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A 44-year-old male patient, with no history of cardiovascular disease, arrived at an emergency room in New York City after experiencing difficulty speaking and moving the right side of his body. The on-call physician quickly determined he had suffered a stroke—a condition that normally affects people who are decades older. In Italy, a 23-year-old man sought care for a complete facial palsy and feelings of “pins and needles” in his legs. Doctors discovered axonal sensory-motor damage suggesting Guillain Barré Syndrome, a rare autoimmune neurological disorder where the immune system, sometimes following an infection, mistakes some of the body’s own peripheral nerve cells as foreign invaders and attacks them. A 58-year-old woman in Detroit was rushed to the hospital with severe cognitive impairment, unable to remember anything beyond her own name. MRI scans showed widespread inflammation across the patient’s brain, leading doctors to diagnose a rare but dangerous neurological condition called acute necrotizing hemorrhagic encephalopathy.
At ﬁrst glance, it may seem that these patients have little in common. Yet all three were also suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, better known as Covid-19. While most individuals infected with this new virus exhibit fever, cough, and respiratory symptoms, doctors across the globe are also documenting patients presenting with a handful of neurological manifestations—leading clinicians and researchers to wonder if Covid-19 also has the ability to invade the human nervous system.
“As more people are being tested and diagnosed with this virus, physicians are starting to see more uncommon symptoms and complications, including neurological ones,” says Diane Grifﬁn, M.D., Ph.D., a researcher at Johns Hopkins University’s Bloomberg School of Public Health. “But as Covid-19 is a new virus, we aren’t yet sure why these things are happening. Is the virus getting into the brain directly? Is it affecting the brain through other means? These are important questions to answer.”
Viruses and the Nervous System
Viruses, simply deﬁned, are submicroscopic infectious agents that can only replicate inside the cells of living hosts. While experts still hotly debate whether these molecules of nucleic acid, protected by a protein shell, should be considered “living,” they are unquestionably insidious in their ability to hijack the inner machinery of cells for their own reproductive purposes, sometimes causing overwhelming damage to their host in the process.
Over the last century, the world has seen outbreaks of numerous virus-caused diseases, ranging from polio to inﬂuenza to the human immunodeﬁciency virus (HIV). Some of these have led to devastating pandemics, resulting in millions of deaths. Others, however, only cause mild symptoms, an expected nuisance to deal with each fall and winter. Kenneth Tyler, M.D., chair of the Department of Neurology at the University of Colorado (UC) Anschutz Medical Center, observes there are many viruses that affect the nervous system. Even garden variety ﬂu can lead to neurological problems in certain patients—yet, it is important to remember that this remains a rare occurrence.
“Millions, perhaps even billions, of individuals are infected with different viruses all the time, and there’s never any issue with the brain,” he says. “Yet, in some cases, we do see encephalitis, or inﬂammation of the brain due to a particular infection. We are learning there are many reasons why that can occur—and it doesn’t always happen in the same manner or even cause the same type of damage. Some viruses can directly infect different brain cells, both the neurons themselves and glial cells. Others may get to the brain in other ways. It all gets rather complicated rather quickly.”
Taking Different Doors into the Nervous System
Dorian McGavern, Ph.D., a senior investigator at the National Institute of Neurological Disorders and Stroke (NINDS), says it is difﬁcult for viruses to gain direct access to the central nervous system (brain and spinal cord).
“It’s a relatively closed compartment,” he says. “To get into the brain or spinal cord, a virus has to essentially invade all the brain’s peripheral defenses like the blood-brain barrier as well as the different immune responses. It’s not that easy.”
Viruses may enter their hosts through the gastrointestinal tract, the respiratory tract including the nose (and the neurons that reside there), or through the bite of a mosquito or infected animal. The point of entry, and how the virus might spread from that point, likely determine which bodily systems may be most affected. For example, some scientists are hypothesizing that Covid-19 may be targeting blood vessels, which is why we see such widespread damage across different organs. Blood vessel infection would help explain the blood clots seen in some of the young stroke patients, not to mention inﬂammatory syndromes observed in the brain.
“The blood-brain barrier is made up of blood vessels,” says Grifﬁn. “So, if a virus can replicate in the cells of blood vessels, it has a rather direct entrance to the brain. But it could also come into the brain from cells in the blood that are allowed to cross the blood-brain barrier. It could come in through the olfactory neurons in the nose, which project to the rest of the brain. Given the number of direct approaches available, it’s actually amazing that we don’t see viruses causing neurological issues more often.”
But it’s just as possible that Covid-19 is not infecting the brain directly, causing neurological impairment through secondary pathways. One hypothesis that many hold is that damage comes from an overactive immune response to the novel coronavirus, a so-called “cytokine storm.” Proinﬂammatory cytokines, proteins produced
by immune cells to ﬁght off the virus, are released in overwhelming numbers and intensity at an infection site, enter the bloodstream, and produce severe and destructive inﬂammation in cells and tissues.
“Sometimes damage comes from the inﬂammatory process and immune response—that’s really the culprit,” says Grifﬁn. “The immune system is there to get rid of the virus. But sometimes the kinds of molecules it produces to ﬁght off the virus can be just as detrimental to the cells as the virus is. It’s a bit of a double-edged sword.”
Finally, some of the brain-related effects documented with Covid-19 may be the result of other bodily systems being compromised by viral infection. The lungs may not be able to supply sufﬁciently oxygenated blood to the brain, resulting in ischemia and cell death. The failure of those vital systems may also lead to more blood clots. Sherry Chou, M.D., an associate professor of Critical Care Medicine, Neurology, and Neurosurgery at the University of Pittsburgh Medical Center, says anecdotal evidence suggests that Covid-19 patients may be more prone to stroke.
“Right now, this is a hunch, based on what physicians are seeing, that needs to be investigated further,” she says. “But, that said, we don’t fully understand what might be behind this phenomenon if it does exist. Could the blood vessels be infected, leading to clots? Could it be the fact that these patients are sick enough that organs start failing which means the clotting system isn’t doing what it is supposed to do and that’s the issue? We just don’t know yet.”
Damage Now, Damage Later
Viruses may also set the brain up for later problems. When Richard Smeyne, Ph.D., a neuroscientist at Thomas Jefferson University who specializes in Parkinson’s disease, viewed a video of a duck infected with bird ﬂu (H5N1), his ﬁrst thought was, “This bird has Parkinson’s disease.” After studying the brains of infected animals, he discovered the virus had the ability to directly inﬁltrate and destroy cells in the substantia nigra, the same part of the brain affected by the neurodegenerative disorder. While human beings with H5N1 did not show full-blown Parkinson’s disease, they did often exhibit symptoms such as tremors—the kind of movement disorder seen in Parkinson’s. Smeyne wonders if there might be a link between viral infection and this or other forms of neurodegeneration.
“We know, for example, that the 1918 ﬂu pandemic killed a lot of people,” he says. “But what a lot of people don’t realize is that starting around 1936 to 1943, there was a dramatic increase in the rate of Parkinson’s disease. It’s the only time, I believe, in history, that the average incidence rate (number of newly diagnosed people at a speciﬁc time point) jumped from two to three percent in people over the age of 55. There could be a link between ﬂu infection and later issues.”
H1N1, or the swine ﬂu, does not directly infect neurons like its bird counterpart. Yet, studies consistently show that it can lead to a cytokine storm or hyperactive immune response in the brain. When Smeyne and his team gave mice that had recovered from a previous swine ﬂu infection small doses of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin that can mimic Parkinson’s disease, they found that evidence of permanent damage.
“The animals that had been infected showed basically a Parkinsonian-type lesion in the (brain’s) substantia nigra. Those who hadn’t been infected showed no effect,” he says. “It suggests that ﬂus or viruses that cause these cytokine storms could prime the brain for later insult. It’s possible that your brain could sustain damage later from the virus you were infected with today.”
Understanding Covid-19 and the Brain
As more case studies about Covid-19 are published, it is becoming clear that SARS-CoV-2 is a virus with immense reach. But to date, much of what doctors and scientists have to go on is anecdotal evidence—not hard data. Moving forward, UC neurologist Tyler says, there are many questions that need to be investigated so we can better understand how the novel coronavirus impacts the brain and neurological function.
“It’s hard to do research in the middle of a pandemic—doctors are focused on saving lives,” he says. “But these case studies are showing that we better pay attention. Future studies should look carefully at how this virus enters the host, what kind of cells it infects, how it spreads in the body, and what kind of damage it is doing. That’s going to take time.”
Pathological studies looking at individuals who have perished from Covid-19 have already started. A small pathological study of 18 patients, published as a letter in the New England Journal of Medicine in June, suggests that most damage occurred due to hypoxia, or a lack of oxygen to the brain. Researchers are also relying organoids, so-called “mini-brains,” to see how the virus may affect the different cells in these three-dimensional, self-organization tissue culture models. Using this approach, researchers from Johns Hopkins University discovered that Covid-19 can both infect and spread across neural tissue—but they cannot say with any certainty that the virus can pass through the blood brain barrier to get into the brain in the ﬁrst place.
While such studies are revealing curious and sometimes contradictory new insights about Covid-19, they are only a ﬁrst step in a long scientiﬁc journey. To more fully understand how this virus affects the nervous system, researchers will need a good animal model and, until a vaccine is developed, a biosafety level 3 laboratory in which to do controlled experiments.
“One of the biggest challenges is ﬁnding an appropriate model—not all viruses affect mice or rats the same way they do humans,” says NINDS scientist McGavern. “A good model system allows us the ability to work out the molecular mechanisms and get a better idea of what the virus is doing, how it’s getting into the body, what cells it infects, and how it’s disrupting those cells.”
Such studies can help illuminate how Covid-19 does neurological damage now—and, potentially, in the future.
Human studies will be vital in developing treatments for the novel coronavirus. Pittsburgh’s Chou and colleagues have already started a multi-center international consortium to look at the links between Covid-19 and stroke.
“The initial phase 1 study is already up and running,” she says. “Its focus is really trying to describe the phenomenon that neurocritical care professionals are seeing. How many people with Covid-19 are having this problem? What does the problem look like, exactly? Once we know that, we can dive in more deeply to ask how this stroke may happen, as well as the possible mechanisms and risk factors involved.”
But both she and other researchers caution that it will take time to fully understand the nature of Covid-19 and how it affects the central nervous system. While that may sound daunting in the midst of the current pandemic, the good news is such research ﬁndings will likely better prepare both scientists and clinicians for the next.
“When you think about the different viruses that have emerged over the last century—AIDS, H1N1, Ebola, West Nile, Zika, just to name a few—the one predictable thing seems to be that new viruses are going to continue to emerge as human pathogens,” says Tyler. “It’s likely that many of them will have an impact on the human nervous system in different ways. The more we can understand the pathogenesis of these viruses, even though they are quite different, the more we can add to our base of knowledge so we can better understand and manage the next virus that comes along, whatever it may be.”