The woman had seen lions and monkeys in her house. She became disoriented and aggressive towards others and was convinced that her husband was an impostor. She was in her mid-50s – decades older than the age at which psychosis usually develops – and had no psychiatric history. What she had, however, was COVID-19. Hers was one of the first known cases of someone developing psychosis after contracting the disease1.
In the early months of the COVID-19 pandemic, physicians struggled to maintain patients’ breathing and focused primarily on treating damage to the lungs and circulatory system. But even then, evidence of neurological effects was accumulating. Some people hospitalized with COVID-1
“The neurological symptoms are only getting worse,” said Alison Muotri, a neurologist at the University of California, San Diego in La Hola.
The list now includes stroke, cerebral hemorrhage and memory loss. It is not unheard of 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 problems for life.
Still, 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 specific symptoms occur.
Although viruses can invade and infect the brain, it is unclear whether SARS-CoV-2 does so significantly. Instead, neurological symptoms may be the result of overstimulation of the immune system. It is extremely important to understand, as these two scenarios require completely different treatments. “That’s why the mechanisms of the disease are so important,” said Benedict Michael, a neurologist at the University of Liverpool in the United Kingdom.
As the pandemic grew, Michael and his colleagues were among many scientists who began compiling reports of neurological complications associated with COVID-19.
In a newspaper from June5, he and his team analyzed clinical details of 125 people in the UK with COVID-19 who had neurological or psychiatric effects. Of these, 62% suffered damage to the blood supply to the brain, such as strokes and hemorrhages, and 31% had altered mental states, such as confusion or prolonged unconsciousness – sometimes accompanied by encephalitis, swelling of the brain tissue. Ten people with altered mental states developed psychosis.
Not all people with neurological symptoms were seriously ill in the intensive care units. “We’ve seen this group of younger people without conventional risk factors who have strokes, and patients with acute mental changes that aren’t explained otherwise,” Michael said.
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 escalate to a severe form called acute disseminated encephalomyelitis, in which both the brain and the spinal cord become inflamed and the neurons lose their myelin sheaths – leading to symptoms similar to those of multiple sclerosis. Some of the most severely affected patients had only mild respiratory symptoms. “It was the brain that was affected as their main disease,” says Zandi.
Less common complications include peripheral nerve damage, typical of Guillain-Barré syndrome, and what Zandi calls a “mix of things,” such as anxiety and post-traumatic stress disorder. Similar symptoms have been observed in foci of severe acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS), also caused by coronaviruses. But fewer people have been infected with these outbreaks, so there is less data.
How many people?
Clinicians do not know how common these neurological effects are. Another study6 published in July, estimates their prevalence using data from other coronaviruses. Symptoms affecting the central nervous system occur in at least 0.04% of people with SARS and 0.2% of those with MERS. Given that there are currently 28.2 million confirmed cases of COVID-19 worldwide, this could mean that between 10,000 and 50,000 people have experienced neurological complications.
But a major problem in case quantification is that clinical trials usually focus on people with COVID-19 who have been hospitalized, often those in need of intensive care. The prevalence of neurological symptoms in this group can be “over 50%,” said neurobiologist Fernanda De Felice of the Federal University of Rio de Janeiro in Brazil. But there is much less information about those who have had a mild illness or no respiratory symptoms.
This lack of data means that it is difficult to understand why some people have neurological symptoms and others do not. It is also unclear whether the effects will slow: COVID-19 may have other health effects that last for months, and various coronaviruses leave some people with symptoms for years.
Infection or inflammation?
However, the most pressing question for many neurologists is why the brain is affected at all. Although the pattern of violations is quite consistent, the basic mechanisms are still unclear, says De Felice.
Finding an answer will help clinicians choose the right treatment. “If it’s a direct viral infection of the central nervous system, these are the patients we should refer to for remdezivir or another antiviral drug,” says Michael. “While if the virus is not in the central nervous system, maybe the virus is clean from the body, then we need to treat it with anti-inflammatory therapies.”
His wrong behavior would be harmful. “It’s pointless to give antivirals to someone if the virus is gone, and it’s risky to give anti-inflammatory drugs to someone who has a virus in their brain,” says Michael.
There is clear evidence that SARS-CoV-2 can infect neurons. Muotri’s team specializes in building “organelles,” miniaturized lumps of brain tissue made by forcing human pluripotent stem cells to differentiate into neurons.
In the May preprint7, the team showed that SARS-CoV-2 can infect neurons in these organelles, killing some and reducing the formation of synapses 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 organelles, brain mice and some post-mortem studies, according to a preprint published Sept. 8.8. But questions remain about how the virus can reach the human brain.
Since the loss of odor is a common symptom, neurologists wondered if the olfactory nerve could provide a way to enter. “Everyone was worried it was an opportunity,” says Michael. But the evidence points against him.
A team led by Mary Fox, a pathologist at Icahn Medical School in Mount Sinai in New York, published a preprint in late May.9 description of deaths in 67 people who died from COVID-19. “We saw the virus in the brain itself,” Fox said: electron microscopes revealed its presence. But the levels of the virus were low and were not constantly detected. In addition, if the virus invades the olfactory nerve, the connected brain region must be the first to be affected. “We just don’t see the virus involved in the olfactory bulb,” Fox said. Rather, she says, infections in the brain are small and tend to cluster around blood vessels.
Michael agrees that it is difficult to find a virus 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 detect any viral particles in the cerebrospinal fluid that surrounds the brain and spinal cord (see, for example, ref. 10)10. One reason may be that the ACE2 receptor, a protein in human cells that the virus uses to enter, does not express much in brain cells.10.
“It seems incredibly rare to get a viral infection of the central nervous system,” says Michael. This means that many of the problems that clinicians see are probably the result of the body’s immune system fighting the virus.
However, this may not be true in all cases, which means that researchers will need to identify biomarkers that can reliably distinguish viral brain infection from immune activity. This means more clinical research, post-mortem and physiological research.
De Felice says she and her colleagues plan to track patients who have recovered from intensive treatment and create a biobank of samples, including cerebrospinal fluid. Zandi says similar research is starting at University College London. Researchers will no doubt sort out such samples for years to come. Although the issues they address have arisen during almost every outbreak, COVID-19 creates new challenges and opportunities, Michael says. “What we haven’t had since 1918 is a pandemic on this scale.”