“They neither conveyed nor felt the feeling of life; they were as insubstantial as ghosts, and as passive as zombies.”
In the 1960s the science historian Oliver Sacks observed survivors of the “sleepy sickness” epidemic caused by the 1918 Spanish Flu, in his book Awakenings. These were patients who continued to suffer extreme fatigue and delirium forty years after contracting the illness. The flu had entered their brain and central nervous system, severely damaging dopamine neurons that regulate mood, pleasure and motivation. Half a century on there is a growing fear that Covid-19 has the potential to do something similar – especially for those “Long Covid” sufferers who can’t shake symptoms for months on end.
For a virus so closely associated with breathing problems, Covid has proved no less frightening as a stealth attack on the brain. The most common symptoms are headaches, fatigue and “brain fog”, which scientists don’t fully understand although they use the term to mean depletion of a combination of memory, attention and cognitive ability. Less common, but not unheard of, are depression, delirium, strokes, PTSD (from the trauma of fighting the virus) and encephalitis (a sometimes life-threatening swelling of the brain).
The most serious neurological conditions tend to occur in older patients, people with pre-existing conditions such as liver or kidney problems, and those who were hospitalised as a result of the virus. But not always.
Predictions vary for how many Covid patients can expect to suffer cognitive problems: early research at the Tongji Medical College in Wuhan suggested 1 in 3, though for those hospitalised it’s more likely to be 1 in 2, according to Fernanda De Felice, a neurobiologist at Rio de Janeiro’s Federal University. And it’s possible that for many with long Covid, without the right treatment, these disorders could have no end-date.
The key question: how?
How does a virus that typically first manifests as a respiratory condition come to affect the brain in such unpredictable and often debilitating ways? There are a number of possibilities, none of them mutually exclusive:
- The body’s inflammatory response goes into overdrive, and organs that don’t contain the virus are mistakenly attacked by the immune system.
- A lack of oxygen to the brain leads to “happy hypoxia”. Doctors have been confused by Covid patients who seem not to be in distress despite levels of oxygen in key organs at a level usually associated with unconsciousness or death.
- Clotting. Doctors at the University College of London Hospital have seen a high number of patients suffering strokes linked to unfathomably high levels of the ‘D-dimer’ clotting marker in their blood.
- The experience of being on a ventilator. Studies in the American Journal of Respiratory and Critical Care Medicine and elsewhere suggest that at least 30 per cent of patients who have been mechanically ventilated in intensive care suffer some form of mental dysfunction – possibly (though it’s unclear) as a result of brain cells being killed in the hippocampus by excessive dopamine production.
But an alternative explanation has surfaced. Earlier this month the preliminary findings of a Yale School of Medicine study showed evidence that Covid was directly attacking brain cells. Typically, the blood-brain barrier, a set of specialist cells that surround the blood vessels in the brain, prevents viruses and toxins getting into the brain itself. But if the virus crosses the barrier it can enter the central nervous system, and could cause lifelong disorders without the right treatment. In short, long Covid could linger in the brain like Spanish Flu.
“It’s looking increasingly likely that this is the case,” says Adrian Owen, a neuroscientist in Ontario leading research into Covid’s neurological effects.
The way forward
Until now the data available to scientists has been patchy: based mainly on hospitalised patients, it ignores the millions living with long Covid at home. So long-term research has begun. Owen’s laboratory at Western University aims to track 50,000 survivors of the virus over the next year, using an online cognitive test taken now, in three and twelve months’ time. It will be the first major study of Covid’s long-term neurological effects.
Owen’s team hopes to identify correlations between patients’ demographic profile and experience of the disease on the one hand, and neurological problems that result on the other.
“Even if we learn that only 10 per cent of people suffer long-term neurological deficits, given we have almost 30m cases worldwide, that’s millions of people severely affected,” Owen says.
A few months into the Canadian study, a majority of patients self-report lingering brain fog that leaves their memory and concentration “not what they were”. A significant proportion report suffering anxiety and depression, too.
What can be done for them? Drugs will have a role. Where patients’ mental problems are due to a direct viral infection of the brain and nervous system, antiviral drugs like remdesivir may be more appropriate than anti-inflammatory therapies. In addition there will be a new cohort of patients needing cognitive therapies and non-clinical help from their communities. Either way, experience says this will be a long journey – and Spanish Flu is not the only precedent. The 1957 influenza pandemic in the UK has been linked to a wave of clinical depression in the 1970s and ‘80s.
“We don’t want to look back in a year and think, ‘wow, we have three million people who can’t do their job or function properly’,” Owen says. “Those people will need help.”