Goal: The goal of this study was to determine the neuroinvasive pathways of SARS-CoV-2 and discuss the neurosympomology of the virus through a comprehensive literature review. 

Results:
- The viral presence of SARS-CoV-1 has been established in the CNS through autopsy analysis
- Studies using mice have shown that SARS-CoV-1 has reached the brain possibly through the olfactory nerves and spread to thalamus and brainstem. 
- Covid-19 neurological symptoms include dizziness, loss of smell and taste, headache, and loss of consciousness
- Research on the type of symptoms that occur in mild vs severe patients - suggest that an early stage of viral transmission can cause direct injury to nasal nerves
- Analysis of incidents of Guillain-Barré syndrome in Covid-19 patients suggests that whether GBS is caused by a direct attack on the myelin sheath, or through blood brain barrier permeability due to the increased inflammation of the cytokine storm in the CNS
- Incidents of Encephalitis have been established in Covid-19 patients across the world. 
- The widespread ACE2 receptor might be the reason for such a variety of symptoms and might explain how the virus makes its way through the olfactory epithelium (OE). The virus might attach to ACE2 receptors and invade the olfactory epithelium, then the olfactory ensheathing cells surrounding the olfactory neurons. Evidence for this route includes that non-neural cells in the OE have the SARS-Cov-2 entry genes. Further, olfactory nerves in autopsy analyses have shown tissue damage.
- Another potential pathways for Covid-19 reaches neurological systems include direct invasion to the nasal cavity, with evidence that this is what causes headaches.
- Another includes direct invasion into the bloodstream via epithelial erosion, which could allow the virus to cross the BBB, with evidence showing this from postmortem analysis. 
- Further, it is possible that the cytokine storm that occurs as an immune response to covid can compromise the blood brain barrier, reduces circulating AE2 and increases angiotensin II, which predisposes patients to stroke and clotting. 


Potential neuroinvasive pathways of SARS-CoV-2: Deciphering the spectrum of neurological deficit seen in coronavirus disease-2019 (COVID-19)

Entry of  SARSCoV-2 into the blood has been described with widely ranging frequencies (1% to 41%) . There are a few possible mechanisms of entry through the BBB:

1. Circulating SARS-CoV-2, associated cytokines, DAMPs, and PAMPs could act on endothelial cells leading to inflammation and opening of the BBB. 

2. Comorbidities often seen in COVID-19, like cardiovascular risk or pre-existing neurological diseases, could, alone or in combination with cytokines, increase BBB permeability. 

3. SARS-CoV-2 could enter the brain through the median eminence of the hypothalamus and other circumventricular organs, brain regions with a leaky BBB due to openings in the capillary wall. The hypothalamus could serve as a gateway to the entire brain. 


SARS-CoV-2 Entry Through the Blood Brain Barrier (BBB)

- Potential neuroinvasive pathways of SARS-CoV-2: Deciphering the spectrum of neurological deficit seen in coronavirus disease-2019 (COVID-19)
- SARS-CoV-2 entry through the blood brain barrier (BBB)

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1. Entry through the naval cavity: because intranasal drug delivery bypasses the blood brain barrier to delivery therapeutic agents directly to the CNS, it is thought that SARS-CoV-2 can likewise infect the brain via olfactory nerves.
  
2. Entry through the lungs: previous speculation that SARS-CoV could infect the , brainstem via chemoreceptors and mechanoreceptors in the respiratory system lend possibility for a neurotropic mechanism for SARS-CoV-2.

These hypotheses have yet to be validated.  
Figure below shows coronavirus infection mechanisms (Wu et. al).

Hypothesized Mechanisms for SARS-CoV-2 Direct Invasion of the CNS 

Baig AM, Sanders EC. Potential neuroinvasive pathways of SARS-CoV-2: Deciphering the spectrum of neurological deficit seen in coronavirus disease-2019 (COVID-19). J Med Virol. 2020 Jun 3:10.1002/jmv.26105. doi: 10.1002/jmv.26105. Epub ahead of print. PMID: 32492193; PMCID: PMC7300748. 

- K18-hACE2 mice brain tissue shows no viral infection in olfactory tissue

Reports Supporting SARS-CoV-2 Direct CNS Invasion Through the Lungs

- Increasing data suggest that ACE2 is not appreciably expressed in neurons in the brain at either the RNA or protein level. 
- scSeq analysis of human prefrontal cortex and hippocampus failed to identify any ACE2- expressing cells 
- multiple immunostaining studies have demonstrated ACE2 expression in brain vasculature but not in neurons or glia 


Support Against SARS-CoV-2 Direct Invasion of Neurons and Glial Cells

SARS-CoV-2 RNA and spike (S) protein have been detected in both the olfactory mucosa and the CNS of COVID-19 patients, with the highest viral loads reported in the olfactory mucosa beneath the cribriform plate. These findings support the hypothesis that the virus exploits the neural–mucosal interface of the olfactory region as a port of entry into the CNS.

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