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For COVID-19 ‘Long-Haulers,’ Neurologists Focus on Acute Symptoms
The Search Is on for Causes of Long-Term Events

Article In Brief

Neurologists and rehabilitation specialists are trying to identify the causes of COVID-19 long-haul symptoms. Etiology matters less than the need to offer symptomatic treatments and reassuring counsel, they said.

Even as clinical experience grows and published studies accumulate, neurologists and rehabilitation specialists say they still have no clear understanding of what is causing COVID-19 “long-haul” symptoms.

Autoimmune reactions? Lingering reservoirs of virus? Functional neurologic disorder? All are being studied. None of these etiologies have been proven.

For now, clinicians at four post-COVID-19 clinics across the United States tell Neurology Today that etiology matters less than the need to offer symptomatic treatments and reassuring counsel.

“I like to explain to patients that we don't know what's going on, but also to highlight some of the more reassuring findings,” said Allison P. Navis, MD, an assistant professor in the division of neuro-infection diseases at the Icahn School of Medicine at Mount Sinai in New York.

Dr. Navis has treated some 200 patients at a clinic for people experiencing post-COVID-19 symptoms “I try not to be dismissive of any symptoms, but also not to assume that every symptom they present with is directly due to COVID-19,” she said. “And I try to emphasize that most of our patients do get better with symptomatic treatment.”

The Typical Long-Haul Patient

Evidence from studies and clinical experience alike is beginning to sharpen the picture of what a typical long-haul patient looks like. So far, they are more likely to be women than men, to be middle-aged rather than elderly, and to be White rather than Black or Hispanic. And according to a new study from Northwestern Medicine, an unusually high number, 42 percent, had depression or anxiety prior to their COVID-19 diagnosis.

Perhaps most puzzling is that very few of the patients with long-haul symptoms were ever hospitalized for acute illness due to COVID-19. In fact, the post-COVID-19 clinics that have opened across the United States, most of which expected to offer rehabilitation services to those who had lingered in ICU beds for weeks, have instead been treating people who never became severely ill.

“Our clinic started with a plan to serve those most seriously ill,” said Ginger Polich, MD, an instructor in physical medicine and rehabilitation at Spaulding Rehabilitation Hospital in Boston. “We didn't seek out to treat the mild cases, but rather [those with] mild cases started calling the clinic and asked to be seen.”

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“I try not to be dismissive of any symptoms, but also not to assume that every symptom they present with is directly due to COVID-19. And I try to emphasize that most of our patients do get better with symptomatic treatment.”—DR. ALLISON P. NAVIS

Even the National Institute of Neurological Disorders and Stroke (NINDS) has had difficulty finding post-COVID-19 long haulers who previously required hospitalization.

“We asked our colleagues who are studying patients who required intensive care if they can refer some to us because we want to study the long-haulers,” said Avindra Nath, MD, FAAN, senior investigator in the section of infections of the nervous system at NINDS.

“They said they don't have any who were in the ICU and are now long-haulers. It's quite likely that the ones who had serious illness don't actually become long-haulers, although they may develop chronic symptoms from multiorgan damage during the acute phase of the illness.”

Latest Study Findings

A paper posted on medRxiv on March 5, ahead of publication, analyzed the electronic medical records of 178,971 patients in California who were PCR-confirmed to have a SARS-CoV-2 infection. From that large group, they identified 1,407 records of people who had never been hospitalized, but had newly emergent symptoms consistent with being long-haulers, including palpitations, chronic rhinitis, dysgeusia, chills, insomnia, hyperhidrosis, anxiety, sore throat, and headache.

Of these, 27 percent reported persistent symptoms beyond 60 days. Women were more likely than men to become long-haulers, accounting for 72 percent of cases. And roughly 32 percent of the long haulers were initially asymptomatic at the time of their SARS-CoV-2 testing. That is, they did not have mild symptoms of COVID-19; they had no symptoms at all.

“We don't know why they initially went for testing,” said the senior author of the paper, Charles A. Downs, PhD, an associate professor of nursing at the University of Miami's School of Nursing and Health Studies. But the fact that so many people without initial symptoms go on to become long-haulers, he said, is “alarming.”

The paper also reported that symptoms that persist for more than 60 days come in one of five clusters: chest pain-cough, dyspnea-cough, anxiety-tachycardia, abdominal pain-nausea, and low back pain-joint pain.

Another paper, published on March 23 ahead of print in the Annals of Clinical and Translational Neurology, described a series of 100 patients who sought care at Northwestern's Neuro-COVID-19 clinic. They had to meet the Infectious Diseases Society of America criteria for symptoms of a COVID-19 infection, but could not have been hospitalized for pneumonia or hypoxemia. And they had to have had neurologic symptoms lasting over six weeks.

The series included the first 50 patients meeting that criteria who also initially tested positive for SARS-CoV-2 and—perhaps surprisingly—the first 50 who tested negative. (Interestingly, then, the patients who tested negative would have been excluded from Dr. Downs's study of California patients, while the 32 percent of the California patients who had no initial symptoms of infection would have been excluded from the Northwestern study.)

The mean age of patients in the Northwestern Neuro COVID-19 clinic study was 42.3 years, and 70 percent were female. The two most frequent comorbidities were depression/anxiety—observed in 42 percent—and autoimmune disease in 16 percent. The main neurologic manifestations were fatigue (85 percent), “brain fog” (81 percent), headache (68 percent), numbness/tingling (60 percent), dysgeusia (59 percent), anosmia (55 percent), and myalgias (55 percent).

Only anosmia was more frequent in SARS-CoV-2-positive patients than in SARS-CoV-2-negative patients (37/50 [74 percent] vs (18/50 [36 percent]; p <0.001).

Sixty-four percent recovered on average after five months. Some continued to experience symptoms more than nine months later.

The treatment approach at the Northwestern clinic, similar to that at other post-COVID clinics, is symptomatic. “You can treat headache, you can treat fatigue, you can treat pain, you can treat insomnia,” said Igor J. Koralnik, MD, FAAN, FANA, senior author of the paper in Annals of Clinical and Translational Neurology. “There is a different treatment for every presentation,” said Dr. Koralnik, the Archibald Church Professor of Neurology and division chief of neuro-infectious diseases & global neurology at Northwestern Memorial Hospital.

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“You can treat headache, you can treat fatigue, you can treat pain, you can treat insomnia. There is a different treatment for every presentation.”—DR. IGOR J. KORALNIK

Search for a Cause

Dr. Koralnik said his group is studying the T-cell response of long-haul patients as a means to understand the long-haul syndrome. “We think there could be a dysregulation of the immune system,” he said.

At NINDS, Dr. Nath said he is interested in studying a viral cause of the syndrome. “I'm a virologist, so I think in terms of viruses. If it's true that only the ones who were mildly sick with COVID-19 develop persisting symptoms, maybe it's because their immune system didn't crank up enough to get rid of the virus. Maybe they have lingering virus resulting in restricted viral replication, and that's what's causing the long haul.”

Dr. Nath cited a recent article in the Washington Post that described anecdotal evidence of long haulers who recovered after receiving one of the vaccines against SARS-CoV-2. “That supports the idea of a persistent viral infection. The vaccine might finally eliminate the lingering virus. But the next question is: For how long do they feel better after the vaccine? Does it last?”

Another possibility is that some of the patients are experiencing a form of functional neurologic disorder (FND). One key sign for diagnosing FND as the cause of a patient's symptoms is internal inconsistency, Dr. Polich said.

“I had a woman come in who reported a lot of cognitive symptoms,” she said. “When we did cognitive testing, she slowed down her speech, and exhibited a lot of effort. But before and after the tests, she talked normally, and she was still working at a challenging job. That inconsistency is key for any functional diagnosis.”

Dr. Navis said she has observed another kind of inconsistency.

“I have had a couple of COVID long-haulers coming in complaining of severe weakness, sometimes in a wheelchair or walker, but their neurologic exam is nonfocal, making the etiology of their weakness appear to not be neurologic,” Dr. Navis said.

Even while studying the role of T-cells, Dr. Koralnik said he was surprised by the high number of long-haul patients who reported depression or anxiety prior to testing positive for SARS-CoV-2.

“It's possible there is a neuropsychiatric aspect to the long COVID syndrome,” he said. “But this is certainly a real syndrome that affects millions of people in the United States, probably dozens of millions in the world.”

Two scientists at the University of Edinburgh recently published a letter in Neurology disputing what they called a “false dichotomy” between a biological disorder and one caused by FND.

“Research over the last 20 years has shown that functional disorders have their own neurobiology, they are commonly precipitated by physical experiences such as injury and (any kind of) infection, and they can affect anyone regardless of education or prior medical history,” wrote Jon Stone, PhD, professor of neurology, and Alan Carson, PhD, consultant neuropsychiatrist and honorary professor, both of them at the university's Centre of Clinical Brain Sciences.

“Functional disorders are genuine conditions, not synonyms for ‘nothing wrong’ or ‘nothing biological,’” they wrote.

Some neurologists said they worry that raising the possibility of FND with patients can backfire.

“Saying that it's functional, which usually implies psychiatric, can be a dangerous pathway to go down,” said Peter D. Donofrio, MD, FAAN, professor of neurology and division chief of neuromuscular disorders at Vanderbilt University School of Medicine. “As a physician, if they had COVID and now they're not feeling well, I am going to treat them as if their symptoms are due to the COVID infection.”

On the other hand, Dr. Polich said, “If you suspect a functional disorder and you don't go there, you could be doing your patient a disservice by letting them be more worried and anxious that something else is going on. There are treatments for FND, and someone can absolutely get better. If it's an inflammatory process that we have no treatment for, FND might have a better outcome.”

More Studies Coming

“I'm trying to finish a grant proposal tonight, to follow these long-haul patients,” Dr. Nath said when reached by telephone. “We already have two protocols to bring patients in, but the amount of investigation we need to do will cost a lot of money. We want to study them from head-to-toe: spinal taps, MRI, immune phenotyping, autonomic function testing, exercise tolerance, mitochondrial function—you name it. The key is we're going in unbiased. Once you're convinced that you know what the cause is before doing unbiased investigation and analysis of data, you're not doing science anymore; you're doing politics.”

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“Its quite likely that the ones who had serious illness dont actually become long-haulers, although they may develop chronic symptoms from multiorgan damage during the acute phase of the illness.”—DR. AVINDRA NATH

On February 23, the director of NIH, Francis Collins, MD, PhD, announced a major new initiative to identify the causes, and find treatments and prevention strategies, for those with “long COVID.” He used a new, more scientific phrase, however, to describe the disorder: post-acute sequelae of SARS-CoV-2 infection (PASC).

“Today, we issued the first in a series of Research Opportunity Announcements (ROAs) for the newly formed NIH PASC Initiative,” Dr. Collins said. “Through this initiative, we aim to learn more about how SARS-CoV-2 may lead to such widespread and lasting symptoms and to develop ways to treat or prevent these conditions.”

Dr. Stone and Dr. Carson are also conducting a Scottish government-funded study of PASC in Edinburgh. “We are doing detailed imaging, testing spinal fluid, etc., but also looking explicitly for positive evidence of functional cognitive disorder,” Dr. Stone said. Echoing the view of Dr. Nath, he added: “We are going into this with an open mind.”

Disclosures:

Dr. Navis, Nath, Stone, and Koralnik had no disclosures.

Link Up for More Information

• Graham EL, Clark JR, Orban ZS, et al. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers https://onlinelibrary.wiley.com/doi/10.1002/acn3.51350. Ann Clin Transl Neurol 2021; Epub 2021 Mar 23.
    • Huang Y, Pinto MD, Borelli JL, et al. COVID Symptoms, symptom clusters, and predictors for becoming a long-hauler: Looking for clarity in the haze of the pandemic https://www.medrxiv.org/content/10.1101/2021.03.03.21252086v1. medRxiv 2021; Epub 2021 Mar 5.
      • Stone J, Carson A. Reader response: Long-haul COVID https://n.neurology.org/content/reader-response-long-haul-covid. Neurology 2021: