Although initially thought to be similar to the flu, COVID-19 has been found to induce negative health effects that may last for years, and possibly a lifetime. Evidence for neurological effects in coronavirus patients has been accumulating since the start of the pandemic. Most neurologically affected patients tend to exhibit symptoms such as headaches, muscle and joint pain or ‘COVID fog,’ a general term used to cover a variety of neurological effects including headaches, dizziness, loss of smell or taste, muscle weakness, nerve damage and trouble concentrating. More severe cases, commonly seen in older patients, can result in stroke or encephalitis, which is the inflammation of the brain.

The cause of these symptoms is still unclear. Alysson Muotri, a Professor of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine, has shown that it is possible for COVID-19 to directly infect neurons. Using organoids, small tissue cultures made from pluripotent stem cells that differentiate into neurons, her research showed that COVID-19 could infect neurons by negatively affecting the synapses formed between them. 

Muotri’s research shows that neurons can be affected, but further research has been performed to understand the mechanism behind how this infection occurs. Additionally, while COVID-19 may be directly impacting the central nervous system (CNS), there is growing evidence that the interaction between the virus and the CNS can be indirect as well. Understanding the possible mechanisms relating to how the brain is affected by COVID-19 is key in determining how to treat patients.

Isaac Soloman, and instructor in pathology at the Brigham and Women’s Hospital in Boston, and his team at Brigham and Women’s Hospital in Boston, Massachusetts studied the brains of 18 patients who died from COVID-19. They utilized various techniques in neuropathology, as well as immunohistochemistry — a microscopy-based staining technique to identify cellular proteins and antigens — and reverse transcriptase quantitative PCR — a technique to detect variations in gene expression. The neuropathology results indicated that the patients were affected by a condition known as hypoxia, which results from oxygen deprivation in tissues. The immunohistochemistry results showed no staining in the neurons, glia, endothelium or immune cells, and subsequently combined with the qRT-PCR results, there was not significant evidence that COVID-19 was present in the brain of these patients. As such, the team concluded that it was unlikely the hypoxia was due to direct infiltration of COVID-19 into the brain. Rather, it is possible the effects were caused by the infection in other areas of the body, and affected the brain in a secondary manner. 

Xavier De Tiège, a neurologist at the Université libre de Bruxelles, Belgium, looked at the occurrence of brain lesions and abnormalities with MRI in patients who died with severe COVID-19. The patients in Tiège’s study were between 49 and 94 years old, and each suffered from a number of pre-existing conditions, including hypertension, cardiac disorder, diabetes mellitus, chronic obstructive pulmonary disorder, chronic kidney disease or a body mass index greater than 25.

In the 19 brains studied, the team found white matter changes, posterior reversible encephalopathy syndrome as well as hemorrhages. White matter is the portion of brain tissue composed of neuron axons, which is lighter in comparison to the gray matter that contains the neuron’s cell bodies. The changes observed in white matter were nonspecific, meaning they differed from patient to patient. Posterior reversible encephalopathy syndrome affects the posterior occipital and parietal lobes, causing symptoms including headaches, seizures, visual loss and altered mental status. Hemorrhages are caused by ruptured blood vessels in the brain. They did not detect any changes in the brainstem that could reflect any brain involvement in respiratory symptoms of COVID-19. Tiège’s team also noted that the changes observed do not necessarily mean that COVID-19 had direct access to the brain, and instead could have resulted from blood–brain barrier breakdown.

Another study by Magnus Gisslén and his team in Gothenburg, Sweden measured plasma levels using blood-based biomarkers to assess astrocytic and neuronal injury. Astrocytes play a broad variety of roles such as providing support to axons and regulating blood flow, including within the blood-brain barrier. The team studied 47 patients with COVID-19. Patients with severe cases of the virus showed elevated levels of the biomarkers being tested. Over time, biomarkers indicating astrocytic injury declined while those for neuronal injury continued to increase. Levels of the biomarkers indicating neuronal injury were also raised in patients with moderate cases of COVID-19. According to Gisslén, the question remains of whether the CNS injury seen in COVID-19 patients is a result of overstimulation of the immune system, or if the direct CNS observations such as hypoxia also play a role.

While the neurological symptoms of COVID-19 are beginning to be understood, more research needs to be done on how the virus reaches the brain. While it is rather rare, some viruses can infect the brain — but there is not yet evidence that COVID-19 can do so. As researchers look into how and why CNS injury occurs in infected patients, it is important to understand how their findings can affect treatment. As Benedict Michael, a neurologist from the University of Liverpool, described, “If this is [a] direct viral infection of the central nervous system, these are the patients we should be targeting for remdesivir or another antiviral … If the virus is not in the central nervous system, maybe the virus is clear of the body, then we need to treat with anti-inflammatory therapies. It’s pointless giving the antivirals to someone if the virus is gone, and it’s risky giving anti-inflammatories to someone who’s got a virus in their brain.”

As the COVID-19 pandemic continues to progress, scientists and doctors are working to bring an end to this pandemic. Further research is being conducted to understand the underlying causes of the neurological effects from COVID-19, progressing doctors’ abilities to adequately treat patients. Until then, understanding the potential risks of this virus is key in keeping communities informed and providing reasons to remain careful in the coming months as a vaccine is developed and distributed.

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