From the first weeks of the covid-19 pandemic, it has been clear that the disease often causes neurological symptoms 鈥� ranging from headaches and brain fog to strokes and paralysis. Sometimes, the symptoms are short-lived; sometimes, they persist as part of long covid. We are now getting a clearer picture of covid-19鈥檚 neurological symptoms and how the SARS-CoV-2 coronavirus indirectly affects the brain, pointing the way to potential treatments.
Furthermore, there is mounting evidence that the virus can sometimes enter the brain itself and infect neurons. However, it is less clear how much of a concern this is, as SARS-CoV-2 has only been detected in low numbers in the brain and doctors haven鈥檛 found that this is associated with notable damage.
Ongoing research into what the virus does inside our brains is highlighting gaps in our understanding: for many kinds of viral infection, we don鈥檛 yet know how long viruses can persist in our bodies and what effect they have on the brain.
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Covid-19鈥檚 neurological symptoms
Covid-19 infections are commonly associated with neurological symptoms. Some studies have estimated that about 1 in 3 people with the disease will subsequently be diagnosed with a neurological or psychiatric condition. Common include loss of sense of smell, weakness and fatigue, headache, mood conditions like depression and cognitive difficulties such as memory loss. A small percentage of cases experience major neurological events like strokes and seizures. While neurological conditions are most likely to arise soon after infection, people who have had covid-19 remain at an elevated risk of developing one for up to two years afterwards.
The consequences can be serious. In a study published last year, at Boston University Chobanian & Avedisian School of Medicine in Massachusetts and her colleagues compiled data on 16,225 people hospitalised with covid-19. They found that 12.9 per cent of those studied developed what they described as 鈥溾��.
This was most commonly encephalopathy, an umbrella term that refers to general brain dysfunction, which can lead to altered mental states or delirium. All the serious neurological symptoms they analysed 鈥� which also included strokes, seizures and meningitis 鈥� were associated with worse outcomes: people who had them were more likely to need intensive care, to die and to have long-term symptoms if they survived.
鈥淭his has been borne out in many studies,鈥� says Cervantes-Arslanian. 鈥淔or people that are more seriously impacted in terms of neurologic conditions, their likelihood of surviving is lower and their likelihood of disability is very high.鈥�
In another 2022 study, at Imperial College London in the UK and his colleagues gave cognitive assessments to 46 people who survived after being hospitalised for severe covid-19. They found the participants were in the assessment than people who hadn鈥檛 been hospitalised with covid-19, and especially struggled with complex tasks like spatial planning and reasoning by analogy.
But it isn鈥檛 just hospitalised patients who are affected. 鈥淣eurological complications are also something that impacts people that have mild covid, meaning they have symptoms, but they don鈥檛 have to be in hospital,鈥� says Cervantes-Arslanian. People with the lingering symptoms dubbed long covid often complain of neurological issues such as brain fog. 鈥淚 think a lot of the neurological symptoms are the most concerning [for people with long covid], because they provide a lot of disability,鈥� she says.
How covid-19 can indirectly affect the brain
There is no single explanation for the neurological impacts of covid-19, but multiple mechanisms have been identified that may be involved.
One pathway could be the effect that SARS-CoV-2 can have on blood vessels and blood flow, causing indirect harm to the brain. In a study published last year, researchers including at University College London in the UK reviewed 83 studies of neurological symptoms associated with covid-19 and found that , such as strokes, in which part of the brain鈥檚 blood supply is cut off. These events were associated with worse outcomes.
Another key factor is disruption to the immune system, which can affect the brain. at the University of Cambridge and his colleagues recently studied 175 people hospitalised with covid-19. Those with more severe illness 鈥� meaning they needed to be given oxygen or ventilation 鈥� showed . They also had higher levels of immune system molecules called cytokines, which promote inflammation, and of autoantibodies: that is, antibodies targeting their own body tissues rather than the virus.
鈥淭his is all, by its nature, observational,鈥� emphasises Needham. 鈥淚t鈥檚 definitely association rather than causation.鈥� Nevertheless, the implication is clear: rather than the virus directly harming the brain, the immune system鈥檚 response to the virus could be doing damage by causing the brain to become inflamed. Needham compares it to friendly fire in a war zone. 鈥淲e know from a myriad of other studies that systemic inflammation triggers neuroinflammation, and neuroinflammation is often detrimental and causes brain injury,鈥� he says.
These findings reflect a broader shift in immunological thinking. It had been thought that the brain was almost entirely cut off from the rest of the body behind the blood-brain barrier, so immune overactivation in the rest of the body wouldn鈥檛 affect it. 鈥淭here is truth to that,鈥� says Needham, but the brain isn鈥檛 as isolated as was believed. 鈥淭he idea that you can have rampant systemic inflammation and your brain sits nicely cocooned away and it鈥檚 not affected by it at all, I think is wrong and has been put to bed.鈥�
For Needham, the pandemic has highlighted the long-term impacts of being severely ill and in intensive care, regardless of cause. He says that about a quarter of intensive care survivors end up with long-term neurological issues, including cognitive problems. 鈥淭hat is a comparatively neglected area,鈥� he says. His hope is that 鈥渢here鈥檚 something we can learn from this terrible period of history that we can then extrapolate more broadly鈥�, thus improving intensive care in general.
What does the virus do inside our brains?
There has also been a shift in thinking on the question of whether SARS-CoV-2 can enter the brain. Despite some early reports, many researchers had been sceptical because . However, it now seems clear that the virus does get in, at least in some cases.
One of the strongest data sets comes from a team led by at the National Institutes of Health in Bethesda, Maryland, which was published last month. They autopsied 44 people who died of covid-19, including 11 where they took multiple samples from the brain. , including the brain, albeit often in low quantities. Furthermore, they were able to grow the virus from the brain samples, showing that it was biologically active. 鈥淚t is there and it is capable of replicating,鈥� says Chertow.
However, the viruses in the people鈥檚 brains weren鈥檛 associated with damage. 鈥淲hat we did not see is pathology that was attributable to viral infection,鈥� says Chertow. Nor did they find evidence of inflammation in the brain.
This aligns with other studies suggesting that SARS-CoV-2 infection in the brain may not cause significant harm. 鈥淚s it neuroinvasive? Yes, we鈥檝e seen evidence of the virus in the brain,鈥� says Benjamin. But is the virus strongly attracted to brain cells and causing damage? 鈥淣ot convincingly,鈥� she says.
Chertow鈥檚 study highlights two uncertainties. The first is the extent to which viruses of any kind can persist in our bodies at low levels, long after the initial infection and when the acute illness has ended. Virologists generally believe that our bodies eliminate many viruses within a few weeks, says Chertow. But 鈥渃learly, there are opportunities鈥� for them to linger on, he says.
The second uncertainty is whether a small number of virus particles can cause meaningful harm in the short or long term, or if there is a threshold below which they don鈥檛 matter. 鈥淚 don鈥檛 think we know that,鈥� says Chertow.
Treating covid-19鈥檚 effects on the brain
Given this complex picture, it is perhaps no surprise that the best treatment for preventing neurological symptoms from covid-19 appears to be a mix of drugs. In a study published last year, researchers led by at the University of Southampton in the UK assessed neurological outcomes in patients given the anti-inflammatory dexamethasone, the antiviral remdesivir or both. The two individual drugs helped, but .
The immediate challenge is to find ways to rapidly determine the cause of neurological symptoms in each person, so that the most appropriate treatments can be given.
But to develop better treatments, we will first need a more detailed understanding of the two key questions covid-19 is raising over viral infections in general: how does being seriously ill harm our brains, and what do viruses do when they manage to get into them?
