What does COVID-19 do to your brain?
Even after the SARS CoV-2 virus has been subdued, the immune system can’t calm down.
That is the current theory about what’s behind the strange, lingering and debilitating neurological symptoms of some COVID-19 patients, such as the commonly reported “brain fog,” according to a recent paper in the journal Science.
The virus doesn’t cause extensive infection in the brain. Instead, the neurological effects seem to be caused by “friendly fire” — an exaggerated or misguided immune response, as well as damage to the brain’s blood vessels, according to Dr. Serena Spudich of the Yale School of Medicine and Dr. Avindra Nath of the National Institutes of Health.
“Immune activation and inflammation within the central nervous system is the primary driver of neurologic disease in acute COVID-19,” they write.
Nervous system problems are among the constellation of diverse symptoms reported by people with Long COVID, a poorly defined syndrome that affects between 7% and 18% of people after infection. Some appear at the same time as respiratory symptoms; others emerge, on average, two weeks later. But they can persist for months. Long COVID is less likely in vaccinated people, according to several recent studies.
Even young and healthy people with mild initial disease can develop these symptoms, which range from brief and mild headaches to persistent mental fatigue, depression and even psychosis. “Brain fog” is one of the most common problems, affecting about twothirds of patients at a postCOVID clinic in New York, according to another recent study. It is not known whether unforeseen problems may emerge years after initial infection.
The conclusions are supported by newly published UC San Francisco research, which found that some patients who develop new cognitive symptoms after a mild bout of COVID have abnormalities in their cerebrospinal fluid similar to those found in people with other infectious diseases.
“It’s possible that the immune system, stimulated by the virus, may be functioning in an unintended pathological way,” said Dr. Joanna Hellmuth, principal investigator of the UCSF Coronavirus Neurocognitive Study.
COVID-19 is not alone: Other infections have been shown to unbalance the immune system. Multiple sclerosis, for example, is likely caused by infection with the Epstein-Barr virus. Cognitive symptoms have been identified in Epstein-Barr infections, as well as HIV, hepatitis C and coronaviruses SARS and MERS.
To be sure, it is normal for us to feel fatigue when we’re infected, according to Spudich and Nath.
“You can have symptoms because you have exhausted all your energy trying to get rid of that organism,” said Nath, clinical director of NIH’s National Institute of Neurological Disorders and Stroke. “But — normally — you recover from it, and that would be it.”
Certain things can go wrong, especially if very small amounts of the virus get into the central nervous system or brain, he said.
The immune system may inadvertently deploy misguided antibodies that attack, not just the virus, but our own tissues and organs. A similar phenomenon is seen in autoimmune diseases like lupus.
Something else can happen: the immune system goes into an overactive “all hands on deck” mode. Frustrated when targeted antibodies don’t get rid of the virus, it uses cells called monocytes and macrophages in a carpet-bombing strategy. Key components of the immune system, these cells are linked to other inflammatory disorders — and can cause longterm damage. They’ve been found in the brains of autopsied COVID-19 victims.
Inflammation is the cause behind other COVID-related medical crises. For instance, children can develop a multisystem inflammatory syndrome. In elders, sudden inflammation of the lungs, called a “cytokine storm,” can be lethal.
In the brain, “if you get small amounts of inflammation, you can recover,” Nath said. “But if you have prolonged inflammation or if you have pretty intense inflammation for shorter periods of time, that can cause permanent damage.”
Signs of inflammation and cell injury have raised concerns that infection may accelerate or trigger future development of neurodegenerative diseases such as Alzheimer’s or Parkinson’s.
It is also possible that the virus causes direct damage to the brain’s vascular system. For instance, infection can cause small clots in damaged blood vessels, increasing the risk of stroke. It can also cause leaks, so blood seeps out into the brain, causing inflammation and cellular damage.
Additionally, any systemic infection can worsen an underlying cognitive problem and unmask it.
Why does a COVID infection become a protracted, debilitating neurologic ordeal for a small group of unlucky people? That is not yet understood, said Nath. Everyone’s immune system is different.
The growing body of research could eventually lead to treatments.
“We hope that understanding these dysregulated biological pathways will allow us to develop targeted therapies to treat our Long COVID patients,” said Dr. Aruna Subramanian, chief of the Immunocompromised Host Infectious Diseases Clinic at Stanford University School of Medicine.
The strange neurological symptoms of Long COVID could also provide insights into other mysterious and poorly understood conditions, such as myalgic encephalomyelitis, more familiarly known as chronic fatigue syndrome.
Many of the symptoms of the two syndromes are shared, said Jaime Seltzer, a Stanford research scientist and director of Scientific and Medical Outreach for #MEAction Network. Just as Long COVID can be experienced by people who never experienced acute illness, perhaps chronic fatigue syndrome is triggered by a “silent” infection, she added.
“Since there is such a striking overlap with symptoms,” said Subramanian, “we are also hopeful that the lessons learned can be used to help a multitude of patients worldwide — even beyond those suffering with Long COVID.”