Before the pandemic, Colleen Prettyman pursued a life of service. A resident of the tiny town of Payson, AZ, the 53-year-old took care of her boyfriend, who has mental health problems. She also was a caseworker for the Arizona state government, helping vulnerable people access their Medicaid and Supplemental Nutrition Assistance Program benefits.

In October 2021, Prettyman developed a cough, some sniffles, a sore throat, and a fever. When her symptoms persisted, she visited an urgent care center, where she took a PCR test for COVID-19 that came back positive. Prettyman was unvaccinated but thought she had taken every other precaution. She always had her groceries delivered and spent time only with her boyfriend and roommate. But shortly after her roommate shopped at a large department store, Prettyman started feeling sick.

Her mild symptoms quickly worsened, and within days, her cough was so bad that her doctor prescribed steroids to reduce inflammation. She also began practicing deep breathing. In late December, other symptoms cropped up, such as trouble concentrating and problems with short-term memory, and she had to go on short-term disability. That ended in January 2022, and she is now on unpaid medical leave while receiving long-term disability and has been asked to resign by mid-December.

More than a year after her initial infection, Prettyman still struggles with her memory. She also has a persistent cough, causing her to pause in the middle of sentences, and often finds herself short of breath. Before getting sick, she had the occasional migraine. But by Christmas 2021, she had a headache almost every day, forcing her to avoid bright lights and keep the shades of her home drawn. Earlier this year, she was officially diagnosed with long COVID.

David Skoog came down with COVID-19 in April 2020. Although not hospitalized, the 53-year-old resident of Syracuse, NY, says, “I was the sickest I've ever been in my entire life.” After two weeks, the flulike symptoms disappeared, but Skoog constantly felt fatigued and needed a nap after simple tasks, like brushing his teeth. His resting heart rate also was abnormally high, hovering at just over 100 beats per minute.

Almost a year later, in February 2021, Skoog, who was vaccinated and had, at the time, one booster, noticed shaking in his left hand. Thereafter, he tested positive for COVID-19 again, and the shaking increased and eventually affected his whole left side. “I couldn't even walk right,” he says.

After visiting his doctor, Skoog was diagnosed with long COVID and prescribed beta-blockers to bring down his heart rate. He continues to work as an audio and video system designer for performing arts centers, a job that requires extensive travel. While he still loves what he does, every trip leaves him exhausted.

Long COVID has affected millions of people like Prettyman and Skoog across the United States. At least one in 13 American adults (7.5 percent) who have had COVID-19 exhibit long COVID symptoms, according to a survey by the U.S. Centers for Disease Control and Prevention. A study published in Neurotherapeutics in September 2022 by Igor J. Koralnik, MD, FAAN, estimates that as many as one-third of patients may experience persistent neurologic symptoms as part of a postacute sequelae of SARS-CoV-2 infection syndrome, also known as long COVID.

In addition to lingering symptoms of the virus, the most common neurologic manifestations include depression and anxiety, cognitive impairment, memory problems, a general feeling of brain fog, and dysautonomia, a disorder of the autonomic nervous system, which can cause a drop in blood pressure upon standing and a rapid pulse, among other symptoms. Even more troubling, new data suggest that long COVID may increase the risk of neurologic disorders, ranging from stroke and Alzheimer's disease to Parkinson's disease, according to a study by Ziyad Al-Aly, MD, director of the Clinical Epidemiology Center at Washington University in St. Louis, published in Nature Medicine in September.

As researchers learn more about how the virus affects people's lives months or even years after infection, they now recognize that these long-term effects can be persistent, widespread, and likely to clog the American health care system for years.

Since the coronavirus was first documented, studies have described how it replicates, its symptoms, the treatments available, and its long-term effects. So when Dr. Al-Aly analyzed data of more than 150,000 military veterans who contracted the virus to see how they had fared in the ensuing 12 months, the results didn't surprise him.

“Seeing these different neurologic outcomes—seizures, headaches, strokes, and transient ischemic attacks—is remarkable,” he says, “but I can't say it's jarring anymore.”

For his study, Dr. Al-Aly compared two control groups—one of veterans who hadn't tested positive for COVID-19 and another of veterans whose medical records predated the pandemic—to a group of veterans who had tested positive for the virus. He found that for every 1,000 people infected with COVID-19, more than 70 went on to develop some form of neurologic condition over the next 12 months. In total, Dr. Al-Aly identified 44 problems, the most common of which were memory difficulties, hearing abnormalities such as tinnitus, and depression. He also reported slight but statistically significant increases in new diagnoses of Alzheimer's and Parkinson's among patients who had been infected with COVID-19.

The study has several limitations—the population was mostly white and male, and less than 1 percent of people in the COVID-19 and contemporary control groups had received the SARS-CoV-2 vaccine—but it highlights the concerns about neurologic symptoms among patients with long COVID, says Sarah Song, MD, MPH, FAAN, associate professor of neurology at Rush University in Chicago.

Possible Causes

While Dr. Al-Aly's study indicates that the damage done by long COVID is greater than previously known, it's still not fully understood why people develop symptoms. Michelle Monje, MD, PhD, professor of neurology at Stanford Medical School in California, believes her research on the effects of chemotherapy on cognition and memory may provide a clue about brain fog. She has studied people with cancer and observed that after chemotherapy some patients exhibit inflammation in the brain, which disrupts communication among neurons. The same thing could be happening in the brains of people with long COVID.

In a 2022 paper published in Cell, Dr. Monje and her team introduced SARS-CoV-2 to mice and examined their brains after they were clear of the virus. They found an elevated level of a specific protein known as CCL11, which has been linked to cognitive impairment (it plays a role in blocking the formation of new neurons in the brain), as well as inflammation that disrupts some neural functions. The researchers then tested people with long COVID and found that they too showed higher than normal levels of CCL11.

To verify their findings, the researchers administered the protein to healthy mice and observed signs of inflammation in their brains as well. At this time, these results suggest an association. A cause and effect has not been proven yet, says Dr. Monje.

As for why a COVID-19 infection could trigger brain fog, Dr. Monje discussed various theories in a 2022 paper in Neuron. The virus could affect the nervous system, it could reactivate viruses already in the body such as Epstein-Barr, or it could trigger a disruption of blood flow in the brain.

The causes could be intertwined, suggests Avindra Nath, MD, FAAN, clinical director and chief of the section of infections of the nervous system at the National Institute of Neurological Disorders and Stroke in Bethesda, MD. Since early in the pandemic, studies, including one published in June 2020 in the Journal of Alzheimer's Disease, have reported that some patients with COVID-19 develop blood clots in their brains and other organs. Researchers still don't understand how these clots and other biological effects of the virus are triggered and interact to cause long COVID.

“Whatever the cause, brain fog should be addressed,” says Dr. Monje. “I wouldn't assume it's going to go away without intervention, because we don't see that happening after cancer therapies in most cases.”

Her lab is working with others to develop therapies for “chemo brain” that might also help people with long COVID. For now, Dr. Monje recommends that patients exercise, reduce screen time, get adequate sleep, and write down things they want to remember.

Confounding Care

As researchers continue to explore why long COVID develops, doctors focus on how best to treat people with such wide-ranging symptoms. Post-COVID clinics, which bring together medical specialists from a variety of fields (including cardiologists, pulmonologists, neurologists, and psychiatrists) to help manage the various ailments affecting patients, have popped up around the country, but they are ill-equipped to handle the volume of patients. In some cases, clinic waiting lists may be as long as a year, Dr. Al-Aly says.

Survivor Corps, a grassroots group that provides education and resources for people with long COVID, has compiled a map of the clinics in the United States. By its count, 237 such facilities exist, but the number constantly changes, says Kathryn Burke, a project associate in the organization. Some clinics have closed because they provided inadequate care or lacked funding. States such as New York, New Jersey, and California have more than 20 centers, while Kansas and South Dakota don't have any.

Another worrying trend is that the people with long COVID most likely to experience memory and cognitive disorders are young adults, according to Dr. Al-Aly's study. In comparing young people (those in their thirties and forties) who had COVID-19 with a control group of people who did not have COVID-19, Dr. Al-Aly found that while people almost no one in the control group had memory problems, many in the COVID-19 group did.

Several clinical studies are underway both in the United States and internationally, but to date no medications have been approved to treat long COVID. A new formulation of dextroamphetamine (a stimulant used to treat attention deficit hyperactivity disorder) designed specifically to treat COVID-19-related brain fog was granted a patent, but no reports of clinical trials to evaluate its effectiveness have been published. Researchers are evaluating several other drugs and nonpharmacological treatments, but the results could be months—or even years—away.

That no clinical definition of the condition exists further complicates progress. “All these mysterious diseases—long COVID, chronic fatigue syndrome, post-Lyme syndrome—look similar, and there is no definitive way to diagnose them. Patients report symptoms; doctors examine them and don't find anything. They send off a bunch of tests, which all come back normal. So it's a huge mystery,” Dr. Al-Aly says. “But just because we don't have diagnostic tests today doesn't mean we won't have any tomorrow.”

Diagnostic tests also may help determine whether some of the symptoms of long COVID can be classified as a functional neurologic disorder, a condition in which the brain cannot properly send and receive signals and a disconnect occurs between the function of the lobes and emotional processing, according to the National Institute of Neurological Disorders and Stroke.

Possible Treatments

Because the mechanism behind long COVID remains a mystery, treating the condition typically involves trial and error, says Fernando Carnavali, MD, an infectious disease specialist and coordinator for Mount Sinai's Center for Post-COVID Care in New York City. Dr. Carnavali helps his patients tackle one symptom at a time. For brain fog, he encourages patients to identify triggers, such as stress or changes in sleep patterns, and try to avoid or modify them. For symptoms that could involve medication, he discusses the risks and benefits of using drugs to treat a condition that still isn't fully understood.

“Patients need to know that we're using medication on a trial basis and want to be mindful not to cause any harm,” he says.

Prettyman doesn't know if she'll ever be able to go back to her job.

“Unfortunately, my job entails quite a bit of brainpower,” she says. “Since having COVID-19, I can't always remember things from one minute to the next.”

Casting about for a new focus, Prettyman joined a long COVID online community and dedicates her time to finding ways to make their voices heard.

“I felt very much alone in the beginning,” she says. “When I found this network, it was empowering. It was like, ‘Here we are, and we're not going away.’ I'm going to move ahead even if I have to stand still sometimes or sit down for a minute.”

Online long COVID communities are not the only groups speaking up. The American Academy of Neurology (AAN) recently supported several bills that focus on research and education and collecting data on long COVID, including the COVID-19 Long Haulers Act, the CARE for Long COVID Act, the TREAT Long COVID Act, and the Brycen Gray and Ben Price COVID–19 Cognitive Research Act. The AAN encourages its members and the public to write to their representatives in Congress and urge them to pass long COVID–related legislation.

The Academy is also monitoring the implementation of an action plan developed by the federal government to prevent, diagnose, treat, and provide services and interventions for people with long COVID and associated conditions. To make your voice heard on this topic, share your story with Brain & Life.