A new paper published in the journal JAMA Neurology in May 2020 discusses the presentation and complications of COVID-19 with respect to the nervous system.
The pandemic of COVID-19 has been causing hundreds of thousands of cases of severe pneumonia and respiratory distress, in 188 countries and territories of the world. The causative agent, SARS-CoV-2, is a novel coronavirus, with well-recognized lung complications. However, the evidence is mounting that the virus also affects other organs, such as the nervous system and the heart.
The Coronaviruses: A Glimpse
The coronaviruses are a group of large enveloped RNA viruses that infect both animals and humans. Human infections have been found to be caused by 7 coronaviruses, namely, the 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 are more associated with respiratory manifestations, three of them are known to infect neurons: HCoV-229E, HCoV-OC43, and SARS-CoV-1.
The current study aims to contribute to knowledge about the neurotropism of SARS-CoV-2, as well as its post-infectious neurologic complications. This virus infects humans via the ACE2 receptor in various tissues, including the epithelium of the airways, the kidney cells, the small intestine, the lung tissue proper, and endothelial cells.
Since endothelium is found within blood vessels throughout the body, this offers a potential route for CoVs to localize within the brain. Moreover, a recent report shows that ACE2 is also found on brain neurons, astrocytes, and oligodendrocytes, especially in a few areas like the substantia nigra, ventricles, middle temporal gyrus, and the olfactory bulb.
Interestingly, ACE2 within neuronal tissue is expressed not only on the surface but also in the cytoplasm. These findings may imply that SARS-CoV-2 can infect neurons and glial cells in all parts of the central nervous system.
How Does Neuroinvasion Occur with SARS-CoV-2?
Current knowledge points to the possibility of viral invasion of nerve cells by several mechanisms. These include the transfer of the virus across the synapses of infected cells, entry into the brain through the olfactory nerve, infection of the vascular endothelium, and the migration of infected white blood cells across the blood-brain barrier (BBB).
Coronaviruses have been shown to spread back along the nerve from the peripheral nerve endings, across the synapses, and thus enter the brain, in several small animal studies. This is facilitated by the presence of a pathway for endocytosis or exocytosis between neurons of the motor cortex, and another secretory vesicular pathway between neurons and satellite cells.
Fast axonal transport occurs by employing axonal microtubules, allowing the virus to reach the neuronal cell body by a retrograde version of this mechanism.
Possible olfactory route spread is signaled by the occurrence of isolated anosmia and ageusia. In such a case, the virus could cross the cribriform plate to enter the central nervous system (CNS) from the nose. However, newer unpublished research suggests that olfactory neurons lack ACE2, while cells in the olfactory epithelium do. This could mean that viral injury to the olfactory epithelium, and not to the olfactory neurons, is responsible for anosmia, but further studies will be required to confirm this.
Crossing the BBB
The virus could also cross the BBB via two separate mechanisms. In the first case, the infected vascular endothelial cells could transport the virus across the blood vessel into the neurons. Once there, the virus could begin to bud and infect more cells.
The second mechanism is via the infected white cells passing through the BBB – the so-called Trojan horse mechanism, well-known through its role in HIV. The inflamed BBB allows an influx of immune cells and cytokines, and even, perhaps, the viral particles into the brain. The T-lymphocytes, however, do not allow the virus to replicate though they can be infected.
Neurological Features In COVID-19
From the limited data on COVID-19-linked neurological manifestations, it is clear that headache, anosmia, and ageusia are among the most common symptoms. However, other findings include stroke and abnormal states of consciousness.
While headache occurs in up to a third of confirmed cases, anosmia or ageusia shows a much more varying prevalence. In Italy, about a fifth of cases showed these symptoms, while almost 90% of patients in Germany had such symptoms.
The researchers say, “Given the reports of anosmia presenting as an early symptom of COVID-19, dedicated testing for anosmia may offer the potential for early detection of COVID-19 infection.”
Impairment of consciousness may occur in up to 37% of patients, due to a variety of mechanisms like direct brain infection and injury, toxic-metabolic encephalopathy, and demyelinating disease. Encephalitis has not been documented as a result of COVID-19.
Toxic-metabolic encephalopathy can occur because of a host of disturbances in metabolic and endocrine function. These include electrolyte and mineral imbalances, renal impairment, and cytokine storm, hypo- or hyperglycemia, and liver dysfunction. Patients who are elderly, sick, or already have dementia symptoms, or 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.
Are COVID-19 Therapies Related to Neurological Manifestations?
At present, many different medications are being used to treat this condition.
Chloroquine and hydroxychloroquine, for instance, may cause psychosis, peripheral neuropathy, and the latter can worsen the symptoms of myasthenia gravis. Tocilizumab, an IL-6 blocker, is meant to reduce the excessive release of cytokines that occurs in severe inflammation. Though its entry into the CNS is limited, it can sometimes cause headaches and dizziness.
Precautions for COVID-19 Patients with Neurological Conditions
If a patient already has neurological conditions that require special care, they are likely to be at higher risk for COVID-19, because of co-existing lung, heart, or liver conditions, have kidney disease (on dialysis), if they are overweight, or on immunosuppressive medications. Also, the chances are high that they may be in a nursing home, where many countries have reported severe outbreaks.
The study sums up: “Clinicians should continue to monitor patients closely for neurological disease. Early detection of neurological deficits may lead to improved clinical outcomes and better treatment algorithms.”
- Zubair, A. S. et al. (2020). Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review. JAMA Neurology. doi:10.1001/jamaneurol.2020.2065.