A new paper published in the journal JAMA Neurology in May 2020 discussed the presentation and complications of COVID-19 with respect to the nervous system.
The COVID-19 pandemic has caused hundreds of thousands of cases of severe pneumonia and respiratory disorders, in 188 countries and regions in the world. The causative agent, SARS-CoV-2, is a new coronavirus, with well-recognized lung complications. However, evidence is increasing that the virus also affects other organs, such as the nervous system and heart.
The Coronaviruses: A Glimpse
That corona virus is a group of large spread RNA viruses that infect animals and humans. Human infections are known to be caused by 7 coronaviruses, namely human coronavirus (HCoV) –229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, MERS-CoV, SARS-CoV-1, and SARS-CoV-2.
Among these, the last three are known to cause severe human disease. While HCoV is more associated with respiratory manifestations, three of them are known to infect neurons: HCoV-229E, HCoV-OC43, and SARS-CoV-1.
Current research aims to contribute to the knowledge of the SARS-CoV-2 neurotropism, as well as post-infectious neurological complications. This virus infects humans through ACE2 receptors in various tissues, including airway epithelium, kidney cells, small intestine, proper lung tissue, and endothelial cells.
Because endothelium is found in blood vessels throughout the body, this offers a potential route for CoV to be localized in the brain. In addition, a recent report shows that ACE2 is also found in brain neurons, astrocytes, and oligodendrocytes, especially in areas such as substantia nigra, ventricles, middle temporal gyrus, and olfactory bulb.
Interestingly, ACE2 in neuron tissue is expressed not only on the surface but also in the cytoplasm. This finding could imply that SARS-CoV-2 can infect neuronal and glial cells in all parts of the central nervous system.
How does neuroinvasion occur with SARS-CoV-2?
Current knowledge indicates the possibility of nerve cell virus invasion by several mechanisms. These include the transfer of viruses across synapses of infected cells, entering the brain through the olfactory nerve, infection of endothelial blood vessels, and migration of infected white blood cells across the blood-brain barrier (BBB).
The corona virus has been shown to spread back along the nerves from the edge of the peripheral nerves, across synapses, and thus into the brain, in several small animal studies. This is facilitated by a pathway for endocytosis or exocytosis between motor cortex neurons, and other secretory vesicular pathways between neurons and satellite cells.
Axonal transport occurs rapidly using axonal microtubules, which allow the virus to reach the body of neuron cells with a retrograde version of this mechanism.
The possibility of spreading the olfactory route is marked by the occurrence of isolated anosmia and age. In such cases, the virus can pass through the latticed plate to enter the central nervous system (CNS) of the nose. However, more recent unpublished research shows that olfactory neurons lack ACE2, whereas cells in the olfactory epithelium do so. This could mean that a viral injury to the olfactory epithelium, and not the olfactory neuron, is responsible for anosmia, but further studies will be needed to confirm this.
Cross the BBB
This virus can also pass through the BBB through two separate mechanisms. In the first case, infected vascular endothelial cells can move the virus across blood vessels to neurons. Once there, the virus can start to bud and infect more cells.
The second mechanism is through infected white blood cells that pass through the BBB – a mechanism called Trojan horse, which is famous for its role in HIV. Inflamed BBB allows the entry of immune cells and cytokines, and even, possibly, viral particles into the brain. T-lymphocytes, however, do not allow viruses to replicate even though they can be infected.
Neurological features of COVID-19
From limited data on neurological manifestations related to COVID-19, it is clear that headaches, anosmia, and age are among the most common symptoms. However, other findings include stroke and an abnormal state of consciousness.
While headaches occur in up to one third of confirmed cases, anosmia or age shows a much more varied prevalence. In Italy, about one fifth of cases show this symptom, while almost 90% of patients in Germany have such symptoms.
The researchers said, “Given the reports of anosmia that appear as early symptoms of COVID-19, specific testing for anosmia can offer the potential for early detection of COVID-19 infection.”
Impaired consciousness can occur in up to 37% of patients, due to various mechanisms such as infection and direct brain injury, metabolic-toxic encephalopathy, and demyelinating disease. Encephalitis has not been documented as a result of COVID-19.
Toxic-metabolic encephalopathy can occur due to a number of disorders of metabolic and endocrine function. These include electrolyte and mineral imbalances, kidney disorders, and cytokine storms, hypo or hyperglycemia, and liver dysfunction. Patients who are elderly, ill, or already have symptoms of dementia, or are malnourished, are at higher risk for this condition.
Less common neurological complications include Guillain-Barre syndrome, which is a post-viral acute inflammatory demyelinating disease, and cerebrovascular events, including stroke.
Is COVID-19 Therapy Related to Neurological Manifestations?
Nowadays, many different drugs are used to treat this condition.
Chloroquine and hydroxychloroquine, for example, can cause psychosis, peripheral neuropathy, and the latter can worsen the symptoms of myasthenia gravis. Tocilizumab, an IL-6 blocker, is intended to reduce excessive cytokine release that occurs in severe inflammation. Although admission to CNS is limited, it can sometimes cause headaches and dizziness.
Precautions for COVID-19 Patients with Neurological Conditions
If a patient already has a neurological condition that requires special treatment, they tend to be at higher risk for COVID-19, due to existing lung, heart, or liver conditions, having kidney disease (dialysis), if they are overweight, or at immunosuppressive drugs. Also, it is likely that they may be in nursing homes, where many countries have reported severe outbreaks.
This study concludes: “Doctors must continue to monitor patients closely for neurological diseases. Early detection of neurological deficits can lead to improved clinical outcomes and better treatment algorithms. “
- Zubair, A. S. et al. (2020). Neuropathogenesis and Neurological Manifestations of Coronavirus in the Coronavirus Era 2019: Overview. JAMA Neurology. doi: 10.1001 / jamaneurol.2020.2065.