Article In Brief
About 30 percent of coronavirus survivors in the US experience long COVID, and several leading health systems have established COVID-19 neurology specialty clinics to help patients address neurologic side effects of the condition.
It’s unusual for a new neurologic subspecialty to emerge, but that is what happened over the past 30 months as post-acute sequelae of COVID-19 (PASC) was recognized as a major neurologic disorder.
Also commonly called “long COVID,” PASC manifests in a variety of multisystemic symptoms, but it predominantly affects the nervous system, with symptoms including brain fog, headache, numbness and tingling, dysgeusia, anosmia, myalgia, and dizziness.
With over 82.5 million COVID survivors in the United States as of mid-2022, and an estimated 30 percent of survivors (or 24.75 million) experiencing long COVID, AAN President Orly Avitzur, MD, MBA, FAAN, noted in her July President’s column that PASC already is the third leading neurologic disorder in the United States, second only to tension-type headache and migraine.
Early in the course of the pandemic, as COVID-19 emerged not solely as a respiratory illness but also a condition with multiple neurologic complications, neurologists at several leading health systems established COVID-19 neurology specialty clinics for both acutely infected patients and those with PASC.
Rutgers’ Comprehensive COVID-19 Neurology Clinic
One of the first of these clinics was the Comprehensive COVID-19 Neurology Care Center of Excellence of Rutgers New Jersey Medical School in Newark, NJ.
“I saw my first COVID-19 patient in March of 2020 and quickly realized that this is a complex, unpredictable, multisystem, and multi-organ disease with significant neurologic manifestations,” said clinic founder and director Nizar Souayah, MD, FAAN, professor of neurology. “By April or May, I had decided that we needed a clinic to take care of patients with neurologic sequelae and complications from COVID-19, and the clinic was officially established in September 2020, by which time we were taking care of patients with the neurologic symptoms of long COVID.”
The clinic works in collaboration with the departments of medicine, ENT, physical medicine and rehabilitation, and psychiatry plus Rutgers’ Pain Management Center.
“We have had more than 1,350 patients admitted to University Hospital during the pandemic, and most of the survivors developed neurological sequelae and/or long COVID,” Dr. Souayah said. “The most common symptoms they report are fatigue and brain fog, with other neurologic symptoms such as neuropathic and fibromyalgia-type pain and persistent loss of taste and smell also common. Data generated from COVID patients in this clinic, as well as from University Hospital and other clinics, are currently analyzed in collaboration with experts from multiple major academic centers to determine the prognosis of long COVID and [to] develop predictive models for the outcomes of these patients.”
Treatment is primarily symptom-based, Dr. Souayah said, and they “take each patient case by case.” “For many patients who have persistent headache, we have had good luck with topiramate,” he added. “For neuropathic pain, we avoid narcotics and instead prefer duloxetine and gabapentin. For patients with fatigue, we prescribe physical therapy and treatments such as acupuncture. And for our many patients with cognitive impairment, we prescribe a full evaluation and management by a neuropsychologist, including cognitive rehabilitation. We are honest with our patients that we are still learning and there is a lot that we still don’t know.”
The clinic sees patients every Tuesday, and no one is turned down for lack of ability to pay. “We are looking for grant funding to support adding a social worker,” Dr. Souayah said. “If a patient’s insurance will not pay or they don’t have insurance, my consultation is basically free.”
Northwestern’s Neuro COVID-19 Clinic
One of the largest COVID-19 neurology clinics is Northwestern Medicine’s Neuro COVID-19 Clinic, which opened in May 2020 and had evaluated 1,650 PASC patients as of November 2022.
“We formed our first neuro-COVID working group in April of 2020, with two neurocritical care attendings and three first-year medical students—Jeff Clark, Nathan Shlobin, and Steven Hoffman—who were looking for a summer project on neuro-infectious disease,” said the program’s director, neuroimmunologist Igor J. Koralnik, MD, FAAN, chief of neuro-infectious disease and global neurology in the Ken & Ruth Davee department of neurology and Archibald Church Professor of Neurology at Northwestern. “They got much more than they bargained for.”
Over the summer of 2020, the group analyzed data on the first 500 COVID-19 patients hospitalized at Northwestern and found that 82.3 percent had some neurologic manifestations. As the clinic has evolved to manage a larger population of patients with PASC, the group found that 85 percent of those patients were never hospitalized.
“The main population of our clinic are the people who were never hospitalized with COVID, who had only a mild sore throat or a cough that went away, but then had the lingering, persistent, and then debilitating brain fog, headaches, dizziness, muscle pain, trouble with smell and taste, blurry vision, tinnitus, and intense fatigue,” Dr. Koralnik said. “The surprising aspect is that the majority of these patients were previously healthy.”
The clinic sees approximately 60 to 70 patients a month. At one point, it had a waiting list of more than two years, but since adding new staff—including an advanced practice provider nurse and additional fellows—and recruiting other general neurologists to assist, wait times have been whittled down to a couple of months.
The cognitive impairment can be particularly debilitating for long COVID patients.
“Many patients who are highly functioning individuals, teachers, nurses, businesspeople, physicians, and so on test below average compared to the US population, especially in measures of attention and memory,” Dr. Koralnik said.
“These are people who are used to multitasking all the time, taking care of patients in the ER or a large workforce in industry, and now they have difficulties just doing their daily activities. About half of the population in our study missed at least 10 days of work, and a report from the US Government Accountability Office noted that 45 percent of long COVID patients had to reduce their work hours. This will have a persistent impact on the workforce.”
PASC symptoms persist in a somewhat unpredictable extended course. In a study published in Annals of Clinical and Translational Neurology in July 2022, Dr. Koralnik and his team reported that non-hospitalized COVID-19 “long haulers” continue to experience neurologic symptoms, fatigue, and compromised quality of life 14.8 months after initial infection. While patients reported some improvements in their recovery, cognitive function, and fatigue, overall quality of life measures remained lower than the general population.
“We were hoping that, with time, patients would improve more significantly,” Dr. Koralnik said. “We asked them about what percentage they feel recovered compared to their pre-COVID baseline and were originally hoping to see a steady trajectory of improvement. Unfortunately, that has not been the case. On average, people say [they feel] 30 to 50 percent [recovered]. Some people are still only 10 percent recovered after nine months, while others may be 90 percent recovered after two months. And it’s not a homogeneous trajectory. Some people have only transient smell and taste disruption but persistent dizziness and brain fog, while others never have brain fog or headache but have persistent disorders of smell and taste where everything tastes like metal and smells like rancid fish.”
Women appear to be significantly more likely to develop neurologic long COVID, with Dr. Koralnik noting that, “among non-hospitalized long-haulers who only had transient respiratory symptoms, the average age was 43, which is about 10 years younger than the average age of those hospitalized, and 70 percent of the group was female.”
An Autoimmune Connection
Approximately 16 percent of long COVID patients at Dr. Koralnik’s clinic have reported experiencing some other autoimmune condition prior to becoming infected with COVID-19, and he said other clinics across the US saw the same thing.
“This fits with our hypothesis that long COVID is not a persistent infection of the meninges or the brain by the virus but rather a post-infectious autoimmune phenomenon in which the virus has confused the immune system to think that there is something foreign in the brain that needs to be attacked,” Dr. Koralnik said.
That’s also a research focus for Michael Carrithers, MD, PhD, head of the division of neuroimmunology at the University of Illinois College of Medicine and the director of post-COVID clinics at University of Illinois Health’s outpatient practice and the Jesse Brown VA Medical Center. Smaller than the Northwestern and Rutgers clinics, with a total of about 60 neurologic PASC patients, his clinics serve a large population of people from underrepresented backgrounds who face significant barriers in access to care.
“As compared to other centers, we do a lot of community outreach for all past patients, particularly in the Black and Latino communities, and we have satellite clinics to bring patients in either for our studies or to get care in general,” he said.
As a multiple sclerosis (MS) specialist, Dr. Carrithers sees intersections between that disease and neurologic post-COVID symptoms.
“We are undertaking a pilot study in which we are doing deep clinical phenotyping, taking out all the signs and symptoms of a condition from the chart and studying those by network analysis, in this case comparing the MS patients and those with similar disorders to neuro-COVID patients,” he said.
“In addition, we have also been studying differential DNA methylation in MS patients, and we are beginning to do the same with long COVID patients. Our theory is that viral infections earlier in life, such as Epstein-Barr, may change DNA methylation patterns and make someone more susceptible to developing MS or severe complications of COVID.”
As part of the MS study, his group is also examining how different MS treatments impact DNA methylation. “Is it possible that one or more of the currently approved treatments for MS might be suitable for a trial in patients with neurological complications of COVID?” he asked.
“If in at least some of these patients their persistent symptoms result from an initiation of an underlying autoimmune reaction without any latent virus present, they might respond to some of the same treatments we use in MS, but that remains speculative at this point.”
The Future for Patients with Long COVID
Something else that remains speculative is the future for these patients. “Long COVID is its own very complicated entity,” Dr. Souayah said. “It’s hard to know what risk factors these individuals may have in the future. If someone experienced a stroke during the acute phase of COVID, for example, are they more likely to have another stroke in the next five to 10 years? Or is someone with cognitive impairment from COVID-19 at greater risk of another form of dementia?”
Recent research suggests that particular concern may be well founded. People 65 and older were nearly 70 percent more likely to be diagnosed with Alzheimer’s disease within a year of their infection, according to a large study published in the Journal of Alzheimer’s Disease in September 2022.
The retrospective study, led by Case Western Reserve University researchers, involved analysis of the medical records of some 6.2 million adults aged 65 and older who had medical visits but no previous diagnosis of Alzheimer’s disease from February 2020 to May 2021. They found that the risk of being diagnosed with Alzheimer’s disease was particularly high for those 85 and older; it nearly doubled in the year after they had COVID, and women had an 82 percent increased risk compared with a 50 percent increased risk for men.
“The factors that play into the development of Alzheimer’s disease have been poorly understood, but two pieces considered important are prior infections, especially viral infections, and inflammation,” study coauthor Pamela Davis, MD, PhD, said in a release accompanying the study.
“Long COVID is going to color everything else going forward,” Dr. Koralnik said. “If you’re 20 years old, previously healthy, and you have brain fog, we don’t know what’s going to happen to you in 40 to 50 years. Will you develop Alzheimer’s disease 20 years earlier than you otherwise would have? We don’t know.”
As there are only a relatively small number of COVID-19 neurology specialty clinics, mostly concentrated in academic research centers, most people with neurologic manifestations of long COVID will be seen by general neurologists, if at all.
“A lot of patients, unless they have severe deficits, may just give up trying to seek medical care. That’s what has happened in the past with conditions such as chronic fatigue,” Dr. Carrithers said. “Nonetheless, there’s the potential for neurologists in general practice to become overwhelmed by this growing new patient group. For example, community behavioral psychologists and neuropsychologists are pretty overwhelmed at this point, so it’s difficult for people to get the cognitive rehabilitation they need.”
The two most important messages a neurologist can give these patients is to validate their concerns and reassure them. They should be told that they are not imagining things.
“Long COVID diagnoses are a heterogeneous group, but this is a well-described entity,” Dr. Carrithers said. “Second, reassure them that even though things are moving slowly, there are potential treatments on the way as trials move forward, and in the meantime, we can do things to help them with some of their medical symptoms. A lot of people figure it’s just their new normal and they have to live with it.”
Dr. Koralnik agreed, pointing out that “one of the overarching sentiments, especially in non-hospitalized patients, is that people don’t take them seriously.”
“They are young, their neurologic exam is usually normal except for cognition, and their MRI is usually normal,” he said. “They’re often told, ‘It’s all in your head; just do relaxation and meditation, and it will all go away.’ Many times, we’ve heard that we are the first people who have agreed to see them.”