurological
symptoms
• All patients with severe Covid-19 should be screened for
hyperinflammation using laboratory trends: increased serum ferritin,
decreased platelet counts, the Erythrocyte sedimentation rate and the
HS score in order to identify subsets of patients who would benefit from
immunosuppression

TREATMENT STRATEGIES
•In hyperinflammation, immunosuppression is likely to be
beneficial
•Corticosteroids not routinely recommended
•Dexamethasone should be reserved for severe cases who exhibit
a cytokine storm
•Vitamin B3 (Nicotinamide) : potent inhibitor of proinflammatory
cytokines
•Magnesium decrease inflammatory cytokines by modulating the
immune system
•Cytokine blocking agents: Tocilizumab®, anakinra®

Early neurological manifestations
• Neurological manifestations occurred in 36,4% of hospitalised patients
• Median time to hospital admission 1-2 days
• CNS symptoms: Dizziness (16,8%) Headaches (13,1%) Seizures (2,4%)
• PNS symptoms: Ageusia (taste impairment): 5.6% Anosmia (sense of smell
imparment: 5.1%
(Mao L et al.,2020)

Late neurological manifestations
• French series of 58 ICU patients, 69% had encephalopathy with confusion and
long tract signs
• United kingdom, 153 cases, 62 % had cerebrovascular events
• 74% had ischaemic strokes
• 12% had intracranial haemorrhage
• 1% had CNS vasculitis
• Guillan-Barre Syndrome (GBS), generalised myalgia, raised muscle enzymes
(Helms J et al., 2020)
(Varatharaj A et al., 2020)
(Toscano G et al., 2020)

THE VAGUS NERVE
• SARS-COV-2 reaches the CNS via retrograde invasion of the sensory fibres of the
vagus nerve
• The vagal nucleus consists of four nuclei including the nucleus ambiguous
situated in the medulla
• The central respiratory centre is situated in the medulla, ventral to the nucleus
ambiguous
• The dorsal motor nucleus of the vagus and the area postrema are the motor output
of respiratory activity
• SARS-COV-2 reaching the CNS via the vagus nerve will invariably affect the
central respiratory centre and exacerbate respiratory dysfunction.

Bonaz, B., Sinniger, V., & Pellissier, S. (2020). Targeting the cholinergic anti-inflammatory pathway with vagus nerve stimulation in patients with Covid-19? Bioelectronic Medicine, 6(1). doi:10.1186/s42234-020-00051-7

•The respiratory distress is not only the result of pulmonary
inflammatory changes but also due to damage of the respiratory
centres in the brainstem, making it difficult to manage.
•It is too early to ascertain the neurodegenerative effects of the
virus as these tend to lag.
•We still have a lot to learn from the novel corona virus and that
journey is proving very exciting.
CONCLUSION

REFERENCES (not exhaustive)
1- https://covid19.who.int/
2- The Lancet. COVID-19: protecting health-care workers. Lancet. 2020;395(10228):922. doi:10.1016/S0140-6736(20)30644-9
3- Tan, Y. T., Wang, J. W., Zhao, K., Han, L., Zhang, H. Q., Niu, H. Q., Shu, K., & Lei, T. (2020). Preliminary Recommendations for Surgical Practice of
Neurosurgery Department in the Central Epidemic Area of 2019 Coronavirus Infection. Current medical science, 10.1007/s11596-020-2173-5. Advance
online publication. https://doi.org/10.1007/s11596-020-2173-5
4- Zoia C, Bongetta D, Veiceschi P, et al. Neurosurgery during the COVID-19 pandemic: update from Lombardy, northern Italy [published online ahead of
print, 2020 Mar 28]. Acta Neurochir (Wien). 2020;10.1007/s00701-020-04305-w. doi:10.1007/s00701-020-04305-w
5- Asadi-Pooya, A. A., & Simani, L. (2020). Central nervous system manifestations of COVID-19: A systematic review. Journal of the neurological sciences,
413, 116832. Advance online publication. https://doi.org/10.1016/j.jns.2020.116832
6- Das, G., Mukherjee, N., & Ghosh, S. (2020). Neurological Insights of COVID-19 Pandemic. ACS chemical neuroscience, acschemneuro.0c00201.
Advance online publication. https://doi.org/10.1021/acschemneuro.0c00201
7- Baig AM. Neurological manifestations in COVID-19 caused by SARS-CoV-2. CNS Neurosci Ther. 2020;26(5):499–501. doi:10.1111/cns.13372
8- Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients [published
online ahead of print, 2020 Feb 27]. J Med Virol. 2020;10.1002/jmv.25728. doi:10.1002/jmv.25728
9- Wende Zhu, MD, Xing Huang, MD, Hongyang Zhao, MD, Xiaobing Jiang, MD, A COVID-19 Patient Who Underwent Endonasal Endoscopic Pituitary
Adenoma Resection: A Case Report, Neurosurgery, , nyaa147, https://doi.org/10.1093/neuros/nyaa147
10- Society of British Neurological Surgeons (SBNS) www.sbns.org.uk
11- Clark IA (June 2007). "The advent of the cytokine storm". Immunology and Cell Biology. 85 (4): 271–3. doi:10.1038/sj.icb.7100062. PMID 17551531.
12- Yokota S. Influenza-associated encephalopathy–patho-physiology and disease mechanisms.Nippon Rinsho2003;61: 1953–1958.
13- Ferrara JL, Abhyankar S, Gilliland DG (February 1993). "Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1".
Transplantation Proceedings. 25 (1 Pt 2): 1216–7. PMID 8442093.
14- Bonaz, B., Sinniger, V., & Pellissier, S. (2020). Targeting the cholinergic anti-inflammatory pathway with vagus nerve stimulation in patients with Covid-
19? Bioelectronic Medicine, 6(1). doi:10.1186/s42234-020-00051-7

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