The woman had seen lions and monkeys in her home. She was becoming disoriented and aggressive towards others and was convinced that her husband was an imposter. He was about 50 years old – decades older than the age at which psychosis typically develops – and had no psychiatric history. What it did have, however, was COVID-19. His was one of the first known cases of someone developing psychosis after contracting the disease1.
In the early months of the COVID-19 pandemic, doctors struggled to keep patients breathing and focused primarily on treating damage to the lungs and circulatory system. But even then, evidence of neurological effects was piling up. Some people hospitalized with COVID-1
“Neurological symptoms are getting scarier,” says Alysson Muotri, a neuroscientist at the University of California, San Diego, in La Jolla.
The list now includes stroke, brain haemorrhage, and memory loss. It is not uncommon for serious diseases to cause such effects, but the scale of the COVID-19 pandemic means that thousands or even tens of thousands of people may already have these symptoms and some may face lifelong problems as a result.
Yet researchers are struggling to answer key questions, including basic ones, such as how many people have these conditions and who is at risk. Most importantly, they want to know why these particular symptoms occur.
Although viruses can invade and infect the brain, it is unclear whether SARS-CoV-2 does so to a significant extent. Neurological symptoms could instead be the result of over-stimulation of the immune system. It is vital to find out, because these two scenarios require completely different treatments. “This is why the disease mechanisms are so important,” says Benedict Michael, a neurologist at the University of Liverpool in the UK.
As the pandemic escalated, Michael and his colleagues were among the many scientists who began compiling case reports of neurological complications related to COVID-19.
In a June newspaper5, he and his team analyzed the clinical details of 125 people in the UK with COVID-19 who had neurological or psychiatric effects. Of these, 62% had suffered damage to the blood supply to the brain, such as stroke and bleeding, and 31% had altered mental states, such as confusion or prolonged unconsciousness, sometimes accompanied by encephalitis, swelling of the brain tissue. Ten people who had altered mental states developed psychosis.
Not all people with neurological symptoms were also seriously ill in intensive care units. “We have seen this group of young people with no conventional risk factors having stroke and patients with acute changes in mental status that would not otherwise be explained,” says Michael.
A similar study1 published in July compiled detailed case reports of 43 people with neurological complications from COVID-19. Some patterns are becoming clear, says Michael Zandi, a neurologist at University College London and lead author of the study. The most common neurological effects are stroke and encephalitis. The latter can degenerate into a severe form called acute disseminated encephalomyelitis, in which both the brain and spinal cord become inflamed and neurons lose their myelin sheath, leading to symptoms similar to those of multiple sclerosis. Some of the most affected patients had only mild respiratory symptoms. “This was the brain affected as their main disease,” Zandi says.
Less common complications include peripheral nerve damage typical of Guillain-Barré syndrome, and what Zandi calls “a jumble of things,” such as anxiety and post-traumatic stress disorder. Similar symptoms have been seen in outbreaks of severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS), also caused by coronaviruses. But fewer people were infected in those outbreaks, so less data is available.
How many people?
Doctors don’t know how common these neurological effects are. Another study6 published in July estimated their prevalence using data from other coronaviruses. 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 could imply that between 10,000 and 50,000 people have had neurological complications.
But a major problem in case quantification is that clinical trials have typically focused on people with COVID-19 who have been hospitalized, often those who have required intensive care. The prevalence of neurological symptoms in this group could be “more than 50%,” says neurobiologist Fernanda De Felice of the Federal University of Rio de Janeiro in Brazil. But there is far less information on those who had mild illness or no respiratory symptoms.
This paucity of data means it’s hard to understand why some people have neurological symptoms and others don’t. It is also unclear whether the effects will persist: COVID-19 may have other health impacts that last for months, and several 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 by it. Although the pattern of disturbances is fairly consistent, the underlying mechanisms are still unclear, says De Felice.
Finding an answer will help doctors choose the right treatments. “If it’s a direct viral infection of the central nervous system, these are the patients we should be targeting for remdesivir or another antiviral,” says Michael. “Considering that if the virus is not in the central nervous system, perhaps the virus is free from the body, then we have to deal with anti-inflammatory therapies.”
To be wrong would be harmful. “There is no point in giving antivirals to someone if the virus is gone, and it is risky to give anti-inflammatories to someone who has a virus in their brain,” says Michael.
There is strong evidence that SARS-CoV-2 can infect neurons. Muotri’s team specializes in building “organoids,” miniaturized clusters of brain tissue, made by inducing human pluripotent stem cells to differentiate into neurons.
In a May prepress7, the team showed that SARS-CoV-2 could infect neurons in these organoids, killing some and reducing synapse formation between them. The work of immunologist Akiko Iwasaki and her colleagues at Yale University School of Medicine in New Haven, Connecticut, appears to confirm this using human organoids, mouse brains, and some post-mortem examinations, according to a preprint published on September 8.8. But questions remain about how the virus could reach people’s brains.
Since loss of smell is a common symptom, neurologists questioned whether the olfactory nerve could provide an access route. “Everyone was worried that this was a possibility,” says Michael. But the evidence is against.
A team led by Mary Fowkes, a pathologist at the Icahn School of Medicine at Mount Sinai in New York City, published a preprint in late May9 describing post mortem in 67 people who had died of COVID-19. “We saw the virus in the brain itself,” says Fowkes: electron microscopes revealed its presence. But the virus levels were low and were not consistently detectable. Also, if the virus was invading the olfactory nerve, the associated brain region should be the first to be affected. “We just don’t see the virus involved in the olfactory bulb,” says Fowkes. Rather, he says, infections in the brain are small and tend to cluster around blood vessels.
Michael agrees that the virus is difficult to find in the brain, compared to other organs. Tests using polymerase chain reaction (PCR) often do not detect it there, despite their high sensitivity, and several studies have failed to find viral particles in the cerebrospinal fluid surrounding the brain and spinal cord (see, for example, ref. 10)10. One reason could be that the ACE2 receptor, a protein on human cells that the virus uses to gain entry, is not expressed much in brain cells.10.
“It seems to be incredibly rare to get a viral infection of the central nervous system,” says Michael. This means that many of the problems doctors are seeing are likely a result of the body’s immune system fighting the virus.
However, this may not be true in all cases, meaning researchers will need to identify biomarkers that can reliably distinguish between a viral brain infection and immune activity. This, for now, means more clinical research, post mortem and physiological studies.
De Felice says she and her colleagues are planning to follow up with patients who have recovered after intensive care and to create a biobank of samples including cerebrospinal fluid. Zandi says similar studies are starting at University College London. No doubt the researchers will select these samples for years. Although the questions they are facing have emerged during nearly every disease outbreak, COVID-19 presents new challenges and opportunities, says Michael. “What we haven’t had since 1918 is a pandemic of this magnitude.”