Long COVID now looks like a neurological disease, helping doctors focus treatments (2023)

Tara Ghormley has always been a standout. She finished top of her class in high school, graduated from college summa cum laude, and received top honors in veterinary school. She then completed a rigorous training program and built a successful career as a specialist in internal veterinary medicine. But in March 2020, she contracted the SARS-CoV-2 virus — just the 24th case in the small coastal town in central California where she lived at the time, near the site of an early outbreak of the COVID pandemic. "I could have done it without being first in this," she says.

Nearly three years after the virus apparently cleared from her body, Ghormley is still suffering. She quickly becomes exhausted, her heartbeat suddenly races and she goes through periods when she cannot concentrate or think clearly. Ghormley and her husband, who have moved to a Los Angeles suburb, once spent their free time visiting their "happiest place on earth" - Disneyland - but her health prevented that for more than a year. She still spends most of her days off resting in the dark or going to her many doctor appointments. Her early infection and persistent symptoms make her one of the first people in the country with "long COVID," a condition in which symptoms persist for at least three months after infection and can persist for years. The syndrome is known by medical professionals as post-acute sequelae of COVID-19 or PASC.

People with long-term COVID have symptoms such as pain, extreme fatigue, and "brain fog," or difficulty concentrating or remembering things. As of March 2023, it is estimated that more than 15 million adults in the US were affected by the syndrome, and a 2022 report found that it had forced between two million and four million Americans out of the workforce. Prolonged COVID is common in otherwise healthy young people and can even follow a mild initial infection. The risk seems to be at least slightly higher in people hospitalized due to COVID and in older adults (who are more likely to end up in hospital). Women and those who are socioeconomically disadvantaged are also at greater risk, as are those who smoke, are obese, or have any of a variety of health conditions, particularly autoimmune diseases. Vaccination seems to reduce the danger, but does not completely prevent long COVID.

The most common, persistent, and disabling symptoms of long-term COVID are neurological. Some are easy to recognize as brain or nerve related: many people experience cognitive impairment in the form of problems with memory, attention, sleep and mood. Others seem to be rooted more in the body than in the brain, such as pain and post-exertional malaise (PEM), a kind of "energy crash" that people experience even after mild exercise. But these, too, are the result of nervous disturbances, often in the autonomic nervous system, which directs our bodies to breathe and digest food and generally puts our organs on autopilot. This so-called dysautonomia can lead to dizziness, palpitations, high or low blood pressure and intestinal disorders, which sometimes prevent people from working or functioning independently.

The SARS-CoV-2 virus is new, but post-viral syndromes are not. Research on other viruses, and in particular on neurological damage from human immunodeficiency virus (HIV), is leading the work on long COVID. And the recognition that the syndrome can produce its many effects through the brain and nervous system is beginning to shape the approach to medical treatment. “I now view COVID as a neurological disease as much as a lung disease, and that is certainly true of long-term COVID,” said William Pittman, a physician at UCLA Health in Los Angeles who treats Ghormley and many similar illnesses. patients.

While 15 million current U.S. patients is a reasonable estimate of the condition's toll, there are other more serious assessments. A meta-analysis of 41 studies conducted in 2021 concluded that globally, 43 percent of people infected with SARS-CoV-2 may develop long-term COVID, with about 30 percent — representing about 30 million people — in the US is affected. more conservative numbers. A June 2022 study reported by the US National Center for Health Statistics found that among adults who had had COVID, one in five experienced long-term COVID three months later; the UK Office for National Statistics put the estimate at one in ten. Even if only a small fraction of infections lead to long-term COVID, experts say they will lead to millions more affected — and potentially disabled.

Most of the first recognized cases of long-term COVID were in patients who required long-term respiratory therapy or who had obvious organ damage that was causing lasting symptoms. People who reported neurological symptoms were often overlooked or dismissed as traumatized by their initial illness and hospitalization. But as 2020 came to a close, says Helen Lavretsky, a psychiatrist at the University of California, Los Angeles, "we're starting to get to a point of figuring out what was really going on...and it became very clear then that neuropsychiatric symptoms were quite common,” usually fatigue, malaise, brain fog, loss of smell, and post-traumatic stress disorder, as well as cognitive problems and even psychosis.

Ghormley was in her late 30s and relatively healthy when she contracted the virus, but she had underlying conditions — including rheumatoid arthritis and asthma — that put her at risk for severe COVID. She spent several days at home struggling to breathe, and then she went to the hospital, where her blood pressure spiked and her blood glucose suddenly dropped. She largely recovered from this acute phase within a few weeks, but, she says, "I never really got better."

Shortly after coming home from the hospital, Ghormley developed what her husband called "goldfish brain." "I put something down and had no idea where I put it," she recalls. “It kept happening over and over. I thought, 'This is getting weird.' My husband said I didn't remember anything. I would try to speak, and I knew what I wanted to say, but I couldn't get the word out.

She also experienced tremors, dramatic mood swings, and painful hypersensitivity to sounds. "My husband, opening a paper bag, felt like knives stuck in my ear," she says. Any exertion - physical or mental - left her exhausted and in pain. The changes shocked Ghormley, who prided herself on her sharp mind. “What bothered me the most was that I was really having trouble thinking, speaking, remembering — trying to complete a task and having no idea what it was. Suddenly I had some pretty serious neurological deficits. Then everything fell apart for me. That was terribly traumatic…it broke me a little bit. I didn't feel like myself."

Roots of dysfunction

As a veterinary internist, Ghormley says, her job is to troubleshoot when mysterious symptoms arise, including her own. "I was actively looking for reasons and found what I could do." She theorized that some of her neurological symptoms could be due to thrombotic events, blood clots that can cause small strokes. Several early studies showed that COVID attacks endothelial cells, which line blood vessels. This can lead to clotting and oxygen deprivation in multiple organs, including the brain. Even subtle disruption of endothelial cells in the brain can contribute to cognitive dysfunction.

One study found that in people with neurological COVID symptoms, the immune system appears to be activated specifically in the central nervous system, causing inflammation. But brain inflammation is probably not caused by the virus directly infecting that organ. Avindra Nath, who has long studied post-viral neurological syndromes at the National Institutes of Health, found something similar in an autopsy study of people who died of COVID. "If you look at the COVID brain, you don't actually find [huge amounts of virus, but] we found a lot of immune activation," he says, especially around blood vessels. The studies suggested that immune cells called macrophages had been agitated. "Macrophages aren't as precise in their attack," says Nath. “They come and start chewing things up; they produce all kinds of free radicals, cytokines. It's almost like general bombing: it ends up doing a lot of damage. And they are very hard to close, so they last for a long time. These are the unwanted guests that can cause persistent inflammation in the brain.

Determining which patients have persistent inflammation can help inform treatments. Early research identified markers that are often elevated in people with the condition, says Troy Torgerson, an immunologist at the Allen Institute in Seattle. Three cell signaling molecules – tumor necrosis factor alpha, interleukin 6 and interferon beta – stood out in lung COVID patients. But this pattern was not found in absolutely everyone. "We're trying to sort through lung COVID patients and say, 'This would be a good group to take to trials of an anti-inflammatory drug, when maybe this group should focus more on rehabilitation,'" says Torgerson. He led a study (currently released as a preprint, without formal scientific review by a journal) in which his team measured proteins from the blood of 55 patients. The researchers found that one subgroup had persistent inflammation. Among those people, they saw a clear immune pathway associated with a lasting response to infection. "One subgroup of patients seems to have an ongoing reaction to some virus," says Torgerson.

Isolated pockets of SARS-CoV-2 or even pieces of viral proteins can remain in the body long after the initial infection and continue to provoke an immune attack. The first solid evidence for "viral persistence" outside the lungs came in 2021 from researchers in Singapore who found viral proteins in the gut in five patients who had recovered from COVID six months earlier. A study conducted at the University of California, San Francisco found evidence of viral particles in the brains of people with lung COVID. Scientists collected exosomes, or small packets of cellular material, released specifically from cells of the central nervous system. The exosomes contain bits of viral proteins as well as mitochondrial proteins, which may indicate an immune attack on those vital cellular organelles. The amounts of such suspect proteins were higher in patients with neuropsychiatric symptoms than in patients without neuropsychiatric symptoms.

The virus could linger in the brain for months, according to research by the nih and reported inNaturein December 2022. The autopsy study of 44 people who died of COVID found rampant inflammation, mainly in the respiratory tract, but viral RNA was detected throughout the body, even in the brain, up to 230 days after infection. Two other studies, both published last year in theProcedures van de National Academy of Sciences USA, showed evidence that SARS-CoV-2 can infect astrocytes, a type of neural support cell, which gain access through neurons in the skin lining the nose.

Researchers are investigating inflammatory signals in patients with long-term COVID in increasingly fine detail. A small study led by Joanna Hellmuth, a neurologist at U.C.S.F., found that patients with cognitive symptoms had immune-related abnormalities in their cerebrospinal fluid, while none of the patients without cognitive symptoms did. At the 2022 meeting of the Society for Neuroscience, Hellmuth reported looking at more specific immune markers in people with cognitive symptoms and found that some patients had elevated levels of VEGF-C, a marker of endothelial dysfunction. Higher VEGF-C levels are associated with higher levels of immune cells entering the brain, she says, and “they are not doing their normal function of maintaining the blood-brain barrier; they are distracted and perhaps activated.” Although the studies are small, Hellmuth adds, they reveal “real biological differences and inflammation in the brain. This is not a mental or psychosomatic condition; this is a neuroimmune disease.”

What keeps the immune system in attack mode? According to Torgerson, "one option is that you have developed autoimmunity," in which antibodies produced by the immune system to fight the virus also mark a person's own cells for an immune attack. The response to the virus "turns on the autoimmunity, and it doesn't get better even if the virus goes away," he says. Several studies have found evidence of autoimmune components called autoantibodies interacting with nerve cells in people with long COVID.

Clues about the inflammatory processes at work may point to treatments for neurological symptoms. "If it's a macrophage-mediated inflammatory process… intravenous immunoglobulin could make a difference [to] dampen down the macrophages," says Nath. The treatment, called IVIg, contains a cocktail of proteins and antibodies that can reduce an overactive immune response.

IVIg can also be used to block autoantibodies. And a therapy called rituximab that targets antibody-producing B cells offers "a proven therapy for many autoantibody-mediated syndromes," says Nath. Another strategy is to use corticosteroids to dampen immune activity altogether, although those drugs can only be used for a limited time. “That is a sledgehammer blow, and you can see if it makes a difference. At least it gives you an idea that, yes, it's an immune-mediated phenomenon, and now we need to find a better way to deal with it," says Nath.

If the virus lingers in some form, antiviral medications may be able to clear it, which can help resolve neurological symptoms. That's the hope of scientists conducting a clinical trial of Paxlovid, Pfizer's antiviral drug for acute COVID.

A chronic fatigue connection?

Post-viral syndromes have been documented for over a century and arise after infection with viruses from HIV to the flu. The Epstein-Barr virus, which causes mononucleosis, is one of many viruses associated with a condition called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is estimated to affect at least one and a half million people in the world. US hits. ME/CFS bears striking similarities to long COVID, with symptoms including immune system dysregulation, fatigue and cognitive dysfunction. “One of the patterns we see is patients who definitely meet the criteria for ME/CFS. This is something we see and treat all the time” in lung COVID patients, Pittman says. ME/CFS can be severe, with some people losing mobility and becoming bedridden.

Nath, who also studies ME/CFS, says "we think they will be mechanically related." Researchers suspect that, like some cases of long-term COVID, ME/CFS could be autoimmune in nature, with autoantibodies keeping the immune system activated. ME/CFS is difficult to study because it often develops long after a mild infection, making it difficult to identify a viral trigger. But with long COVID, says Nath, "the advantage is knowing exactly what started the process, and being able to spot cases early in the [development of] ME/CFS-like symptoms." In people who have had ME/CFS for years, "it's done damage, and it's hard to undo that." Nath speculates that if doctors could study people for a long time in the early stages of the disease, they would have a better chance of reversing the process.

Torgerson hopes researchers will eventually gain a better understanding of ME/CFS because of COVID. “COVID has been studied more carefully with better technology in the time we've had it than any other infectious disease ever. I think we will learn things that will apply to other inflammatory diseases that are caused by infection followed by an autoimmune process."

Team treatment

After months of illness, Ghormley sought care at UCLA Health's Long COVID Clinic, one of the country's few comprehensive, multidisciplinary programs for people with this syndrome. Although her symptoms are rooted in nervous system dysfunction, she required a range of medical specialists to treat them. The clinic grew out of a program aimed at coordinating care for medically complex COVID patients, says director Nisha Viswanathan, internist and general practitioner. When following up on COVID patients after several months, she realized that “we had a group of patients who were still having symptoms. There was no understanding of the condition; we were just trying to see what we could offer them. Viswanathan and others convened a biweekly gathering of UCLA Health physicians in pulmonary disease, cardiology, neurology, psychiatry and other specialties to discuss individual cases and overall trends.

At UCLA Health, Pittman coordinates Ghormley's treatment. He says the interdisciplinary team is crucial to providing patients with the best possible care. "Often there are so many symptoms," and some patients have seen multiple specialists before arriving, but not necessarily the right one. As long as COVID primary care providers, he says, "we'll do the initial tests and get them to the right person." For Ghormley, that list of caregivers includes Pittman, along with a neurologist, pulmonologist, cardiologist, psychiatrist, trauma counselor, rheumatologist, and gynecologist.

The team approach has also been critical for doctors trying to understand an entirely new disease, Pittman says. "It's been a very interesting journey from knowing almost nothing to knowing a little bit now, and we're learning more every day, every week, every month," he says. The term "long COVID" "is an umbrella, and I think there are multiple illnesses that fall under that umbrella." While each long COVID patient is unique, Pittman says, “we are starting to see patterns emerge. And with Ghormley, we saw a pattern of dysautonomia, which we often see.”

Dysautonomia impairs the autonomic nervous system, a network of nerves that branch from the brain or spinal cord and extend throughout the body, controlling unconscious functions such as heart rate, breathing, sweating, and dilation of blood vessels. For Ghormley, like many people with long-term COVID, dysautonomia takes the form of postural orthostatic tachycardia syndrome, or POTS. The syndrome includes a collection of symptoms, including rapid heart rate, especially when standing, and fatigue, and can cause bowel and bladder irregularities. POTS can also be part of the exhaustion associated with PEM. While the symptoms appear to affect the body, they stem from nervous system dysfunction.

Ghormley's dysautonomia led her to see cardiologist Megha Agarwal at a UCLA clinic near her home. Many doctors are unfamiliar with POTS, but Agarwal is particularly set on it, having seen it in some of her patients before COVID hit. "There's a dysregulation of the nervous system and so many things can cause it: some cancer therapies, viruses, autoimmune diseases." Agarwal recognized POTS in Ghormley in the fall of 2020, when very little was known about long-term COVID. Now she believes that "POTS is really what causes long-term COVID" in many patients. Fortunately, Agarwal says, there are medical interventions that can help.

Tachycardia -- the T in POTS -- causes the heart rate to accelerate, contributing to exhaustion and fatigue, in addition to stress for the heart itself. Drugs called beta-blockers (for the beta-adrenergic receptors they turn off in the heart) can lower heart rate and improve symptoms. "When the heart rate is controlled, not only does the pump improve," says Agarwal, "[but people's energy] improves, their fatigue is gone, and sometimes there's better mental clarity." For some patients, like Ghormley, beta-blockers aren't enough, so Agarwal adds a drug called ivabradine. "It's a little bit off-label, but it's being aggressively studied right now" for POTS. For Ghormley, the combination led to real improvements, "so now she doesn't feel like she ran the Boston Marathon when all she did was sit down and get up at work or take a shower," says Agarwal.

One of Ghormley's most severe symptoms is her brain fog, a collective term for a whole range of cognitive problems that make it difficult for her to function. For days when Ghormley works, her psychiatrist prescribes Adderall, a stimulant used to treat attention deficit hyperactivity disorder that helps her focus and stay focused. That has "helped tremendously," says Ghormley.

Ghormley thanks her doctors and Agarwal in particular for the detective work to investigate her symptoms. "No one knew about it, but everyone listened to me," says Ghormley. Perhaps because she was a professional from a medical field, no one "pushed me aside."

That's unusual for people with long-term COVID, many of them women, who are often dismissed by doctors who question their symptoms. "Patients just don't feel heard," says Viswanathan. "I had a patient tell me everything, and then I just said, 'This must be so hard for you.' I want you to know that everything you feel is real, and I've seen so many patients like you.” And she started to cry. She said, “No one told me that. I can't tell you how many times I was told it was in my head.'”

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In addition to medications, other types of therapies, including physical therapy, may help improve some symptoms. But people who experience PEM face a particular challenge when using exercise therapies. Pittman says the exercise can make these patients feel worse. "We don't want patients to not move at all, but sometimes the kind of movement they do can make their symptoms flare up." He notes that PEM often affects young, rather healthy people who will say, "'I have to push myself,' and then they go way too far and get worse. Our job is to try to find that middle ground and then consistent over time so they don't get deconditioned further, but they don't have the PEM, which has been shown to deteriorate.

The long distance

Some patients, says Pittman, "have an expectation that they come in and within a month they will be back to normal." And resetting those expectations can be very challenging. You really have to be empathetic, because people's lives have changed completely.” But sometimes patients' quality of life can noticeably improve if they can adjust to a new normal. Still, he says, “patients have so many questions and I can't lead them along a physiological path. I can tell them there's neuroinflammation, maybe autoimmunity, but we still don't have any answers. Sometimes it is very difficult for us to accept and for the patient to accept that we just have to do our best.”

A number of people, Viswanathan says, benefit from cutting back on various treatments they've accumulated. Some people become so desperate that they try everything from supplements to off-label drugs to untested potions off the internet. Stopping them sometimes leads to improved symptoms, she says.

Psychological care and support groups can help. Lavretsky adds that "lifestyle choices can play a big role in improvement," especially better sleep habits and using breathing exercises to manage anxiety. She tells people that their bodies can heal themselves if the patients and clinicians find the right tools.

Whether that applies to everyone remains to be seen, Viswanathan says. “We see a lot of patients who have gotten better with time. I have patients whose complaints have disappeared over the course of a year, or disappear and occasionally flare up again.” But for some, she says, "it can take many years."

"We're probably going to be doing this for decades," says Viswanathan. "COVID won't so much go away, we'll just have to get used to living with it, but part of that means people will continue to develop COVID for a long time."

Vaccination seems to reduce the risk of long-term COVID. But a study published in May 2022 inNaturopathysuggests that the protection, while real, is not as good as one might hope. The U.S. Department of Veterans Affairs electronic health record study looked at the relatively small proportion of vaccinated people who subsequently became infected. For a long time, they developed COVID only 15 percent less often than unvaccinated people. “These patients can have symptoms for one to two years or more, and so you accumulate more patients every month. Even if it is 15 percent less, the overall patient population is still growing and exploding,” says Pittman. Experts all agree that the best way to avoid getting COVID for a long time is to not get COVID at all.

The syndrome is still mired in much medical uncertainty. Patients may have one or a combination of the problems studied so far: Long COVID can be caused by viral particles that persist in the brain or other parts of the nervous system. Or it could be an autoimmune disease that persists long after the virus is gone. Perhaps overactive immune cells continue to disrupt the nervous system and nearby blood vessels. Fortunately, the increasing ability to recognize specific problems helps clinicians hone in on treatments that give patients the best chance of recovery.

Although Ghormley says her care has dramatically improved her symptoms and allowed her to "do some normal things again," she continues to suffer from flare-ups that make it impossible for her to work for weeks at a time. One day last year, she skipped a dose of her heart medication and went on a Target run in the Southern California heat. “I came home and basically collapsed in the hallway,” she says, and even months later things “were not right. When I try to move, my legs give way.” Most frustrating - and scary - for Ghormley is the unpredictability of her symptoms: "They've changed so much; some are manageable, some are debilitating. One will get better and the other will come back. I always have hope that it will get better, but I just don't know.”