“The human brain has 100 billion neurons, each neuron connected to 10 thousand other neurons. Sitting on your shoulders is the most complicated object in the known universe.” - Michio Kaku, professor of theoretical physics, City College of New York
“The brain is the last and grandest biological frontier, the most complex thing we have yet discovered in our universe. It contains hundreds of billions of cells interlinked through trillions of connections. The brain boggles the mind.”
- James D. Watson, “Discovering the Brain”
The brain is the organ that captured my research interest throughout my career. Thus, when COVID-19 emerged in December 2019, I began paying special attention to a rapidly growing literature on how SARS-CoV-2, the virus that causes COVID-19, affects the nervous system. The goal of this Germ Gems post is to distill some of the reporting to date on how COVID-19 is affecting the brain.
In defense of the brain. I agree with Professor Kaku’s opinion (quoted above) that the brain is “the most complicated object in the known universe.” And, I’m sure he’d agree with me—it’s also the most astonishing object. From this infectious disease specialist’s simple-minded point-of-view, the brain is composed of only four types of cells: neurons (the most commonly known cells), astrocytes, microglia, and oligodendrocytes. Microglia and astrocytes both play a prominent role on how the brain defends itself against foreign invaders such as SARS-CoV-2.
The brain is surrounded by the “blood-brain barrier” (BBB)—a remarkable structure, generally tasked with keeping the brain clear of foreign invaders. This barrier is composed of endothelial cells which line the blood vessels that course through the brain and of astrocytes, a type of glial cell which regulates transmission of electrical impulses within the brain. When the BBB is breached, cells of the immune system—T and B lymphocytes, monocytes, and neutrophils—are summoned to help eradicate the invader.
Many research groups, including ours, focused on defense of the brain against viruses that cause encephalitis (inflammation and damage to the substance of the brain itself) or meningitis (inflammation and damage to the meninges, which are the membranes that surround the brain and spinal cord). Herpes simplex virus, cytomegalovirus, West Nile virus, and HIV are examples of such neuropathogenic viruses.
Because of the large number of COVID-19 patients (globally more than 34 million cases and 1 million deaths by the end of September), many comprehensive reviews have been published on the neuropathological features of COVID-19. These studies show that both encephalitis and meningitis are quite rare in COVID-19 patients. (This shouldn’t be too surprising, however, because none of the six other kinds of coronaviruses that are known to infect humans are neuropathogenic.) It therefore appears that the brain’s defenses, by and large, are doing their job.
Neurological havoc caused by SARS-CoV-2. While it is reassuring that SARS-CoV-2 seems to be barred from the brain itself, this doesn’t mean that COVID-19 patients are spared neurological symptoms or complications. In fact, the evidence is to the contrary.
One large study in Spain found that more than half of hospitalized COVID-19 patients had neurological symptoms, including headaches, dizziness, disordered consciousness (confusion, agitation), seizures, anosmia, and strokes. The authors of this study found that neurological manifestations occurred at all stages of COVID-19 illness. A more recent study of COVID-19 patients in 10 Chicago hospitals reported that 82 percent had a neurological symptom at some point in their illness.
Here are some of the more striking neurological manifestations that have now been associated with COVID-19.
· Ansomia. As discussed in my May 7th Germ Gems post, between 20 and 80 percent of people afflicted with COVID suffer the loss of the sense of smell (anosmia) and taste. The basis of this rare complication of a viral infection of the nervous system is under investigation.
· Stroke. Stroke is rarely, if ever, observed in other infections, yet it is another very striking clinical feature of COVID-19-related brain disease. A stroke happens when blood flow to the brain is blocked. This prevents the brain from getting oxygen and nutrients from the blood. Without oxygen and nutrients, brain cells begin to die within minutes. Limb weakness or paralysis is a common manifestation of a stroke.
But it was recognized early on that COVID-19 is a “highly thrombogenic disease,” meaning that blood clots form in large blood vessels to the brain. The exact mechanism for this disorder is under intensive investigation, as are preventative and treatment measures. Beginning in April, doctors began sounding the alarm that young and middle-aged people, barely sick with COVID-19, were dying from strokes and that thromboses (blood clots) in large vessels feeding the brain were involved. In fact, subsequent reports indicated that stroke might be the first symptom of COVID-19 in younger patients.
· GBS. Guillain-Barré syndrome (GBS) been increasingly reported in COVID-19 patients. It is an unusual neurological disorder that has been associated, however, with a variety of other infections. The damage in GBS patients is not to the brain but rather to peripheral nerves. It is thought that GBS is caused by an activated immune system. (Most recently, GBS has been associated with another emerging viral infection—Zika.)
· Psychosis. Another startling manifestation of COVID-19-related brain damage that’s increasingly being reported is psychosis. A September 15th article in Nature: “How COVID-19 can damage the brain,” described a psychotic patient. The woman was in her mid-50s and had no prior history of psychiatric illness. After contracting COVID-19, she suddenly began hallucinating—seeing lions and monkeys in her house and accusing her husband of being an imposter. In a June article in the New York Times, “They Want to Kill Me’: Many Covid Patients Have Terrifying Delirium,” a 31-year-old woman in an intensive care unit paralyzed by COVID-19 thought she was being burned alive and then attacked by cats. Such paranoid delusions have accompanied other infectious diseases, but not as commonly as with COVID-19. It is too soon to know whether on-going neuropsychiatric diseases will be sequelae of COVID-19 brain damage.
· Post-COVID-19 Fatigue. As described in my August 5 Germ Gems post, “Post-COVID-19 Fatigue: The New Chronic Fatigue Syndrome?,” an illness akin to the baffling disease called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is being recognized increasingly in patients who have recovered from acute COVID-19. These patients, often referred to as “COVID-19 long-haulers,” like those with ME/CFS, suffer from debilitating fatigue, unrefreshing sleep, and neurocognitive symptoms (described by many as “brain fog”). Of course, nobody yet knows how common this complication of COVID-19 will be. But even if it only affects 10 percent of COVID-19 patients, it could result in a massive societal and economic burden for years to come.
· Quarantine fatigue (“Covid brain”). Clinical psychologists and neuroscientists are describing a substantial decline in the mental health of many Americans due to social distancing and the onslaught of worry and insecurity wrought by the COVID-19 pandemic. This has nothing to do with SARS-CoV-2-mediated brain damage per se. Nonetheless, it is worrisome.
According to a June 3 article by Sara Berg, a Senior News Writer for the American Medical Association, 39 percent of Americans say that coronavirus stress is taking a toll on their mental health. In a July article in Inc., “Neuroscientist: Covid Brain is Real. Here’s How to Deal with It,” Jessica Stillman and her colleagues describe the thinking of some neuroscientists about the basis of what they call “Covid Brain.” They claim: “You’re not just sleep deprived and stressed, you’re experiencing the effects of very real brain changes brought on by the trauma of uncertainty of the pandemic.”
Sleep on this. Perhaps, we all need more sleep. In an article appearing in the October 1st issue of National Geographic, Emily Sohn opined: “Want to reduce your COVID-19 risk? You need to sleep more.”
The question, “Why do people sleep?” has intrigued philosophers for millennia. (All animals do in fact sleep.) In recent years, sleep experts and their neuroscience colleagues have come up with a potential answer: it’s all about flushing the brain of neurotoxins that accumulate during the course of the day. The glymphatic system, a recently discovered brain structure, is responsible for this phenomenon. The “g” in glymphatic stands for brain glial cells called astrocytes. Along with a previously unrecognized lymphatic system, it functions as a waste clearance system that promotes efficient elimination of soluble proteins and metabolites from the central nervous system during sleep. Maiken Nedergaard, a Danish Professor of Glial Cell Biology at the University of Copenhagen with joint appointments in the Departments of Neuroscience and Neurology at the University of Rochester Medical Center, is credited with this discovery.
It appears that getting a good night of 7 to 8 hours of refreshing sleep depends on a well-functioning glymphatic system. While we are only beginning to learn about the glymphatic system, it is tempting to speculate that symptoms such as the fatigue, unrefreshing sleep, and brain fog described by COVID-19 long-haulers is due to a “glymphopathy.” And who knows, it may even underlie some of the symptoms of Covid brain that almost everyone is experiencing these days.