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It was nearly a year ago when Larissa Malcolm, 47, a social worker in the Cleveland area, tested positive for Covid-19. “I wasn’t sick enough to be hospitalized,” she says. “I never coughed.” But she did have a gallery of—then, anyway—mysterious symptoms. “I lost my sense of smell; I felt tingly, like electric shocks through my body. I felt there was a short in my brain.”
For the first time in her life, she had panic attacks. She felt generally confused and reported this to the local health department. “I was told it isn’t part of Covid,” she says.
Malcolm’s sense of smell never returned completely. She still takes medication to keep her anxiety at bay. And she still struggles with confusion and memory loss. “I go into a room and can’t remember why,” she says.
As the outbreak of a virulent new disease—Covid-19—spread relentlessly across continents, doctors were not entirely surprised to see neurological problems. “If this was like other viral infections, there would be fatigue, cognitive complaints, and the like,” says neurologist Ayush Batra of Northwestern University. Reports of related coronavirus infections—SARS and MERS—cited severe central nervous system (CNS) disease, including encephalitis and stroke.
But the extent of Covid’s impact on the brain was striking. In a published retrospective study of 509 hospitalized patients, Batra and colleagues saw neurologic manifestations in 83 percent. These ranged from headaches and dizziness to strokes and seizures.
A larger prospective study reported symptoms severe and pronounced enough to meet diagnostic criteria for neurological disorders in 13.5 percent of 4,491 patients hospitalized with laboratory-confirmed Covid-19. The most common of these disorders was encephalopathy, alterations in consciousness ranging from confusion and disorientation to coma. “A lot of people came in because they were confused, and some developed it later in their hospital stay,” says Jennifer Frontera, professor of neurology at New York University (NYU) and lead author of the study. “It was often related to low oxygen levels and low blood pressure.”
In some, prolonged hypoxia and hypotension led to brain damage verified by magnetic resonance imaging (MRI) or computerized tomography (CT) scans.
Age and sex were factors: Those who developed neurological disorders were significantly older than those who did not, and more likely to be male. Comorbid disorders, such as hypertension, diabetes, and atrial fibrillation, were more common as well. Obesity did not play a role; in fact, “patients who had neurological damage had slightly lower BMI (body mass index) than those who did not,” says Frontera.
It is unlikely that neurological disorders were the effects of treatment rather than disease in either study. “At that time [early in the pandemic], hydrochloroquine and azithromycin were the most commonly used medications, and [neurological events] are not known side effects [of these drugs],” Frontera says. Some hemorrhagic strokes (seen in 0.4 percent of patients in her series) may have been secondary to anticoagulation, however.
Nearly two percent of the patients in Frontera’s group suffered strokes (the majority ischemic), confirming what had been reported elsewhere: A study of patients with PCR-confirmed Covid-19, who were hospitalized or treated in the emergency department of two NYC hospitals, found the risk of stroke to be 7.6-fold larger than with influenza. An unlikely proportion occurred in younger patients. One New York City hospital reported that five Covid-positive patients under 50 were admitted with strokes in a two-week period, seven times the rate for this age group the year before.
Over the Long Haul
“I had a fever and a bit of a cough, but I wasn’t that sick,” says Sarah Ehekircher of her bout of Covid-19 in August. “I’d feel really good for a couple of days and think I could come out of quarantine, and then I was sick again.”
But ever since, the 52-year-old Seattle resident says, she has suffered from profound fatigue—“I can’t walk up a flight of stairs without having to stop”—and disturbing mental problems. “I have difficulty coming up with words. I constantly lose my train of thought. I can’t concentrate enough to read a book. I feel an overwhelming wash of brain fog, and I can’t function.
“A couple of months ago, I literally thought I had dementia,” she continues. “I couldn’t figure out a bus schedule! I thought I’d need to have someone come in to help me.”
Equally troubling has been the effect on her relationships. “I’d fire off hurtful text messages and ask myself, ‘why did I do that?’ It was like being a teenager with no impulse control. I didn’t recognize myself.”
Ehekircher’s symptoms are typical of what many Covid patients experience. When one thinks the disease is over, all too often it’s not all over. “The acute infection doesn’t last very long—you can’t detect it after a week or two,” says Avindra Nath, intramural clinical director of the National Institute for Neurologic Disorders and Stroke (NINDS). “The virus has gone, but the music lingers on.” Extreme fatigue, worsened by exercise, “resembles to some degree chronic fatigue syndrome, which occurs after a viral infection. As soon as the pandemic started, we knew we were going to see these patients.”
The “music” involves a good deal more than fatigue. Sufferers frequently find it hard to think, focus, or remember. Some become clinically depressed or anxious. A galaxy of physical problems, most prominently shortness of breath, but including diverse aches, pains, and troubling symptoms fill out the picture of what has come to be called “Long Covid” or “Long-haul Covid.”
“I suspect that much of this broad effect is related to some kind of neurological injury, whether to the brain, muscles, or immune system, and needs to be really studied,” says Nath. Such common problems as racing pulse, constipation, dizziness due to low blood pressure, or even shortness of breath, may reflect dysfunction in the autonomic nervous system.
In recent months in particular, research and clinical efforts have increasingly focused on Long Covid. Dozens of online support groups for sufferers have appeared, along with an expanding universe of clinics, nationwide and abroad, dedicated to their care.
In a study (which has not undergone peer review), Eric Song, a researcher at Yale University, and his colleagues found evidence of immune activity in the cerebrospinal fluid (CSF) of Covid patients who had neurological complications. This included more cytokines and activated B cells than in the bloodstream, and antibodies that target both the viral spike protein and brain tissue. “This not only suggests viral invasion, but that neurological symptoms might be driven by autoantibodies—think of an autoimmune condition like multiple sclerosis,” he says. “That one of the antibodies specific to spike protein is also binding to human tissue suggests that molecular mimicry seen in other viral diseases could also be here.”
Such a process, Song says, might explain the tenacity of Long Covid. “In a lot of these kinds of diseases, the autoimmune response persists for a decade. It’s like a floodgate: Once it’s open, you can’t close it back up.”
While estimates vary widely, from ten percent upward, chronic problems clearly bedevil an enormous number of Covid-19 survivors. One study of 143 patients who had been hospitalized for Covid found that 87.5 percent had at least one persistent Covid-19-related symptom, chiefly fatigue and shortness of breath, two months after their disease began; 55 percent had three symptoms or more.
Neurological symptoms in Long Covid can be diverse, persistent, and by no means limited to those who had been ill enough to require hospitalization. In a series of 100 patients at a Northwestern Covid-19 clinic who had neurological problems six weeks after initial Covid diagnosis, 85 percent still had four or more symptoms an average of three months later.
“These patients had had mild Covid, in that they had never needed oxygen,” says Edith Graham, a clinical neuroimmunology fellow at Northwestern and lead author of the study. “Some had horrible fever and were very sick for two or three weeks, but others had felt they just had a cold for a few days. There was no association between initial severity and later symptoms.”
“Brain fog”—the kind of memory, thinking, and focusing problems that Ehekircher describes —was the most common neurological symptom, affecting 81 percent of patients. [Such phenomena might arguably reflect, at least in part, anxiety or depression surrounding the illness, or the stress of living in a world in turmoil. A study now in progress might help illuminate this question.]
In addition to cognitive dysfunction, two-thirds had persistent headache, and more than 50 percent had numbness and tingling, muscle pain, and/or disorders of taste and smell. Nearly one-third had tinnitus or blurred vision.
The patients in the study were predominantly female (70 percent) and young (average age, 43), mirroring sex and age demographics for Long Covid generally.
Whether strictly biological or partly psychological, the mental effects of Long Covid are apparently substantial. A self-administered cognitive assessment of 84,000 people in the UK found those who had had confirmed or suspected Covid-19 one to three months earlier performed more poorly than others in many ways.
“There were particular deficits in executive function—decision-making and concentration—and higher language functions,” says Adam Hampshire, of the Computational, Cognitive, and Clinical Neuroimaging Laboratory at Imperial College London, first author of the paper, which has yet to be peer reviewed. His preliminary findings accord with subjective reports, he says.
Deficits were most marked in the patients who had been sickest: the equivalent of an 8.5-point drop in IQ for those who had needed ventilators. Declines were more modest but still significant in individuals who had remained at home.
“A lot of these people say they have sleep disturbances,” Hampshire says. “And if you look at the cognitive pattern, it’s similar to what you’d expect after several days without sleep: brain fog, trouble finding words, forgetting what you’re doing. What we don’t know is: what’s cause, what’s effect?”
Depression and anxiety “had little association with cognitive performance,” Hampshire observes.
But such mental maladies are a significant problem in their own right. One study examined records of 62,354 patients, both hospitalized and non-hospitalized, weeks to months after their bouts with Covid-19, and found the incidence of psychiatric symptoms pronounced enough for clinical diagnosis (most frequently, anxiety and mood disorders) to be 18 percent. This was significantly more than the rate in comparison groups of individuals who had had other illnesses. Among Covid survivors with no prior psychiatric history, the rate of mental maladies was 5.8 percent—double what it was in the comparison groups.
Post-traumatic stress disorder is not rare: A paper reported that one-third of 381 patients who had come to a hospital emergency department with Covid-19 were diagnosed with post-traumatic stress disorder when evaluated one to three months later.
Parsing biological, situational, and psychological factors in mental disorders can be daunting in the best of times, but all the more so in a year when psychosocial stressors and mental health problems constitute a pandemic of their own.
Although definitive conclusions in some cases aren’t yet possible pending the gathering of additional data, speculation by scientists who have studied Covid and brain patterns for months have led to some well-honed observations. In February, for example, “just after the second surge,” Frontera’s group at NYU compared individuals (999 in all) who had been diagnosed with Covid-19, but not hospitalized, with those who had not had the disease.
“We’re examining the question, ‘What is the additive effect of Covid on top of the fatigue and the mood and cognitive insults of being socially isolated, under financial stress, and threatened by serious disease?’” he says. “We asked about stuff like financial insecurity, food insecurity, homelessness, childcare, relationship problems,” Frontera says. “There was a lot of political conflict—with family, friends and colleagues.”
The survey explored the place of pre-existing psychiatric, neurological, and medical conditions. “We asked about fear of illness and about personal illness as a stressor.” The participants self-tested with a battery that evaluated anxiety, depression, fatigue, sleep, and cognitive dysfunction—“how they feel about their thinking processes,” Frontera says. Because the paper is still under review for publication, she could not disclose findings.
The Enemy Within
Research into neural effects of Covid-19 began in the earliest days of the pandemic and has accelerated ever since. “The pace has been exponential,” says Batra at Northwestern. “There’s been a lot of fantastic scientific work worldwide, and it’s been stunning to see the rate of progress… a heroic and unprecedented achievement.”
Much of this work has sought to clarify the underlying mechanisms by which Covid-19 wreaks its havoc in the CNS. But though much has been learned, answers to perhaps the most fundamental question—does the virus attack the brain directly?—are elusive. “Viral invasion? I think everyone agrees this remains controversial,” says Nath. Although some researchers have found signs of infection in neural tissue, “there’s no evidence of overwhelming virus in the brain. I don’t think that alone explains all this.”
Two recent papers suggested how the virus might gain access. Using an animal model, one showed the spike protein—the projection by which Covid latches onto and attacks cells—crossing the blood-brain barrier to be taken up by brain tissue. In the other, post-mortem analysis found the virus in the mucosa of the nose and throat, and along the olfactory nerve, and in a path through the brain.
At Yale, Song was also the first author of a recent paper that explores neuroinvasion using an organoid—a three-dimensional neural tissue culture—a mouse model, and brain autopsy of people who had died of Covid. “Every model has its limitations; we used all three to see what they had in common,” he says. Besides the presence of virus, “we found metabolic changes and vascular remodeling, and we think long-term changes in the CNS might have to do with destruction of vasculature.”
His own findings notwithstanding, Song sees a multifactorial picture. “The field as a whole has been approaching [mechanisms] in multiple avenues—there’s the direct neuroinvasion portion, and how systemic inflammation and hypoxemia are affecting the brain. I think it’s hard to call the neurological sequelae of Covid a single disease. You have to keep an open mind.”
Some researchers, like Frontera, lean toward a systemic explanation. In the NYU series of hospitalized Covid-19 patients, “we did not detect meningitis or encephalitis due to direct invasion by SARS-CoV-2,” she explains. “Our paper highlighted the idea that most neurological manifestations were secondary effects of the virus, related to being hypoxic, uremic, or in sepsis.”
A key to Covid injury, she speculates, may be microvascular damage. “Small vessels become leaky, prone to bleeding. We have patients with multifocal hemorrhages.”
Other researchers agree. “The SARS-COV-2 (Covid’s formal title) virus has a special predilection for the ACE2 receptors, which is expressed [in the lining of blood vessels] all across the body,” says Batra. “Pulmonary symptoms are what got all the attention early on, but it’s not surprising to see neurological symptoms as well, there’s such a vast network of blood vessels in both the lung and brain.”
A post-mortem study of 13 patients who had died of Covid-19 found signs of microvascular injury in brain tissue, thinning of the cells lining blood vessels, and signs of congested blood vessels. There were indications of microhemorrhages in the olfactory bulb and other areas.
“Quite possibly, the virus first attacks endothelial cells,” says Nath, an author of the study. “Then the immune system targets those cells, leading to blood vessel damage. There is a hypercoagulable state which leads to occlusions, and some patients develop hemorrhages, too. I suspect that’s the major initial pathophysiology.”
A Bigger Picture
Other researchers are looking at larger brain structures. Kyle Pattinson, senior clinical research fellow at University of Oxford, heads an MRI project that focuses on the brainstem. “Other coronaviruses have been shown to be neurotropic to the brainstem,” he says. “If the virus enters via the nasal mucosa, it will have a direct route through the olfactory bulb down to the ventrolateral medulla, which regulates heart and lung function.”
Brainstem structures also govern perception of internal sensations, and their dysfunction might account for “’happy hypoxia’, a condition where acutely ill Covid-19 patients don’t sense they’re having respiratory compromise,” he says. Conversely, brainstem involvement “may make breathlessness feel worse than it should be if only the lungs were affected.”
Pattinson himself struggled with post-Covid fatigue as well as breathlessness—the two most common phenomena—for six months. “Probably all the symptoms in Long Covid will be from a multitude of factors, and the brainstem will be one of these factors,” he says.
His study will look at higher centers as well; he is working with Hampshire to correlate structural changes with cognitive decline, and with fellow Oxford researchers to explore neurotransmitter systems, inflammatory markers, and neuronal integrity. “We’re hoping to get an idea just what neural effects occur,” Pattinson says. His group has a particular interest in following people who are having prolonged symptoms but were not hospitalized when acutely ill.
The Oxford brain study is one of an increasing number that are tracking the course of Covid-19 over time. How long does Long Covid last? When will the “brain fog” lift? What can help? Researchers, clinicians—and above all patients—are eager for answers. The National Institutes of Health is allocating more than $1 billion to research investigating Long Covid in all its multi-organ complexity—causes, manifestations, natural history, and treatments.
Frontera has finished a six-month follow-up evaluation of anxiety, fatigue, and other neurological symptoms in her NYU group of hospitalized Covid-19 patients and plans another at one year. “We’re looking at trajectories of recovery,” says Frontera, who is also on the steering committee of the Covid-19 Neuro Databank/Biobank, funded by the NINDS and maintained by NYU. This project will collect information on neurological symptoms and the course of the disease from health care providers, hospitals, and researchers across the country, along with biological materials such as blood and CSF.
“We may see regional variations in viral genotype and get information on different strategies used with different patients,” she says. “Hopefully we’ll answer some questions about underlying etiology.”
A consortium of researchers from 30 countries are participating in a study to trace a possible path from Covid-19 to neurodegenerative diseases, particularly dementia. “It’s a ‘study of studies,’” says Heather Snyder, vice president, Medical and Scientific Relations, of the Alzheimer’s Association, which is funding the initial effort. “Groups around the world will collect blood, MRI images, clinical data, depending on their resources. Some studies will involve hospitalized individuals only; other studies, patients in the community.”
The resulting trove of data will be pooled, shared, and subjected to meta-analysis “to identify associations and connections, and answer some of the big questions about the long-term impact of Covid-19 on the brain and nervous system,” she says.
Sudra Seshadri, founding director of the Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases at University of Texas, San Antonio, and coauthor of a paper that outlined the rationale for the project, notes that inflammation is prominent among the effects of SARS-CoV-2. “We know that immune problems have a role in Alzheimer’s disease, too. And direct effects of the virus, such as increasing clotting tendency, might lead to small strokes, which tend to worsen dementia.”
Earlier researchers have suggested a link between diverse viral infections and Alzheimer’s disease, she points out. The plan is to follow participants for 18 months or longer, tracking variables including cognitive functioning. All ages will be involved, “but we are focusing on older people [including] some who have MCI (mild cognitive impairment) and early Alzheimer’s,” says Seshadri.
This particular area of research is poised to accelerate. The National Institute on Aging recently called for grant proposals to fund projects exploring the impact of Covid-19 on neurodegenerative disorders and the aging process.
A year-plus into the pandemic, the story is far from over. Although vaccination stands to stem the tide, Covid-19 won’t be gone overnight, and variants of the SARS-CoV-2 virus, according to many experts, are likely to be around for a long time.
And even if just ten percent of those infected develop persistent symptoms, with 130 million cases worldwide and counting, that’s a lot of need for whatever neuroscience can deliver. “If we know whether they are due to neuroinvasion, autoimmune, vascular, or other mechanisms, it will change how we manage symptoms and the disease long-term,” says Song. “We often forget why we do this research. Ultimately, it’s to help patients.”