Brain fog, fatigue and depression: Solving the mystery of Long Covid and what can be done about it

Credit: Vanessa Branchi/New Scientist
Credit: Vanessa Branchi/New Scientist

COVID-19 entered my home a year ago today when my 16-year-old daughter Molly first developed the tell-tale cough. By March 17, 2020, my symptoms had begun. Molly recovered almost entirely after three weeks, but I’m still sick, and that makes me a COVID long hauler.

These are the haunting words of Ann E. Wallace, a poet and essayist from Jersey City one year after being infected with the coronavirus. Unfortunately, her story, recounted in an essay in Huffington Post, is not unique; it’s the ordeal that thousands of people face very day.

For many, the experience of contracting coronavirus is scary, but usually short lived. But many patients find themselves in a position just like Ann’s, struggling many months after the initial infection. These are the victims who have recovered from their original bout with the coronavirus, but are plagued by lingering illnesses—persistent symptoms like fatigue, depression and loss of concentration. They are suffering from what scientists have called Long Covid and it can have devastating neurological side effects. 

Ann E. Wallace during her fifth trip to the emergency room due to COVID-19 in July 2020. Credit: Ann E. Wallace

Published studies (see here and here) and surveys conducted by patient advocates indicate that 50% or more of patients continue to have bothersome symptoms three months after the onset of COVID-19 — even after tests no longer detect virus in their body. 

The percentage of victims who face neurological symptoms like brain fog is smaller, but still significant. A study released April 6 of data from 81 million patients found 34% of Covid-19 survivors received a diagnosis for a neurological or psychological condition within six months of their infection.

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“That rate increased progressively as the severity of the Covid-19 illness increased. If we look at patients who were hospitalized that rate increased to 39%,” said Maxime Taquet, an academic clinical fellow in psychiatry at the University of Oxford, and a co-author of the new study. Doctors fear that for some, COVID and its aftermath may pose a lifelong neurological complications

Ann still lurches through each day, often stuporous.

I have experienced brain fog and impaired verbal recall to mental and physical exhaustion to insomnia and nightmares. Each day, getting up, showered and dressed, is a painful hours-long process that leaves me short of breath and lightheaded. … [T]he inflammation that seems to be raging throughout my body will not quit.

It has been a long and difficult year for her, but, fortunately, Ann’s recovery and rehabilitation are now at least possible. 

Dr. Noah Greenspan and physical therapist Marion Mackles of the Pulmonary Wellness Foundation in New York have devoted themselves to solving long COVID. They are one of dozens of ad hoc teams around the world that are tackling these debilitating side effects of the virus. Each day, they instruct Ann to follow a strict regimen of mental and physical therapy.

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“I have built up the ability to walk on the treadmill at increased speeds and inclines, with shorter recovery times and without relapse,” she wrote. “[Recently], I was retested on the treadmill and had a 96% improvement in exercise capacity over my initial test in November.”

Targeting old and young

COVID infection frequently leads to brain damage, particularly in those over 70. While sometimes the brain damage leads to major cognitive impairment, more frequently the damage is mild, leading to difficulties with sustained attention. And often younger people are targeted.

Samar Khan is one such case, contracting COVID in Chicago in fall 2020. Months after infection she continues to experience neurological symptoms that impair her ability to live her day-to-day life. She has blurred vision, she told the New York Times, and her ears ring constantly. Fog invaded her brain. She finds herself struggling in her job in financial services, often forgetting what she wants to say in discussions. 

Samar Khan. Credit: Taylor Glascock/The New York Times

Worryingly, this is not the story of an old, more vulnerable patient struggling with co-morbidities. Khan is only 25 years old, and she joins an increasingly long list of young people battling with Long COVID. 

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What can be done? Doctors are trying different treatment methods, hoping something, anything works.

Dr. Igor J. Koralnik of Northwestern Medicine is now overseeing her recovery. The therapy focusses on providing patients with strategies to manage and improve memory and cognitive difficulties. “We are seeing people who are really highly, highly functional individuals, used to multitasking all the time and being on top of their game,” he said, “but, all of a sudden, it’s really a struggle for them.” Khan now finds herself wondering what the future holds as she starts this new regime of cognitive therapy; “I have to wonder: Am I going to recover, or am I going to just figure out how to live with my new brain?”

Major cognitive effects of COVID

What causes long Covid?

“We cannot treat long Covid as one disease, because they may be driven by different things,” says Professor Akiko Iwasaki of Yale University, who is studying the persistent health challenges from the virus.

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According to studies, of people who were treated for COVID in intensive care units and suffered from respiratory failure, one-third show such a profound degree of cognitive impairment that performance on neuropsychological testing is comparable to those with moderate traumatic brain injury, similar to post-traumatic stress disorder. One possibility is that patients with COVID suffered a lack of oxygen to the brain, perhaps caused by a silent stroke. That’s happened a lot over the past year in elderly patients. The strokes could damage the wiring between brain cells that enables parts of the brain to ‘talk’ with each other.

“A key question is whether it is just the decrease in oxygen to the brain that is causing these white matter changes or whether the virus is itself attacking the white matter,” says Iwasaki, who is leading a long-term study.

Chinese doctors found that many neurological symptoms of COVID persisted even in those thought to have fully recovered from COVID infection. They thought the persistent attention impairment might be linked to what is now often referred to as “COVID-brain” — the presence of persistent inflammation

Consultant neurologist Arvind Chandratheva points out brain damage on a scan. Credit: BBC

In most COVID patients, the inflammatory pathway runs its course and eliminates the virus, allowing the individual to make a full recovery. In some long COVID patients, however, it appears the inflammatory pathway can go into overdrive and trigger similar processes of brain inflammation that are observed in many forms of neurological disorders. 

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It’s thought the persistent inflammation might be triggered by remnants of the virus that persist long after the original infection. New findings suggest the virus can cause damage to the blood vessels of the brain, paving the way for a cascade of inflammatory events that can lead to brain damage.

Oxygen deprivation

The other major explanation for persistent mind fog revolves around the flow of oxygen to the brain. A small trial of magnetic resonance imaging (MRI) of COVID “long haulers” by researchers at Harvard-affiliated Massachusetts General Hospital has found evidence emerged of a type of oxygen deprivation in the brain called hypoxia.

Hypoxia’s ability to quietly inflict damage is why it’s been coined “silent.” In coronavirus patients, it’s thought that the infection first damages the lungs, rendering parts of them incapable of functioning properly. It also restricts blood flow and ultimately damages the brain.

When the brain is deprived of oxygen for an extended period of time, neurons begin to die, which tends to be most evident in the hippocampus, cerebellum and cerebral cortex.

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Brain hypoxia can result in severe neurological symptoms as the brain struggles to maintain function in the presence of decreased oxygen. Alterations in brain structure were observed in some of the COVID patients leading some researchers to conclude that the virus could trigger long term neurological damage. 

Are there any effective treatments?

We have an increasing number of long COVID cases to draw on but not a huge amount in the way of definitive treatment regiments. But doctors and researchers are making progress.

At Memorial Sloan Kettering Cancer Center, for example, studies on applying steroid-based anti-inflammatories to reduce the inflammation in the brains of long haulers are underway. The work involves the use of drugs that already have FDA approval and early data is positive. 

“Many of (the patients) are already getting steroids, and it’s possible they may be benefitting,” says Jessica Wilcox, the chief fellow in neuro-oncology at MSK, “We saw people getting sick, and we were able to use our observations to ask big clinical questions and then take these questions into the lab to answer them.”

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Hypoxia-related brain damage may also be treatable via tried and tested rehabilitation processes often employed in other neurological conditions. Constraint-Induced Therapy (CI Therapy) is commonly used to treat patients with traumatic brain injury, cerebral palsy and many other disorders in which a change in brain structure is observed. It focuses on trying to rewire the neural circuitry of damaged brains. CI Therapy has shown high efficacy in repairing brain damage after stroke and trials are already underway at the University of Alabama to test CI therapy in long COVID patients. 

“The therapeutic principles are not specific to a particular condition or type of damage,” says Dr. Gitendra Uswatte, Professor of Psychology and Physical Therapy at the university. “We would expect that similar mechanisms apply in stroke and COVID-19.”  

We are at the start of the journey to treat the neurological effects of COVID-19, both short and long term. We have an idea of what is causing the symptoms, but any pharmaceutical treatment is still in early development and would have to pass the same rigorous clinical trials that the newly-approved vaccines did.  Which raises an intriguing twist. It appears one answer may come in the form of the COVID-19 vaccine rollout. New evidence suggests it may bring relief to some long-haul patients. 

Darren Brown, a frontline worker in London was plagued with COVID for over a year, “I ended up being bed-bound, I couldn’t function,” he said. After receiving his second vaccination dose in March 2021, he is now often symptom free, one of many COVID victims who received a vaccine to report, anecdotally, a feeling of having “a cloud lifted.” 

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The potential mechanisms behind this new development are still being explored. The vaccine could be aiding recovery by stimulating the immune system to “hunt down” and destroy the remaining “viral reservoir”. This could alleviate the damaging inflammation and bring relief to the patient. 

Yale professor Iwasaki urges caution about being too optimistic that vaccines are the ‘silver bullet’ cure. These numbers are still very small, she says, “so even though it’s statistically significant, we need to see if this holds up in a larger scale study.” 

She then repeated what she and other researchers says is critical to understand about COVID: “These symptoms can be driven by many causes. That means there may be many solutions for long-time victims.” 

Sam Moxon has a PhD in tissue engineering and is currently a research fellow in the field of regenerative medicine. He is a freelance writer with an interest in the development of new technologies to enhance medical therapies. Follow him on Twitter @DrSamMoxon

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