Article In Brief
Three years into the COVID-19 pandemic, neurologists say an appreciation for the effects infectious diseases can have on the brain and peripheral nervous system is growing. But more training programs and a better infrastructure for addressing emerging diseases that have neurologic complications are sorely needed.
When Anthony Fauci, MD, retired last month after 38 years of breakthroughs and innovations at the helm of the National Institute of Allergy and Infectious Diseases (NIAID), he left the field with this message: “The devastation that COVID-19 has inflicted globally...highlights the world's overall lack of public health preparedness for an outbreak of this magnitude....,” he wrote in an editorial in the New England Journal of Medicine. “There is no reason to believe that the threat of emerging infections will diminish, since their underlying causes are present and most likely increasing.”
As neurologists struggle to understand and treat the primarily neurologic symptoms of post-acute sequelae of COVID-19 (PASC), Dr. Fauci's message resonates strongly, they told Neurology Today. The next neuroinfectious pandemic could be right around the corner, and they are not nearly as prepared as they ought to be.
Allison Navis, MD, assistant professor in the division of neuroinfectious disease at the Icahn School of Medicine, said the question is not if, but when, another pandemic will emerge that causes severe neurologic morbidity. Yet, she said, “There are very few neuroinfectious disease programs, and few rehabilitation programs. Pre-pandemic, nobody knew what I did. It's a little better now, but we still don't have a neuroinfectious disease society. There is so much more work to do.”
Part of the problem might be, experts said, that the subspecialty is not as clearly defined. “Neuroinfectious disease has not been taken as seriously as it deserves,” said Avindra Nath, MD, FAAN, senior investigator in the section of infections of the nervous system at the National Institute of Neurological Disorders and Stroke (NINDS). “It doesn't fall clearly in neurology; it doesn't fall directly in infectious disease. It falls through the cracks.”
Three years into the COVID-19 pandemic, however, an appreciation for the effects of infectious diseases on the brain and peripheral nervous system is growing, said Walter Koroshetz, MD, FAAN, director of NINDS.
“The most obvious improvement is that for years people doubted that there was any such thing as a post-infectious neurological condition,” he said. “That fact is now pretty much accepted. I don't think anyone questions that today.”
NINDS is now gearing up to run clinical trials, he said, to test therapies for people who have persistent cognitive or other neurologic effects of COVID-19. Pathological studies are likewise underway to investigate the mechanisms behind PASC, he said.
“We don't have all the answers,” Dr. Koroshetz said. “But we definitely are learning more about the neurological effects of COVID-19 and other viruses.”
Keith Van Haren, MD, an assistant professor of neurology and pediatrics at Stanford University, said he sees a growing appreciation for the importance of neuroinfectious diseases among younger physicians.
“I do see a growing interest among the younger generation of trainees,” Dr. Van Haren said. “But I agree with Dr. Nath that it feels like the clinical and scientific community are still feeling our way around the edges of something that is much larger than we had appreciated.”
Long Time in Coming
The pandemic exposed some systemic shortcomings. Months into the COVID-19 pandemic, Dr. Nath said, he was unable to find a facility equipped to safely perform brain autopsies. Likewise, nowhere on the NIH campus was there a biosafety level 3 laboratory prepared to safely process samples or conduct research with live virus.
“The one we had was being used for storage,” Dr. Nath said. “It took them almost nine months before they could get it up and running again.”
As a result, he said, for months it was impossible to obtain brain samples to determine if the SARS-CoV-2 virus was present there.
“Nobody would do the autopsies,” he said. “They were afraid of the dust that would go into the air from sawing the skull. You need a negative-pressure room, a vacuum saw, PPE [personal protective equipment], and stainless steel-mesh gloves so you don't cut your fingers. Nobody was set up for it. Now finally a number of places have everything they need.”
COVID-19 is hardly the first virus whose impact on the nervous system scientists initially failed to appreciate.
“When the AIDS pandemic started, patients were getting demented, but people said it was just because they were so sick,” Dr. Nath said. “It took many years to convince people that actually HIV does go into the brain and affects the brain. The same thing happened when Ebola came around. Everybody was focused on the diarrhea. When I went to Liberia, I found that nearly 50 percent of survivors had meningoencephalitis.”
Likewise, when the COVID-19 pandemic began, “everyone focused on its effects on the lungs,” Dr. Nath said. “It took a long while before the effects on the brain were understood. Every time, the focus is on the primary symptoms, not what's happening in the brain.”
Although slow in starting, research into the neurologic effects of COVID-19 received a large boost in September 2021 when NIH awarded nearly $470 million in funding to build a national study of PASC. The NIH REsearch COVID to Enhance Recovery (RECOVER) initiative, will involve over 100 researchers at 30 universities. The goal is to determine why some people develop PASC and its most common symptoms, most of which are neurologic: pain, headache, fatigue, brain fog, anxiety, depression, and sleep problems.
“I don't think we have any good idea what causes it,” said Dr. Navis, who spent over a year working as the primary neurologist in Mount Sinai Health System's COVID-19 clinic. “I firmly believe there are a lot of things that cause it. It's not the same for any two people. And we don't really have effective treatment options.”
Other research programs, however, are beginning to pay off. Dr. Koroshetz pointed to the UK Biobanks study, published earlier last year in Nature, which described brain-volume changes after COVID-19. That study identified post-infection shrinkages compared to controls in global brain size and reduction of grey matter thickness in regions connected to the primary olfactory cortex.
“What we don't know,” Dr. Koroshetz said, “is whether all these changes are simply due to loss of smell, because pre-pandemic, cross-sectional MRI studies showed similar changes due to decreased neural input in people who lost their sense of smell due to trauma or infection.”
Another study, published in March 2021 in the Journal of Experimental Medicine, used both human tissue and a mouse model to demonstrate that the SARS-CoV-2 virus can infect the brain. But, Dr. Koroshetz said, “The role of active infection in the brain itself remains controversial.” Even now, however, the definition of what constitutes long COVID is relatively fuzzy, Dr. Nath said.
“The problem is that long COVID is a term coined by patients, not by physicians,” he said. “It's a mixed bag of clinical phenotypes, not a single disease. There are people with sleep disorders, psychiatric manifestations, brain fog, all kinds of things.”
Topping Dr. Navis's wish list for strengthening the study and treatment of neuro-infectious diseases is the expansion of research opportunities.
“Research is the number one thing we need, in infectious diseases in general and neuroinfectious diseases in particular,” Dr. Navis said. “We don't have enough good treatments, or enough specialists.”
Neuro-rehabilitation programs are also too scarce, she said. “Even here in New York City, there is a huge wait list to get into any outpatient clinic, I can't imagine what it's like in places around the country where there is less health care available generally.”
Dr. Nath said he believes that every state in the country should have at least one autopsy facility capable of safely accessing the brain in order to respond to neuroinfectious disease outbreaks.
“The whole way of how we do autopsies needs to be thought through entirely differently,” he said. “Let's say there's an outbreak in North Dakota. They should be in the position to do a high-risk autopsy. Setting up the infrastructure is going to cost a fair amount of money. But once you have it iin place, it can be used or lots of things. It should become routine practice.”
More antiviral medications also are necessary to better respond to neuroinfectious diseases, Dr. Koroshetz said.
“The trouble is the infections happen so fast,” he said. “It's almost like an acute stroke. It would be amazing if we had better antivirals. Unfortunately, not much research is going on in that area. NIAID gravitates much more toward making vaccines.”
Although some of the major drug companies are working on antiviral medications, it's rare for them to test whether the drugs cross the blood-brain barrier (BBB), Dr. Nath said.
“From a neurological standpoint, it's very important for us to know that an antiviral drug can cross the BBB,” he said. “Right now they can get approval from the FDA for treating systemic infections. It's not a requirement that they test for crossing the BBB.”
Despite the challenges, Dr. Nath is engaged in a number of studies into the neurologic effects of COVID-19.
“We've been screening people who have cognitive deficits following an infection,” he said. “We bring them to NIH to do MRIs, spinal taps and cognitive batteries and to take blood and other bodily fluids. We're looking for immune abnormalities and any evidence of viral products, proteins or RNA.”
Dr. Nath is leading a randomized trial comparing intravenous immunoglobulin with placebo in people with immune abnormalities and cognitive deficits associated with PASC.
“We're gearing up to do clinical trials, to have master protocols to test therapies for people who have cognitive problems or exercise intolerance,” Dr. Koroshetz said. “There's a lot going on in that space right now. We also welcome applications from people outside NIH. Anybody who has good ideas about how to get to the bottom of this, we're very interested.”
Perhaps the main lesson of COVID-19 for neurologists and other physicians can be summed up by how Dr. Fauci concluded his essay in the New England Journal of Medicine: “It is now clear that emerging infectious diseases are truly a perpetual challenge,” he wrote.
“As one of my favorite pundits, Yogi Berra, once said, ‘It ain't over till it's over.’ Clearly, we can now extend that axiom: when it comes to emerging infectious diseases, it's never over.”