In the early months of the COVID-19 epidemic, doctors struggled to keep patients breathing, and focused primarily on treating damage to the lungs and circulatory system. But still, evidence for neurological effects was accumulating. Some people hospitalized with COVID-19 were experiencing delirium: they were confused, disorganized, and agitated.2. In April, a group was published in Japan3 The first report of someone with COVID-19 who had swelling and inflammation in brain tissue. Another report4 One patient was described with worsening of myelin, a fatty coating that protects neurons and is irreversibly damaged in many sclerosis-like neurodegenerative diseases.
“Neurological symptoms are only getting more frightening,” says neuroscientist, Alison Muotri, of the University of California at San Diego, La Jolla.
The list now includes stroke, brain haemorrhage and memory loss. It is not unheard of for serious illnesses to cause such effects, but the scale of the COVID-19 epidemic means that thousands or tens of thousands of people may already have these symptoms, and some may have a lifelong result. Problems may be encountered.
Yet researchers are struggling to answer key questions – including basic ones, such as how many people have these conditions, and who are at risk. Most importantly, they want to know why these particular symptoms are appearing.
Although viruses can invade and infect the brain, it is unclear whether SARS-CoV-2 does so to a significant extent. Neurological symptoms may instead be the result of overstimulation of the immune system. This detection is important, as these two scenarios require completely different treatments. “Therefore disease mechanisms are very important,” says Benedict Michael, a neurologist at the University of Liverpool, UK.
As the epidemic spread, Michael and his colleagues were among several scientists who began compiling case reports of neurological complications associated with COVID-19.
In a june paper5, He and his team analyzed clinical details in the United Kingdom for 125 people with COVID-19 who had neurological or psychiatric effects. Of these, 62% had a change in the brain’s blood supply, such as stroke and bleeding, and 31% had a change in mental status, such as confusion or prolonged unconsciousness – sometimes inflammation of brain tissue, with encephalitis. Ten people with altered mental status developed psychosis.
Not all people with neurological symptoms have become seriously ill in intensive-care units. “We have seen this group of young people without traditional risk factors having strokes, and acute changes in mental status in patients that are not otherwise explained,” says Michael.
A similar study1 A detailed case report of 43 people with neurological complications was compiled from COVID-19, published in July. Some patterns are becoming evident, says neurologist Michael Zandi of University College London and a lead author on the study. The most common neurological effects are stroke and encephalitis. The latter can spread to a severe form called acute diffuse encephalomyelitis, in which both the brain and spinal cord are inflamed and neurons lose their myelin coatings – due to symptoms similar to multiple sclerosis. Some of the most affected patients had only mild respiratory symptoms. “This brain was being killed as their main disease,” Zandi says.
Less common complications include peripheral nerve damage, typical symptoms of Guillain-Barré syndrome, and Zandi is said to be “a type of stuff”, such as anxiety and traumatic stress disorder. Similar symptoms have also been seen in outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which are also caused by coronavirus. But fewer people were infected in those outbreaks, so fewer data are available.
How many people?
Physicians have no idea how common these neurological effects are. Another study6 Their prevalence was estimated using data from other coronaviruses published in July. Symptoms affecting the central nervous system occurred in at least 0.04% of people with SARS and 0.2% of those with MERS. Given that there are now 28.2 million confirmed cases of COVID-19 worldwide, this may mean that between 10,000 and 50,000 people have experienced neurological complications.
But a major problem in determining the amount of cases is that clinical studies have generally focused on people with COVID-19 who were hospitalized, often those who require intensive care. The prevalence of neurological symptoms in this group may be “more than 50%”, says neurobiologist Fernand de Felice at the Federal University of Rio de Janeiro, Brazil. But little is known about those who had mild illness or no respiratory symptoms.
The lack of data means why some people have neurological symptoms and it is difficult for others not to work. It is also unclear what effects will be affected: COVID-19 may have other health effects that last for months, and various coronaviruses have left some people with symptoms for years.
Infection or inflammation?
The most pressing question for many neuroscientists, however, is why the brain is affected at all. Although the pattern of disorders is quite consistent, the underlying mechanisms are not yet clear, says De Felice.
Finding an answer will help physicians choose the right treatment. “If it is a direct viral infection of the central nervous system, then these are the patients that we should be targeted for reminiscent or any other antiviral,” says Michael. “Whereas if the virus is not in the central nervous system, perhaps the virus is clear from the body, then we need to be treated with anti-inflammatory therapies.”
It would be harmful to consider it wrong. “It’s pointless that if the virus is gone, it’s risky to give someone an antiviral, and it’s anti-inflammatory to someone who has got the virus in their brain,” Michael says.
There is clear evidence that SARS-CoV-2 can infect neurons. Muotri’s team specializes in the creation of ‘organoids’ – small segments of brain tissue, which are formed in association with human pluripotent stem cells to differentiate into neurons.
In a May print7The team showed that SARS-CoV-2 can infect neurons in these organoids, killing some and reducing the formation of synapse between them. The work by immunologist Akiko Iwasaki and his colleagues at Yale University School of Medicine, New Haven, Connecticut, confirms this using human organs, mouse brains, and some postmortem examinations, according to an assumption published on September 8.8. But the question is how the virus can reach people’s brains.
Because odor loss is a common symptom, neurologists wondered whether the olfactory nerve could provide a route of entry. “Everyone was worried it was a possibility,” Michael says. But the evidence points against it.
A team led by pathologist Mary Fox at the Icahn School of Medicine at Mount Sinai in New York City posted one in late May9 Describe postmortem in 67 people who died from COVID-19. “We have seen the virus in the brain itself,” says Fox: electron microscopes detected its presence. But the virus level was low and not consistently detectable. Furthermore, if the virus was attacking via the olfactory nerve, then the associated brain region must first be affected. “We’re not just looking at the viruses involved in the olfactory bulb,” Fox says. Rather, she says, brain infections are small and cluster around blood vessels.
Michael agrees that the brain is harder to find in the brain than other organs. Tests using polymerase chain reaction (PCR) often do not detect it there, despite its high sensitivity, and many studies have failed to find any virus particles around the brain and spinal cord (e.g. For, see, ref. 10)10. One reason may be that the ACE2 receptor, a protein used on human cells to gain virus penetration, is not over-expressed on brain cells10.
“It seems incredibly rare that you get viral central nervous system infection,” Michael says. This means that many problems that physicians are seeing are likely the result of the body’s immune system fighting the virus.
Nevertheless, this may not be true in all cases, meaning that researchers will need to identify biomarkers that can reliably differentiate between viral brain infections and immune activity. For now, this means more clinical research, post mortem and physical studies.
De Felice says that he and his co-workers plan to follow patients who have recovered after intensive care, and create a biobank of samples, including cerebrospinal fluid. Zandi says that similar studies are beginning at University College London. Researchers will no doubt spend years sorting through such samples. Although the questions they are addressing have come up during almost every disease outbreak, COVID-19 presents new challenges and opportunities, Michael says. “What we haven’t had since 1918 is an epidemic on this scale.”