What's driving 'brain fog' in people with COVID-19
Memorial Sloan Kettering Cancer Center
It's
characterized by confusion, headaches, and loss of short-term memory. In severe
cases, it can lead to psychosis and even seizures. It usually emerges weeks
after someone first becomes sick with COVID-19.
In the February 8, 2021, issue of the journal Cancer Cell, a multidisciplinary team from Memorial Sloan Kettering reports an underlying cause of COVID brain: the presence of inflammatory molecules in the liquid surrounding the brain and spinal cord (called the cerebrospinal fluid).
The findings suggest that anti-inflammatory
drugs, such as steroids, may be useful for treating the condition, but more
research is needed.
"We were initially approached by our colleagues in critical care medicine who had observed severe delirium in many patients who were hospitalized with COVID-19," says Jessica Wilcox, the Chief Fellow in neuro-oncology at MSK and one of the first authors of the new study.
"That meeting turned into a tremendous collaboration between
neurology, critical care, microbiology, and neuroradiology to learn what was
going on and to see how we could better help our patients."
Recognizing a Familiar Symptom
The medical term for COVID brain is encephalopathy. Members of MSK's Department of Neurology felt well-poised to study it, Dr. Wilcox says, because they are already used to treating the condition in other systemic inflammatory syndromes.
It is a side effect in
patients who are receiving a type of immunotherapy called chimeric antibody
receptor (CAR) T cell therapy, a treatment for blood cancer. When CAR T cell
therapy is given, it causes immune cells to release molecules called cytokines,
which help the body to kill the cancer. But cytokines can seep into the area
around the brain and cause inflammation.
When the MSK team first began studying COVID brain, though, they didn't know that cytokines were the cause. They first suspected that the virus itself was having an effect on the brain. The study in the Cancer Cell paper focused on 18 patients who were hospitalized at MSK with COVID-19 and were experiencing severe neurologic problems.
The
patients were given a full neurology workup, including brain scans like MRIs
and CTs and electroencephalogram (EEG) monitoring, to try to find the cause of
their delirium. When nothing was found in the scans that would explain their
condition, the researchers thought the answer might lie in the cerebrospinal
fluid.
MSK's microbiology team devised a
test to detect the COVID-19 virus in the fluid. Thirteen of the 18 patients had
spinal taps to look for the virus, but it was not found. At that point, the
rest of the fluid was taken to the lab of MSK physician-scientist Adrienne
Boire for further study.
Using Science to Ask Clinical
Questions
Jan Remsik, a research fellow in Dr. Boire's lab in the Human Oncology and Pathogenesis Program and the paper's other first author, led the analysis of the fluid.
"We found that these
patients had persistent inflammation and high levels of cytokines in their
cerebrospinal fluid, which explained the symptoms they were having," Dr.
Remsik says. He adds that some smaller case studies with only a few patients
had reported similar findings, but this study is the largest one so far to look
at this effect.
"We used to think that the nervous system was an immune-privileged organ, meaning that it didn't have any kind of relationship at all with the immune system," Dr. Boire says.
"But the more we look, the more we find connections between the two."
One focus of Dr. Boire's lab is studying how immune cells are able to cross the
blood-brain barrier and enter this space, an area of research that's also
important for learning how cancer cells are able to spread from other parts of
the body to the brain.
"One thing that was really
unique about Jan's approach is that he was able to do a really broad molecular
screen to learn what was going on," Dr. Boire adds. "He took the
tools that we use in cancer biology and applied them to COVID-19."
The inflammatory markers found in the COVID-19 patients were similar, but not identical, to those seen in people who have received CAR T cell therapy. And as with CAR T cell therapy, the neurologic effects are sometimes delayed.
The initial inflammatory response with CAR T cell treatment is very similar to the reaction called cytokine storm that's often reported in people with COVID-19, Dr. Wilcox explains.
With both
COVID-19 and CAR T cell therapy, the neurologic effects come days or weeks
later. In CAR T cell patients, neurologic symptoms are treated with steroids,
but doctors don't yet know the role of anti-inflammatory treatments for people
with neurologic symptoms of COVID-19. "Many of them are already getting
steroids, and it's possible they may be benefitting," Dr. Wilcox says.
"This kind of research speaks
to the cooperation across the departments at MSK and the interdisciplinary work
that we're able to do," Dr. Boire concludes. "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."
Dr. Boire is an inventor on a patent
related to modulating the permeability of the blood-brain barrier and is an
unpaid member of the scientific advisory board of EVREN Technologies.
This work was funded by National
Institutes of Health grant P30 CA008748, the Pew Charitable Trusts, the Damon
Runyon Cancer Research Foundation, and the Pershing Square Sohn Cancer Research
Alliance GC239280. It was also supported by the American Brain Tumor
Association Basic Research Fellowship, the Terri Brodeur Breast Cancer
Foundation Fellowship, and the Druckenmiller Center for Lung Cancer Research.
