June 30, 2020
Written by: Nitsan Goldstein
The novel coronavirus has infected close to 8 million people worldwide, with infections in every US state and nearly every country on Earth. Most people develop fever, cough, and shortness of breath. However, as more people become infected, less common symptoms are being documented by doctors around the world. Among these are a set of neurological symptoms that suggest that SARS-CoV-2, the virus that causes COVID-19, may affect the brain. Here we will examine what these symptoms are, what is known about how SARS-CoV-2 and other coronaviruses can damage the brain, and how much work is still needed to understand the impact of this virus on the human body.
Reports of neurologic symptoms with SARS-CoV-2 infection
There have been several reports of neurologic symptoms in COVID-19 patients. One such study in China found that, of 214 patients with COVID-19, 36.4% of them had neurologic symptoms, described below1. Patients with more severe cases of the disease were more likely to develop these symptoms, as were older individuals or those with underlying conditions. Following this study, doctors in Europe and the United States have noted similar symptoms2.
Acute cerebrovascular disease. Vascular events such as strokes have been reported in COVID-19 patients. It is thought that SARS-CoV-2 causes a thickening of the blood, which leads to blood clots3. A stroke occurs when those clots block blood vessels in the brain, depriving it of the oxygen it needs to function properly.
Anosmia. Loss of smell has emerged as one of the more common symptoms of COVID-19 and is often present in otherwise asymptomatic carriers of SARS-CoV-2.
Inflammation. Mild cases of COVID-19 can rapidly become severe when the immune system goes into overdrive. The immune cells that are released to fight the virus instead cause a massive inflammatory response that damages organ systems, including the brain. As a result, patients have experienced seizures and loss of consciousness2.
Reflexes. There have been anecdotal observations that some patients do not gasp for breath even when their oxygen levels are very low2. This suggests that the brain stem, a region that senses oxygen levels and coordinates the appropriate reflexes to maintain proper oxygen levels, may also be affected by the virus.
How do we interpret these observations?
While it is clear that neurologic symptoms are quite common in patients with COVID-19, it is still very difficult to determine the underlying causes of these symptoms. The big question is whether or not the SARS-CoV-2 virus itself infiltrates the brain and causes neuronal damage. For example, one case study described a person who was infected with SARS-CoV-2 and developed meningitis and encephalitis, which involves severe inflammation in the brain and surrounding tissue4. Interestingly, the swabs taken from the patient’s nose were negative for SARS-CoV-2 but samples taken from the spinal fluid were positive. This indicates that the virus was not in the nasal passages where it typically resides, but had instead infected the central nervous system. Though rare, this case study is an important demonstration that the virus itself is capable of infiltrating the brain and spinal cord.
Many of the more commonly experienced neurologic symptoms, however, can be explained by the virus’s effects on other organ systems that then manifest as neurologic symptoms. One study examined the brains of patients who had died of COVID-19 and found evidence of brain damage that could not be linked to active infection in the brain5. Neurons showed evidence of hypoxia (lack of oxygen), but the tissue itself showed very low or no levels of virus. In this case, brain damage was a result of respiratory failure rather than direct viral infection in the brain.
It is also important to take note of biases in the samples of such studies. Most were hospitalized patients who had severe cases of COVID-19 and are more likely than the general population to have risk factors such as diabetes and cardiovascular disease. These conditions may put them at greater risk for developing nervous system dysfunction. Additionally, many of these patients need mechanical ventilation and are sedated, further complicating the assessment of neurologic symptoms and why they occur. It is likely, therefore, that symptoms in less severe cases that do not require hospitalization go undetected, and may even be drastically different than those described here.
What we do know
What do we know about how this virus and other similar viruses may affect the nervous system? Viruses infect their host by gaining access to the hosts’ cells, and using those cells to reproduce and spread. Scientists have identified angiotensin-converting enzyme 2 (ACE2) as the protein on the outside of our cells that SARS-CoV-2 uses to gain access to our cells and reproduce. The levels of ACE2 are higher in some cells than others, which can give scientists a clue as to which cell types and organs are more susceptible. Lung cells, for example, have high levels of ACE2, which explains why the virus easily infects the lungs and replicates in our nasal passages. Intestinal cells also contain high levels of ACE2, which may explain the prevalence of gastrointestinal symptoms like diarrhea in many COVID-19 patients6. In the brain, ACE2 is present at significant levels in the brain stem, an area which regulates reflexes such as breathing2. This may explain some of the reports describing a lack of gasping in response to low oxygen levels. The fact that respiratory distress may be caused both by lung dysfunction and improper control by the central nervous system is concerning and an example of how complicated this disease is.
To fully understand the disease process and how it affects the nervous system, we have to turn to animal models. While there are large-scale efforts underway to learn more about SARS-CoV-2, we may be able to learn from a recent relative of the virus. The SARS outbreak in 2003 was caused by SARS-CoV, a virus very similar to SARS-CoV-2 in that it also used ACE2 to get into cells. Scientists engineered mice to have the human form of ACE2, which would allow the SARS-CoV virus to infect mice and model what might happen when a human is infected7. They found that when virus was delivered into the nose, it reached the brain and infected areas of the brain known to contain ACE2, like the brain stem. Remarkably, when the scientists infected only the brain with SARS-CoV, the mice still died of respiratory failure even though no virus was present in the lungs. These findings add to evidence that the virus itself may be damaging the nervous system and compounding respiratory problems in severe cases.
Studies like these are critical in enhancing our understanding of how a viral infection could cause widespread damage in the body. While we can make hypotheses based on work done with SARS-CoV, the new virus SARS-CoV-2 may behave differently. It is not only important to identify and treat neurologic symptoms in COVID-19 patients, but doctors and scientists will have to continue monitoring patients that have recovered to determine whether there are long-term neurologic deficits associated with COVID-19. Many laboratories have shifted their research to help answer some of these questions, and the hope is that these efforts result in better treatments and health outcomes in COVID-19 patients.
- Mao, L., Jin, H., Wang, M., et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. e201127 (2020).
- Wadman, M., Couzin-Frankel, J., Kaiser, J., & Metacic, C. How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes. Science (2020).
- Panigada, M., Bottino, N., Tagliabue, P., et al. Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis. J Thromb Haemost. (2020).
- Moriguchi, T., Harii, N., Goto, J., et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. 94, 55-58 (2020).
- Solomon, I.H., Normandin, E., Bhattacharyya, S., et al. Neuropathological Features of Covid-19. N. Engl. J. Med. (2020).
- Xiao, F., Tang, M., Zheng, X., Liu, Y., Li, X., Shan, H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology 158, 1831-1833.e3 (2020).
- Netland, J., Meyerholz, D.K., Moore, S., Cassell, M., Perlman, S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol. 82, 7264-7275 (2008).
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