Headache, confusion and delirium in some Covid-19 patients could be the result of the coronavirus entering the brain directly, according to a study published on Wednesday.
The research is still preliminary – but offers several new lines of evidence to support a previously largely untested theory.
According to the article headed by Yale immunologist Akiko Iwasaki, the virus is able to replicate in the brain, and its presence causes nearby brain cells to stop receiving oxygen, although the prevalence is not yet clear.
S Andrew Josephson, chairman of the Department of Neurology at the University of California at San Francisco, praised the techniques used in the study and said, “It is extremely important to understand whether or not there is direct virus involvement of the brain.”
But he added that he would remain cautious until the paper was peer reviewed.
It wouldn’t be completely shocking if SARS-CoV-2 could break the blood-brain barrier, a structure that surrounds the blood vessels in the brain and tries to block foreign substances.
The Zika virus, for example, does this too, causing considerable damage to the brains of fetuses.
However, until now, doctors had believed that the neurological effects seen in roughly half of all patients could instead be due to an abnormal immune response known as a cytokine storm, which causes inflammation of the brain – rather than the virus that directly invaded it.
Iwasaki and colleagues decided to approach the question in three ways: by infecting laboratory-grown mini-brains known as brain organoids, by infecting mice, and by examining the brain tissue of deceased Covid-19 patients.
In the organoids of the brain, the team found that the SARS-CoV-2 virus can infect neurons and then hijack the machinery of neuron cells to make copies of itself.
Infected cells, in turn, promoted the death of the surrounding cells by stifling their oxygen supply.
One of the main arguments against the direct brain invasion theory was that the brain lacks high levels of a protein called ACE2, to which the coronavirus attaches and which is abundant in other organs like the lungs.
However, the team found that the organoids had enough ACE2 to facilitate virus entry, and that the proteins were also present in the brain tissue of dead patients.
They also performed a spinal tap on a delirious Covid-19 patient in the hospital and found that the person had neutralizing antibodies to the virus in their spinal fluid – further proof of their theory.
The team then looked at two groups of mice – one group that was genetically engineered so that ACE2 receptors were only present in the lungs and the other only in the brain.
Those infected in their lungs showed some signs of lung injury, while those infected in the brain lost weight quickly and died quickly, indicating a possible increased lethality if the virus invaded this organ.
Finally, they examined the brains of three patients who died from severe complications related to Covid-19 and found evidence of the virus to varying degrees.
Interestingly, the infected regions showed no evidence of infiltration by immune cells such as T cells, which rush to take the place of other viruses such as Zika or herpes to kill the infected cells.
This could suggest that the overloaded immune response known as a cytokine storm, which is responsible for much of the damage seen in the lungs of Covid-19 patients, may not be the main cause of neurological symptoms.
It was thought that the nose might be the route to the brain, but the authors wrote that this needed further study to confirm.
They added that more autopsies will be needed to find out how common a brain infection could be.