Article In Brief
COVID-19 has forced many clinical and basic trials to shut down, compromising data collection and years of data from animal models that cannot be maintained. The impact will be felt long after the crisis of the pandemic eases, neurology researchers told Neurology Today.
First the good news: Neurologists who are unable to get into their laboratories and clinics due to COVID-19, and who are not being redeployed to serve in emergency departments, have more time to write up their results for publication.
“It may end up being a very productive period of time for one aspect of research, which is reporting data,” said Serena Spudich, MD, MA, the Gilbert H. Glaser professor of neurology, chief of neurological infections & global neurology, and director of the Center for Neuroepidemiology and Clinical Neurological Research at Yale School of Medicine.
“In normal times, people do studies and present them at a conference, but then it can take a year or so to get the work actually published and available to the field,” Dr. Spudich said. “Instead, for some people who are not working on the front lines in COVID-19-related clinical or research work, writing and submitting manuscripts is taking more like weeks. That's a positive.”
Now the bad news: Aside from having more time to analyze and write up results, academic neurologists are facing a myriad of difficulties, some of which could prove to be far more than temporary inconveniences.
“It's having a major impact on both basic and clinical research,” said Erik S. Musiek, MD, PhD, associate professor of neurology at Washington University in St. Louis. “In the clinical research world there's going to be a lot of problems. There will be at least several months where the protocol wasn't followed. There will be data abnormalities that have to be dealt with.”
For ongoing drug trials at the university's Knight Alzheimer Disease Research Center (ADRC), in-person visits for infusions have been temporarily suspended, Dr. Musiek said. “There's been a tightening of safety regulations aimed at keeping participants home. In some cases, attempts are being made to do infusions at home; in others, the studies are allowing a drug hiatus. And many investigational drug trials outside of the Alzheimer's center have also been suspended.”
Getting medications to trial participants requires innovative approaches when hospitals are off-limits for all but the most critically ill, said Dr. Spudich, who is leading a study aimed at treating the cognitive deficits associated with HIV.
“We were not actively enrolling due to the mandate, but we had a patient come in with COVID and CSF pleiocytosis. We were able to enroll that patient. But that's the only research I've had for three weeks, besides retrospective chart reviews.”—DR. KEVIN MESSACAR
“For each individual person, we contact them and figure out how to get them their medications,” she said. “For some, we use the mail or a courier who goes to their home. And for those who don't have an address, we prepare a package for them at the study site so they can come pick it up.”
The longer the COVID-19 delays continue, the greater the damage to the validity of natural history studies and clinical trials, said David K. Simon, MD, PhD, professor of neurology at Harvard Medical School and director of its Parkinson's Disease and Movement Disorders Center.
“We're part of a Parkinson's Foundation registry,” Dr. Simon said. “The study is shut down. There are over 10,000 patients in it. There will be missing data. It doesn't negate the value of the data collected before or after. It will be okay, especially if it doesn't last too long. But the longer it goes, the greater will be the harm.”
Financial Challenges
Equally serious are the potential financial consequences of lengthy disruptions in carrying out those studies.
“If you add up the number of RO1s across the country that have been affected by COVID, and if you extrapolate out how long those grants would need to be extended, bridge funding results in an enormous sum,” said Justin C. McArthur, MBBS, MPH, FAAN, chair and professor of neurology at the Johns Hopkins University School of Medicine. “I don't know that the NIH is going to be able to do that. Maybe they will, if the CARES Act includes sufficient stimulus for the NIH. But we don't know that yet and that's still a concern.”
Financial concerns are particularly acute for postdoctoral researchers whose salaries depend on their participation in grant-funded studies, “During this time of delay, one of the postdocs in my laboratory is working on preparing figures from the data we have so far, but there's only a limited amount of time one can spend doing that,” Dr. Simon said. “It creates a financial problem, because I'm still paying the postdocs. When the project resumes, we'll have less money remaining. It's a tough problem, and the guidelines from NIH are not yet clear.”
“In the clinical research world there's going to be a lot of problems. There will be at least several months where the protocol wasn't followed. There will be data abnormalities that have to be dealt with.”—DR. ERIK S. MUSIEK
The challenges for neurology postdocs forced to work from home can be especially difficult for those with young children, said Keith Van Haren, MD, assistant professor of neurology and pediatrics at Stanford University Medical Center.
“Younger children especially have full-time care needs. If you are a single parent of a young child, work is all but impossible, at least while your child is awake,” Dr. Van Haren said. “For these reasons, the COVID-19 shutdown will probably push more parents than non-parents, out of the research workforce.”
Of Mice and Meningitis
Maintaining mouse colonies and conducting time-sensitive experiments have been possible for most neurologists doing basic research—but not all.
“One of my colleagues in Europe told me it will take him a year and a half to get back to where he was,” said Kevin Graber, MD, clinical professor of neurology and director of the epilepsy fellowship program at Stanford University.
Justin M. Long, MD, PhD, a postdoctoral clinical fellow at Washington University's Knight ADRC, said he has been going into the center's mouse vivarium about once a week.
“We have experiments where animal specimens must be collected at a critical time after mice have aged for up to nine months,” he said. “During the pandemic, my work has been restricted to collecting brain specimens to store for later analysis. If we would miss these critical collections, we could lose years' worth of work.”
Tending to large numbers of mice can be daunting when only a small number of staff are permitted on campus.
“We have probably about 300 cages, with up to a thousand mice,” said Dr. Musiek. “My research is on how the circadian clock influences neurodegeneration in Alzheimer's disease. We have genetically engineered colonies that have their circadian genes knocked out that we cross with different models of neurodegeneration. We've spent many years generating them, so we are trying to not lose them.”
Clinical research has also been reduced to only the most necessary. “I've had a study going for almost eight years now, for kids with encephalopathy and meningitis, enrolling and doing next-generation sequencing on their spinal fluid,” said Kevin Messacar, MD, assistant professor in the department of pediatrics at the University of Colorado. “We were not actively enrolling due to the mandate, but we had a patient come in with COVID and CSF pleiocytosis. We were able to enroll that patient. But that's the only research I've had for three weeks, besides retrospective chart reviews.”
Once the COVID-19 shutdown is eventually lifted, the pace of research activities will still not be returning to normal anytime soon, Dr. Graber said.
“We have pain now, but as soon as the crisis resolves, our pain is going to get worse,” he said. “Making up for lost time will mean heavy workloads.”
Opportunities for COVID Research
Because Dr. Spudich's research has long focused on understanding how HIV infiltrates and injures the brain, she is now conducting similar studies involving the novel coronavirus.
“There's a real interest in how COVID-19 may be causing neurological effects. We already have a broad clinical study up and running.”—DR. SERENA SPUDICH
“There's a real interest in how COVID-19 may be causing neurological effects,” she said. “We already have a broad clinical study up and running. One of my mentees, Shelli Farhadian, MD, PhD, is leading the neurology part. They're collecting data from hundreds of COVID-19 patients admitted to the hospital. The samples include blood, nasopharyngeal swabs, sputum, and in some cases we're collecting spinal fluid when it seems appropriate, looking to see where the virus can be detected.”
The study is also seeking to systematically collect neurological data on the patients. “Some people seem to have had seizures, some have headache or loss of smell. But the findings have mostly been case reports. We're trying to do something systematic.”
Dr. Spudich and colleagues are also offering neurology consults for COVID-19 patients when requested. “I'm leading this special team to provide expertise for those patients clinically,” she said. “Many of those patients we're also trying to engage in the research.”
