On March 17 this year, a man was taken to hospital in Israel suffering from a dry cough and a loss of sense of smell.
He developed a fever and felt tired but, after three days as an in-patient, was released to quarantine. Then something strange started happening.
His handwriting changed. It became smaller, crabbed and unreadable. Not just that, but he struggled to speak clearly or write texts on his phone. His right hand began to tremble.
Eventually, symptoms became so bad that he returned to hospital, this time to the department of neurology, dealing in disorders of the brain and nervous system.
A battery of tests was performed. Then doctors gave him a devastating diagnosis: Parkinson’s. The man was just 45. It was two months since his positive test for Covid-19.
This case, newly described, is not unique. Across the world, doctors have noticed that Covid is often accompanied not just by the familiar shortness of breath and coughing that affect the body, but also by a huge range of conditions hitting the brain – from foggy thinking, through delirium, all the way to strokes and Parkinsonism.
So serious was this in Britain that, as the pandemic took hold early this year, doctors set up a monthly committee to coordinate reports of brain disorders.
Neurologist Dr Hadi Manji was among them. Very quickly, he says: “We had to make the meeting weekly because of the numbers of referrals.”
Indeed, new research from Chicago in the US reports that one third of Covid patients hospitalised early in the pandemic suffered some form of altered mental state – from confusion to unresponsiveness.
That in itself is not so unusual. Being seriously ill affects lucidity. According to Mary Ni Lochlainn, fellow in Geriatric Medicine at King’s College London, up to 80 per cent of those in intensive care suffer delirium.
But the consequences with Covid, the Chicago statistics suggest, are dramatic. Those with brain disorders needed three times as long in hospital as those without and were seven times more likely to die. On discharge only a third could perform routine tasks.
Back in Britain, Manji and his colleague Benedict Michael, neurologist at the University of Liverpool’s Institute of Infection and Global Health, were seeing for themselves how serious things were.
There were strokes in patients without any normal risk factors like age, diabetes, or history of smoking. Not just any strokes, but powerful, multiple strokes, causing life-changing disability.
There were episodes of psychosis, with patients previously untroubled by mental disorders having powerful delusions and having to be restrained.
“They had visual hallucinations, auditory hallucinations, agitation, running around and thinking that the police are coming for them and the nurses are poisoning them,” says Michael.
He even describes Covid bringing on myoclonus, where the eyes move and muscles jerk spontaneously and simultaneously while the patient is acutely confused.
There was inflammation of the brain too, potentially devastating for an organ trapped in a hard shell and, unlike several other organs, with little regenerative capacity.
“One of our patients had brain inflammation,” Manji recalls. “We had to take off half his skull to reduce the pressure.”
Links with 'brain fog'?
What neurologists are now struggling to determine is whether these few, truly serious brain complications of Covid are linked to the far greater number of enduring cases of “brain fog” and fatigue that can contribute to long Covid.
“These people who’ve got the milder symptoms in the community, the brain fog, do they represent the continuum of those with severe neurological disease who’ve been hospitalised?” asks Michael. “That’s the big question. That’s the real controversy here.”
Certainly, says Manji, there is no obvious physical reason why milder syndromes like brain fog, where scans reveal no brain damage, should not eventually clear up. “Though it may take months.”
There is precedent for significant long-term neurological complications after a pandemic, says Dr Jonathan Rogers at UCL, who has studied the psychiatric consequences of prior viral outbreaks.
“People developed what looked like Parkinson’s in the years after the Spanish flu pandemic; it was a small proportion relative to those who had been infected but still tens of thousands worldwide.”
The tremors and loss of motor control were eventually traced back to the kinds of brain swelling doctors are seeing with Covid, sometimes years later, raising fears that a similar shadow may haunt Covid once it too has passed.
Two potential explanations
From the outset, there have been two potential explanations of Covid’s impacts on the brain. The first was that the novel coronavirus itself was attacking the central nervous system.
Loss of the sense of smell was a clue – perhaps the olfactory nerve was providing a way in, a backdoor for Sars-Cov-2 into the brain. But then patients gradually began to recover their smell, which would be unlikely if the relevant part of the brain had been damaged.
Attention instead began to turn to the body’s own immune response. When doctors began to examine patients suffering brain conditions, says Manji, they found “the markers for immune response are sky-high”. What is not yet clear is why some people’s immune system betrays them in this catastrophic way and others not.
For those affected, recovery is very uneven. “Some patients who’ve had strokes or brain inflammation make a complete recovery, but a lot will be left with some sort of residual disability.”
Manji cites his own work with nine such patients. Three recovered, five had ongoing paralysis or behavioural and cognitive impairment, and one died.
“This is not necessarily elderly people,” says Michael. “This is occurring in all age groups. And if you sustain a brain injury in your 20s and 30s, you’re likely to survive with significant lifelong disability with limited opportunities for recovery.”
There is good news. As researchers home in on the precise mechanisms causing so much damage, it allows them to deploy existing treatments to control the immune response – like steroids.
Moreover, only a tiny percentage of those who contract Covid develop the most serious brain conditions. Michael says he is aware of five or six hundred in the UK.
What is certain is that, for all the misery it is inflicting, the current pandemic represents a unique opportunity to answer some of these mysteries.
“With every large scale respiratory epidemic or pandemic we’ve seen a proportion of patients severely affected in the brain,” says Benedict Michael. “And these questions about the role of the virus, does the virus get in the brain … these questions have plagued neuroscience for centuries.
“This is the first time we’ve had a pandemic on this scale, combined with the internet to connect us up to do studies globally, and the genetic and neuroimaging technology to understand it.
“When the next inevitable pandemic comes, if we do the work collaboratively now, we will be much better placed to face it.”
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