For many people, a sudden loss of smell is the first sign that something’s wrong. “One gentleman said he realized it with hand sanitizer,” says Carol Yan, a rhinologist at the University of California, San Diego. “All of a sudden it was like water to him.” The loss of smell, or anosmia, is such a common symptom of Covid-19 that the US Centers for Disease Control and Prevention recently added it to its official list.
The loss of smell (or taste) is one of many emerging hints that the SARS-CoV-2 virus may affect the nervous system. Physicians around the world have documented neurological symptoms in a significant fraction of Covid-19 patients. Some patients have experienced headaches, dizziness and other relatively minor symptoms, while others have had more serious problems like confusion and impaired movement, and even seizures and strokes.
Such reports have been circulating on message boards used by physicians, and they are just now making their way into the peer-reviewed scientific literature. Nobody knows at this point how widespread neurological symptoms are, nor the extent to which they contribute to the overall clinical picture for Covid-19.
Another huge unknown is whether SARS-CoV-2 can attack the nervous system directly by infecting neurons — as rabies and a number of other viruses do — or cause neurological symptoms indirectly, by triggering rampant inflammation or blood clotting.
These are critical questions, says Samuel Pleasure, a neuroscientist and neurologist at the University of California, San Francisco. For a small number of patients, neurological symptoms seem to be the earliest or even the only indicator of infection. For others, lingering or post-infection neurological problems could complicate recovery. “We don’t know whether or not that’s going to be the case yet, but it’s an important unanswered question,” says Pleasure.
No-smell test
Reports of lost taste and smell — often in the absence of the kind of nasal congestion that interferes with olfaction with the common cold — have been circulating for months. In one of the first peer-reviewed journal articles on the subject, Yan and colleagues describe results from an online survey of 262 patients in the UCSD hospital system. Slightly more than two-thirds of those who tested positive for Covid-19 experienced taste and smell deficits.
The deficits weren’t subtle, Yan says. “Most people went from like a ten to zero.” Fortunately, as patients get better, they seem to be regaining their sensory abilities, usually within a few weeks, the team reported April 12 in the International Forum of Allergy & Rhinology.
In an April 22 letter to the Journal of the American Medical Association, physicians reported a similar prevalence of anosmia in Covid-19–positive patients at a regional hospital in Treviso, Italy. For 12 percent of these patients, the loss of smell occurred prior to other symptoms. For 3 percent, it was the only symptom they ever experienced.
Such reports have prompted several medical associations for ear, nose and throat specialists to issue statements urging physicians to consider anosmia as a potential screening tool for Covid-19 and to advise patients who experience a sudden loss of smell to consider self-isolating.
In theory, SARS-CoV-2 could get into the brain through several routes. The virus could enter the brain through the bloodstream if it can get past the cellular defense wall known as the blood-brain barrier. Or it could conceivably infect olfactory neurons in the nasal cavity or peripheral nerves elsewhere in the body and hitchhike into the brain along their axons. Scientists don't yet know which, if any, of these routes the virus can take.
Yan speculates that the presence of anosmia could turn out to be a a clue to how the disease might progress. She notes that most patients in her study had relatively mild cases of Covid-19 — most were not hospitalized, and none required a ventilator to help them breathe. In contrast, other researchers have found a lower prevalence of anosmia among sicker patients. One possibility, Yan says, is that anosmia is more common in mild cases because the virus mostly stays in the nasal cavity. In more severe cases, it infiltrates the lungs, causing more dangerous respiratory symptoms but fewer sensory deficits. At this point it’s just a hypothesis, but it’s one she and her colleagues plan to investigate.
Preliminary evidence suggests that SARS-CoV-2 does not directly infect olfactory neurons, the odor-detecting cells at the top of the nasal cavity, at least by its usual route. In April, two RNA sequencing studies — one led by researchers at Harvard, another by a group in Switzerland — concluded that olfactory neurons do not make two key proteins, including the ACE2 receptor, used by the virus to break into cells. (The findings were posted before publication on the website bioRxiv and have not yet been peer-reviewed.)
However, neighboring support cells do appear to produce these proteins. The sudden loss of smell in Covid-19 patients could result from the virus infecting these support cells and then either causing local inflammation or disrupting the cells’ role in maintaining the balance of ions that olfactory neurons need to function properly, says neuroscientist Sandeep Robert Datta, who led the Harvard study.
Other warning signs
Reports of other neurological symptoms in Covid-19 patients have emerged from China, France and elsewhere. In one of the first studies, doctors in Wuhan, China, reported April 10 in JAMA Neurology that of 214 patients hospitalized there between mid-January and mid-February, slightly more than a third experienced neurological symptoms that ranged from dizziness and headache to (less commonly) impaired consciousness, movement difficulties and seizures.
In an April 15 letter to the New England Journal of Medicine, doctors in Strasbourg, France, reported an even higher prevalence of neurological symptoms in a group of patients there: 84 percent experienced symptoms that included “prominent agitation and confusion” and alterations to reflexes and muscle contractions that suggested neurological problems in the brain.
The role SARS-CoV-2 plays in such symptoms remains an open question, especially for sicker patients who are likely to have low oxygen levels or preexisting conditions that could cause the same symptoms, says Pleasure, who cowrote an editorial on the Chinese study. “The kinds of symptoms that were more common in the more severe patients could be happening in part because the patients are so sick, not because they have Covid-19,” he says.
There were scattered reports of neurological problems with SARS and MERS, respiratory syndromes caused by coronaviruses related to the one causing the current pandemic, but the prevalence of such symptoms wasn’t well documented. There seem to be more such reports with Covid-19, but that could be because so many more people have been affected in total, not necessarily that those symptoms occur in a higher proportion of patients, says Stanley Perlman, an infectious disease researcher at the University of Iowa Carver College of Medicine. More than four million people (and counting) have been infected in the current pandemic, compared with about 8,000 for SARS and 2,500 for MERS.
Some researchers have speculated that SARS-CoV-2 may invade the nervous system and suppress respiratory centers in the brain, contributing to the severity of breathing problems. So far there’s no direct evidence for that, but scientists say it’s not out of the question.
Pierre Talbot, a virologist at the Armand-Frappier Santé Biotechnologie Research Centre near Montreal, has long argued that coronaviruses could be an underestimated threat to the nervous system. In experiments with mice and cultured human neurons, his group has found evidence that a human coronavirus called OC43, a frequent cause of the common cold, can travel from the respiratory tract to the nervous system. In 2016, the researchers reported finding the virus in brain tissue from an 11-month-old boy who died of encephalitis, or inflammation of the brain. Coronaviruses can do much more than cause respiratory diseases, Talbot says. “The neurological aspects of Covid-19 are not surprising.”
In experiments with genetically engineered mice, Perlman and his colleagues previously found that SARS and MERS can infect olfactory neurons and travel along their axons to the brain’s olfactory bulb. From there, the viruses spread quickly throughout the brain. His lab plans to repeat those experiments with SARS-CoV-2, but he cautions that mouse experiments may not replicate what a virus does in people in real-world conditions. And the new virus may act differently — as suggested by the bioRxiv studies that showed that the virus likely can’t infect the human olfactory neurons using its usual tactics.
Many viruses, Perlman says, have evolved other ways of getting into the nervous system — including tricks for slipping past the guardian cells of the blood-brain barrier, which normally keep blood-borne pathogens out of the brain. It’s still far too early to know all that SARS-CoV-2 is capable of. “This virus is teaching us so much,” Perlman says. “I wouldn’t draw any conclusions.” Experiments that might help resolve the issue, such as tests on spinal fluid or autopsied brain tissue from Covid-19 patients, have been delayed by safety concerns.
Loss of smell has been reported in many Covid-19 patients. Inhaled air comes into contact with olfactory neurons at the top of the nasal cavity, raising the possibility that SARS-CoV-2 could infect the neurons and travel into the olfactory bulb, a part of the brain. But preliminary work suggests the virus may not be able to infect olfactory neurons. Instead, it may infect the adjacent supporting and stem cells in the olfactory epithelium.
Even if SARS-CoV-2 does not directly attack the nervous system, it could cause neurological problems indirectly. One way it could do this is through rampant inflammation known as a cytokine storm. In a case study published in Radiology, doctors in Detroit reported brain scan abnormalities indicative of a rare encephalopathy linked to cytokine storms in an airline worker in her mid-50s who tested positive for the virus. Another concern is reports of mysterious abnormalities in blood clotting in young and middle-aged Covid-19 patients that may increase the risk of stroke.
Some secondary effects could take time to develop. In an April 17 letter tothe New England Journal of Medicine, Italian doctors described five Covid-19 patients who developed Guillain–Barré syndrome, a condition that starts with weakness and tingling in the extremities and can progress to more serious movement difficulties. Guillain–Barré syndrome occurs after infection, such as with Campylobacter bacteria, a frequent cause of food poisoning, when antibodies made by the immune system to fight the bacteria end up attacking the nervous system instead.
If the same thing happens with SARS-CoV-2, Pleasure says, doctors may see a wave of post-infection neurological conditions like Guillain–Barré in the months ahead. As with nearly everything related to Covid-19, the full impact won’t be known for some time.
