In his compact office at Northwestern Medicine’s Searle Medical Research Building in Streeterville, Igor Koralnik leans into one of two computer screens perched atop his uncluttered desk. The neurologist’s team of doctors, researchers, and medical students has assembled for a video meeting to reveal their latest findings about patients with long-term effects from COVID-19. Koralnik, now 60, softly yet insistently directs a question at a young doctor presenting fresh data.

“What jumps to your mind?” he asks. “What is something that we’ve never, ever thought about?”

Senior neuroimmunology fellow Gina Perez-Giraldo says she’s surprised the rates of depression and anxiety are higher for long-COVID patients who weren’t hospitalized than for those who were — 16 percent compared with 9 percent. It’s counterintuitive because you’d think milder cases would lead to fewer ongoing complications.

But that’s not the case. Lingering post-COVID headaches, for instance, are also more common among patients who have not been hospitalized. Same for the loss of smell and taste. Brain fog, an umbrella term covering various neurocognitive symptoms, is present at similar levels among the hospitalized and nonhospitalized, but the causes may differ. For the former, “we think it’s mostly caused by brain damage during hospitalization,” Koralnik tells me, citing the trauma of being on a ventilator. For the latter, it more likely stems from the virus lingering in the body or the autoimmune system’s reaction to it.

These are just some of the perplexing findings about a condition that has confounded medical experts from the start. The Centers for Disease Control and Prevention defines long COVID, also known as “post-COVID conditions,” as symptoms that appear, persist, or return at least four weeks after the initial infection. But more than two years into the pandemic, many aspects of this syndrome — notably its causes and remedies — remain a mystery.

The Swiss-born Koralnik, who is Northwestern’s chief of neuroinfectious disease and global neurology, is at the forefront of the quest to better understand long COVID’s effects on the brain. After making his name studying various neurological disorders, including those associated with HIV, he arrived at Northwestern on the eve of the pandemic. Since then, he has become one of the world’s leading experts, opening a clinic to treat neurologically affected long-COVID patients and publishing numerous papers to boost our understanding of this condition and its ominous implications for all of us.

The upshot: There may be no correlation between the severity of your COVID case and the lasting effect on your brain. You thought COVID felt like having a cold? Great, but you still may not know what the virus has done, or is doing, to your body. “Acute COVID-19 is a respiratory disease,” Koralnik says. “But long COVID is mostly about the brain.”

And plenty of people are developing it. Long COVID is now the country’s third leading neurological disorder, the American Academy of Neurology declared in July. As of the end of May, there were 82.5 million COVID survivors in the United States, and 30 percent of them — about 24.8 million — were considered “long-haulers.” A recent study of Northwestern’s Neuro COVID-19 Clinic patients showed that most neurological symptoms persist for an average of nearly 15 months after the disease’s onset.

The vaccines are certainly helping. Before they became available, about one-third of everyone infected with the virus came down with long COVID, Koralnik says. “There is brand-new data showing that if you’ve been double vaccinated and boosted, then the risk of developing long COVID, if you get COVID, is probably more like 16, 17 percent.” That’s the good news. The bad news is those 1-in-6 odds still translate to a lot of people: For every million vaccinated people who get COVID, 160,000 to 170,000 will develop long COVID.

“A lot of people think, Well, COVID is going away. But in fact, it’s not,” Koralnik says. “People still get COVID after the vaccination and double booster, and they can still get long COVID despite that.”

So Koralnik and his neuro-COVID research team are taking an all-hands-on-deck approach to cracking the long-COVID code and developing treatments to alleviate the often incapacitating neurological symptoms. And they’re also scrambling to persuade others to care — including, crucially, those with the power to finance their research.

Koralnik finds it infuriating that critical funding has been slow in coming. “Where is the sense of urgency?” he asks. “If this is not enough to create urgency, what is?”

In January 2020, Jenny Nowatzke, Northwestern Medicine’s national media relations manager, introduced herself to Koralnik and asked whether he could talk on a local TV news program about a new virus from China.

“I don’t know much about it,” he responded. “It’s a respiratory disease. I’m a neurologist.”

But Koralnik, who had been at Northwestern for only two months, agreed to go on camera with the caveat that he’d need a tie. Nowatzke borrowed one from someone down the hall.

Koralnik had spent the previous three years as the neurology department chair at Rush University Medical Center. For the 21 years before that, he was at Harvard Medical School, where he rose to chief of the neuroimmunology division at Beth Israel Deaconess Medical Center, making his reputation with his work on HIV.

Koralnik attended medical school in Geneva in the mid-1980s, at the onset of the HIV/AIDS epidemic. He studied neurology because, as Koralnik puts it, “I’m interested in how the brain works.” HIV was not initially thought to be a neurological disease, but over time young patients started experiencing such symptoms as dementia and spinal cord issues, suggesting to Koralnik “a new area” of study. “Neurologists are not necessarily drawn to infectious diseases, and infectious disease physicians don’t practice neurology,” he says. “So I decided to specialize in the neurologic manifestation of HIV and, by extension, of infectious diseases.”

At Beth Israel, he founded and directed the HIV/Neurology Center, a clinic focused on treating the often overlooked neurological symptoms of HIV. “He made a name for himself in recognition that HIV had neurological implications to it and advocating for those patients,” says Eric Liotta, an associate professor of neurology at Northwestern and a neurocritical care specialist on Koralnik’s research team. “He is, in a little way, repeating history now with COVID.”

Koralnik also became known for studying progressive multifocal leukoencephalopathy, or PML, a rare and deadly neurological disorder. Affecting 5 percent of HIV patients, he says, PML is caused by the JC virus, which is harmless in most people but can be fatal to those with weakened immune systems. “I became specifically interested in PML because it is a disease for which there is no known cure,” Koralnik says. By studying how the virus grows in the brain and how the immune system fights it, he was able to develop new therapies. Omar Siddiqi, an assistant neurology professor at Harvard Medical School, says Koralnik’s seminal work on PML once led a prominent neurologist to refer to it as “Koralnik’s disease.”

While at Beth Israel, Koralnik mentored Siddiqi, a neurology resident who wanted to deliver neurological care to underserved populations in Africa. Siddiqi and Koralnik collaborated on what would become a neuroscience center in Zambia, a country that had lacked neurologists and experience in treating HIV and nervous system disorders. Siddiqi, who moved to Zambia in 2010, says Koralnik not only supported the research but also helped him navigate the National Institutes of Health funding system and directed grant money to him. “He provided me with a major portion of my salary support for two to three years,” says Siddiqi, who had a young family at the time. “I can’t thank him enough for that.” The Zambian program, directed by Johns Hopkins Medicine neurologist Deanna Saylor, now includes an inpatient treatment center and a teaching hospital that trains neurologists.

Koralnik is currently helping to create neuro-COVID programs in Nigeria and Colombia; Perez-Giraldo, a Colombia native, is taking the lead on the latter. By collecting data from different spots around the globe, she says, their hope is to gain a broader understanding of long COVID.

Koralnik views that search for answers — as well as the mentoring of the next generation of practitioners — as critical to his mission at a university hospital. “He’s definitely a calm and collected individual, but he’s extremely motivated to answer questions that he thinks are important and to ensure that his patients are being taken care of,” says Jeffrey Robert Clark, a fourth-year medical student on his research team.

Clark initially sought out Koralnik based on the neurologist’s work on the JC virus. This was in early 2020, around the time Nowatzke was asking the doctor to appear on live TV to discuss that new infectious disease from China. Little did Koralnik know that this virus would soon dominate his professional life — and the lives of every single person watching that night.

By April 2020, the world had changed. Obscure no more, COVID had exploded across the United States, leading to exponential increases in hospitalizations and deaths. While the disease was known to attack the lungs, Koralnik suspected greater implications, and that month he formed his neuro-COVID research team, including Liotta and Clark.

They ran an analysis of the first 509 COVID patients treated at Northwestern Memorial Hospital and, in a paper published later that year, reported that 42 percent of them experienced neurological symptoms upon contracting COVID, 63 percent upon being hospitalized, and 82 percent over the entire course of the disease.

In May 2020, Koralnik and his team opened the Neuro COVID-19 Clinic at Northwestern Memorial Hospital. One of the first of its kind in the nation, it not only treats patients but also collects data on demographics, quality of life, and cognitive test results. “We thought that we were going to see mostly patients who were hospitalized, who survived and now needed some ongoing care for neurology as an outpatient,” Koralnik says. “But what we saw is the opposite. The main population of the clinic is the people who were never hospitalized with COVID, who had only a mild sore throat, a cough that went away, or a bit of fever — and then [experienced] the lingering, persistent, and then debilitating brain fog, headaches, dizziness, muscle pain, trouble with smell and taste, blurry vision, tinnitus, and intense fatigue.”

Other research has backed that up. “Turns out people with the mild cold-like symptoms are the people with the neurological manifestations,” says Avindra Nath, clinical director of the NIH’s National Institute of Neurological Disorders and Stroke.

Those symptoms corresponded with patients’ self-reporting of a lower quality of life and issues regarding cognition, anxiety, depression, and sleep. The patients also performed worse than expected on tests of processing speed, attention, executive function, and memory.

The consequences can be profound. “Cognition may be affected in a way that you can’t multitask the way you were multitasking before,” Koralnik says. “You can’t be, you know, a reporter because you can’t figure out all the different deadlines that you have. You can’t be a police officer or a nurse or a businessperson. So that affects people in their ability to keep their current job.” The Brookings Institution reported in August that between two million and four million Americans aren’t working because of the effects of long COVID. Says Nath: “Once you damage the brain, the societal consequences are enormous.”

Northwestern Medicine expanded its efforts to treat COVID patients in January 2021 by opening the Comprehensive COVID-19 Center, which covers 12 subspecialties, including clinics for pulmonology, cardiology, dermatology, endocrinology, ENT, gastroenterology, hematology, infectious diseases, and nephrology. Koralnik says the Neuro COVID-19 Clinic has the most patients “by far.”

Koralnik and his team have authored a dozen COVID-related papers, with three more on the way, and their work has drawn much attention in the medical world and beyond. Koralnik uses Altmetric, a data tracking tool, to monitor the many mentions of their research across social and traditional media. “It’s important in the sense that people learn about what you’re doing, and so they learn about what long COVID is doing to the brain,” he says. A paper he wrote with Liotta and Northwestern neurologist Edith Graham published in July by the journal Neurotherapeutics states that given the large number of individuals experiencing a diminished quality of life and productivity, the neurological manifestations of long COVID are “likely to have major and long-lasting personal, public health, and economic consequences.” It notes the “critical need” for a greater understanding of how the disease works and the development of therapies to treat these serious, persistent symptoms.

That “critical need” is the backdrop for Koralnik’s current frustration. He was able to land ample financial support to study and treat the neurological effects of HIV. Same with PML, a rare brain disease affecting “only a handful of people in the world,” he says. Citing his 25-year track record of obtaining funding, he makes a point of saying: “I love NIH. I think it’s the greatest institution that supports research in the world.” That said, he is dismayed that the government agency overseeing public health has been much less responsive to the neurological issues associated with long COVID, a disease afflicting close to 25 million Americans. “Now I’m studying the most frequent disease in the world, which is COVID, and the third most frequent disease in the U.S. today, which is long COVID, and I have to spend even more time to convince people that, one, it’s real; two, it should be studied; and, three, it should be funded by NIH,” he says.

So where is the federal government’s long COVID research funding going? In late 2020, Congress granted the NIH $1.15 billion, which the agency has committed to an initiative called RECOVER, a four-year data-collecting study seeking to assess COVID’s long-term effects. As of presstime, RECOVER reported it had enrolled 7,758 adults of an intended 17,680. A June 2022 Science magazine article noted that the study “has come under fire from patient advocates and some scientists who say it lacks transparency and is moving far too slowly — a ponderous battleship when a fleet of hydroplanes are what’s needed.”

Koralnik complains that no government money has been earmarked specifically for research into long COVID’s significant neurological manifestations, and that the NIH hasn’t assigned a neurologist to review such grant applications. “Therefore, it’s been very difficult, if not impossible, to get funded for the research for neuro-COVID,” he says.

His Northwestern team partnered with a large consortium of research teams in the United States, Latin America, and Europe to apply for a grant, but Koralnik says their application wasn’t selected. His team has submitted eight COVID-related grant applications to the NIH so far, and the only success has been a one-year supplement to an existing grant to a neurologist examining the impact of sleep on cognition in older adults. As part of that study, Koralnik will focus on the impact of sleep on cognition in older adults with COVID.

Meanwhile, more than 1,450 patients have come through Northwestern’s Neuro COVID-19 Clinic, many “affected by terrible brain fog or headaches or fatigue despite the fact that they were vaccinated and boosted,” Koralnik says. Desperate for a cure, they ask him whether they can participate in a clinical trial or whether he has identified a cause for their symptoms. Which is what he is working to do. “This is the most important health crisis in our lifetime, hopefully, and the fact that there hasn’t been a more comprehensive response outside of the RECOVER initiative is really mind-boggling,” he says.

A request to interview RECOVER cochair Walter Koroshetz, the director of NIH’s National Institute of Neurological Disorders and Stroke, about Koralnik’s work was met with a response that he was unavailable. But the NIH’s Nath agrees with Koralnik about the need to study long COVID. “Chronic fatigue syndrome, Gulf War syndrome, post-Lyme syndrome, sick building syndrome — nobody knows what causes them, but if you look at them, they’re very similar complaints,” Nath says. “If you study long COVID and figure this one out, maybe we can benefit these other ones at the same time.”

For Koralnik, “it’s been a difficult and frustrating journey,” he says, but he isn’t pessimistic. “You need to have a certain amount of optimism that at the end of the day, the greater good will prevail.”

So he’s placing his bets, once again, on science, research, and the power of the brain. They’ve worked for him so far.