SARS-CoV-2, the virus that causes COVID-19, likely does not directly infect
the brain but can still inflict significant neurological damage, according
to a new study from neuropathologists, neurologists, and neuroradiologists
at Columbia University Vagelos College of Physicians and Surgeons.
"There's been considerable debate about whether this virus infects the
brain, but we were unable to find any signs of virus inside brain cells of
more than 40 COVID-19 patients," says James E. Goldman, MD, PhD, professor
of pathology & cell biology (in psychiatry), who led the study with
Peter D. Canoll, MD, PhD, professor of pathology & cell biology, and
Kiran T. Thakur, MD, the Winifred Mercer Pitkin Assistant Professor of
Neurology.
"At the same time, we observed many pathological changes in these brains,
which could explain why severely ill patients experience confusion and
delirium and other serious neurological effects--and why those with mild
cases may experience 'brain fog' for weeks and months."
The study, published in the journal Brain, is the largest and most detailed
COVID-19 brain autopsy report published to date, suggests that the
neurological changes often seen in these patients may result from
inflammation triggered by the virus in other parts of the body or in the
brain's blood vessels.
No Virus in Brain Cells
The study examined the brains of 41 patients with COVID-19 who succumbed to
the disease during their hospitalization. The patients ranged in age from 38
to 97; about half had been intubated and all had lung damage caused by the
virus. Many of the patients were of Hispanic ethnicity. There was a wide
range of hospital length with some patients dying soon after arrival to the
emergency room while others remained in the hospital for months. All of the
patients had extensive clinical and laboratory investigations, and some had
brain MRI and CT scans.
To detect any virus in the neurons and glia cells of the brain, the
researchers used multiple methods including RNA in situ hybridization, which
can detect viral RNA within intact cells; antibodies that can detect viral
proteins within cells; and RT-PCR, a sensitive technique for detecting viral
RNA.
Despite their intensive search, the researchers found no evidence of the
virus in the patients' brain cells. Though they did detect very low levels
of viral RNA by RT-PCR, this was likely due to virus in blood vessels or
leptomeninges covering the brain.
"We've looked at more brains than other studies, and we've used more
techniques to search for the virus. The bottom line is that we find no
evidence of viral RNA or protein in brain cells," Goldman says. "Though
there are some papers that claim to have found virus in neurons or glia, we
think that those result from contamination, and any virus in the brain is
contained within the brain's blood vessels." "If there's any virus present
in the brain tissue, it has to be in very small amounts and does not
correlate with the distribution or abundance of neuropathological findings,"
Canoll says.
The tests were conducted on more than two dozen brain regions, including the
olfactory bulb, which was searched because some reports have speculated that
the coronavirus can travel from the nasal cavity into the brain via the
olfactory nerve. "Even there, we didn't find any viral protein or RNA,"
Goldman says, "though we found viral RNA and protein in the patients' nasal
mucosa and in the olfactory mucosa high in the nasal cavity." (The latter
finding appears in an unpublished study, currently on BioRxiv, led by
Jonathan Overdevest, MD, PhD, assistant professor of otolaryngology, and
Stavros Lomvardas, PhD, professor of biochemistry & molecular biophysics
and neuroscience.)
Hypoxic Damage and Signs of Neuronal Death
Despite the absence of virus in the brain, in every patient the researchers
found significant brain pathology, which mostly fell into two categories.
"The first thing we noticed was a lot of areas with damage from a lack of
oxygen," Goldman says. "They all had severe lung disease, so it's not
surprising that there's hypoxic damage in the brain."
Some of these were large areas caused by strokes, but most were very small
and only detectable with a microscope. Based on other features, the
researchers believe these small areas of hypoxic damage were caused by blood
clots, common in patients with severe COVID-19, that temporarily stopped the
supply of oxygen to that area.
A more surprising finding, Goldman says, was the large number of activated
microglia they found in the brains of most patients. Microglia are immune
cells that reside in the brain and can be activated by pathogens.
"We found clusters of microglia attacking neurons, a process called
'neuronophagia,'" says Canoll. Since no virus was found in the brain, it's
possible the microglia may have been activated by inflammatory cytokines,
such as Interleukin-6, associated with SARS-CoV-2 infection.
"At the same time, hypoxia can induce the expression of 'eat me' signals on
the surface of neurons, making hypoxic neurons more vulnerable to activated
microglia," Canoll says, "so even without directly infecting brain cells,
COVID-19 can cause damage to the brain."
The group found this pattern of pathology in one of their first autopsies,
described by Osama Al-Dalahmah, MD, PhD, instructor in pathology & cell
biology, in a case report published last March in Acta Neuropathologica
Communications. Over the next few months, as the neuropathologists did many
more COVID brain autopsies, they saw similar findings over and over again
and realized that this is a prominent and common neuropathological finding
in patients who die of COVID.
The activated microglia were found predominantly in the lower brain stem,
which regulates heart and breathing rhythms, as well as levels of
consciousness, and in the hippocampus, which is involved in memory and mood.
"We know the microglia activity will lead to loss of neurons, and that loss
is permanent," Goldman says. "Is there enough loss of neurons in the
hippocampus to cause memory problems? Or in other parts of the brain that
help direct our attention? It's possible, but we really don't know at this
point."
Persistent Neurological Problems in Survivors
Goldman says that more research is needed to understand the reasons why some
post-COVID-19 patients continue to experience symptoms.
The researchers are now examining autopsies on patients who died several
months after recovering from COVID-19 to learn more.
They are also examining the brains from patients who were critically ill
with acute respiratory distress syndrome (ARDS) before the COVID-19 pandemic
to see how much of COVID-19 brain pathology is a result of the severe lung
disease.
Reference:
Thakur KT, Miller EH, Glendinning MD, et al. COVID-19 neuropathology at
Columbia University Irving Medical Center/New York Presbyterian Hospital.
Brain. 2021;(awab148). doi:
10.1093/brain/awab148