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Patients with COVID-19 Face Prolonged Neurocognitive Recovery After Ventilation

An unexpectedly large number of COVID-19 patients who require mechanical ventilation are taking days or weeks to awaken from sedation, according to anecdotal reports from neurointensivists and brain rehabilitation specialists who treat them. And it appears these patients may require months of rehabilitation to return to their neurocognitive baseline, the specialists told Neurology Today.

While sobering, neurologists with direct experience with severely ill COVID-19 patients say their primary message to clinicians across the United States is one of hope. Don't let a few weeks of unresponsiveness convince you of a dire prognosis, they said: significant recovery is possible, given time and care.

"There should be guarded optimism for a wide range of these COVID-19 patients," said Nicholas D. Schiff, MD, the Jerold B. Katz professor of neurology and neuroscience and co-director of the Consortium for the Advanced Study of Brain Injury at Weill Cornell Medicine.

"If the brain doesn't look like it's had widespread loss of neurons, if there's no great structural damage and their brain volume looks good, we need to have humility and not rush to judgment. We're only a few months out with this pandemic. Nobody yet knows the natural time course for these patients' recovery."

Admittedly, Dr. Schiff said, "Seeing a patient who is in a coma for weeks who then regains consciousness and becomes fully oriented has been like finding a needle in the haystack. But that's not the case now with COVID-19. We have ten consults a day like this in New York."

Critical-care neurologists at Harvard, Columbia, Northwestern, New York University, the University of Texas and the University of Liège, Belgium, told Neurology Today that they share Dr. Schiff's nuanced views about not only the unusually long recovery times some COVID-19 patients are having, but also the urgent need to learn much more about the phenomenon.

Jan Claassen, MD, FNCS, associate professor of neurology at Columbia University Medical Center, head of Neurocritical Care, and medical director of the neurological intensive care unit there, said he cannot offer even an estimate as to how many such patients he has seen in the past few months.

 "I've encountered it more than I expected," Dr. Claasen said. "I could say it's not infrequent. That perception is shared by other physicians across institutions. It's convinced us that this is something we need to focus on, to get a better handle on."

Abhay Kumar, MD, a neurointensivist and associate professor in the department of neurosurgery at the McGovern Medical School of UTHealth in Houston, described a recent case revealing how even the sickest COVID-19 patients can surprise clinicians with their neurocognitive recovery.

 "I had somebody who spent close to six weeks before we could finally extubate her," Dr. Kumar said. "She initially came in for respiratory failure due to COVID-19, and then she had a moderate-sized stroke on top of that. When we finally lightened her sedation, we expected her to be more responsive. It reached the point where we had a discussion with her family, her husband, about care. We decided on palliative extubation and to provide comfort measures only.

"To our surprise," Dr. Kumar said, "she did pretty well with her breathing. She continued to improve. After weight weeks of hospitalization, she was able to wake up enough to be moved to rehabilitation."

The lesson, he said, is that "being cautious in making your prognosis is the right way to go. This disease is hardly six months old. Recovery just might take longer than we would otherwise expect."

To learn more, Dr. Schiff at Weill Cornell has received funding for a three-site study with neurologists and brain rehabilitation specialists at Harvard and Columbia.

In Chicago, meanwhile, Igor J. Koralnik, MD, FAAN, chief of neuroinfectious diseases and global neurology at Northwestern Medicine has announced the opening of a neuro COVID-19 Clinic to study and treat the disease's neurological symptoms. In addition, the Neurocritical Care Society is leading a multicenter collaboration to develop guidelines and tools to align data and sample collection for future analysis.

Clinical Observations

No published paper has yet described the phenomenon of COVID-19 patients taking days or weeks to awaken from the deep sedation required for optimal ventilation, but every neurointensivist and brain rehabilitation specialist contacted by Neurology Today said they have seen them.

 "We're getting a lot of these patients having difficulty waking up," said Ross Zafonte, DO, chair of the Harvard Medical School department of physical medicine and rehabilitation at the Spaulding Rehabilitation Hospital in Boston. "Some have cognitive, functional, and even affectual disturbances. We need to follow these people long-term. That they're discharged from the ICU is of paramount importance, of course, but we need to follow and treat the kinds of deficits they're going to have. There needs to be a national effort."

Brian S. Im, MD, director of the Brain Injury Rehabilitation Program at Rusk Rehabilitation at NYU Langone Orthopedic Hospital, said he was concerned that medical ICU physicians might not think to refer such patients upon discharge for rehabilitation.

"From my standpoint, treating people with brain injuries, we usually work with neurologists or neurosurgeons," Dr. Im said. "They're familiar with the work we do. We provide cognitive stimulation, retraining, and medications to try to improve arousal, interaction, and function. Unfortunately, many of the physicians treating COVID-19 patients aren't aware of the role of rehabilitation services for patients with disorders of consciousness."

Kevin N. Sheth, MD, FAAN, professor of neurology and neurosurgery and chief of the division of neurocritical care and emergency neurology at the Yale School of Medicine and Yale New Haven Hospital, said that one of the reasons why some COVID-19 patients take so long to recover may be because of the length of time they require ventilation.

"These folks are on sedation and paralytics, many for long periods of time, longer than we might expect for other ICU patients," Dr. Sheth said. "Whether how long they take to wake up is because of the long exposure to sedation, or to the underlying disease itself, I don't think anyone has clear answers on yet."

Neurologists are pressing on in their search for causes of the prolonged recoveries. Many cited the decreased oxygenation patients may have before and during ventilation.

"These COVID-19 patients have a smoldering decrease in oxygen that can extend over hours and days," said Brian L. Edlow, MD, associate professor of neurology at Harvard Medical School, and director of the Laboratory for NeuroImaging of Coma and Consciousness. "Even if there is never a respiratory or cardiac arrest, persistently low levels of oxygen can cause swelling of the brain or structural injuries. When we monitor these patients for signs of recovery of consciousness, we have to keep in mind that some can't move their limbs due to ICU myoencephalopathymyoneuropathy— so it can be very challenging to identify purposeful movements."

Edward M. Manno, MD, MS, FAAN, vice chair of clinical affairs in the department of neurology at Northwestern University Feinberg School of Medicine, described another curious observation that some other neurointensivists have also seen: Some Covid-19 patients requiring ventilation need remarkably high doses of sedatives to control their delirium.

"It's confounding, but there's a certain percentage of these patients who have a really horrific, agitated delirium," Dr. Manno said. "They end up requiring enormous amounts of sedation. Whether this is just an ordinary consequence of viral pneumonia or is due to the cytokine storm that has been described, I think it may be a contributing factor to their taking longer than usual to wake up."

A Hopeful Comparator?
Dr. Schiff said that a useful point of comparison for COVID-19 might be seen in a paper he coauthored in the April issue of the Annals of Neurology. The case series describes three patients who suffered cardiac arrests outside of the hospital, endured 10 to 20 minutes before circulation was restored by emergency medical technicians, and then spent 17 to 37 days in eyes-closed comas. Yet all three eventually made excellent cognitive recoveries.  

"Many COVID-19 patients who take weeks to awaken look very similar to the cardiac arrest patients in this paper," Dr. Schiff said. "They don't have major structural injuries or a tremendous loss of neurons."

Dr. Schiff said that he and a coauthor and colleague at NYU Langone, Orrin Devinsky, MD, FAAN, both examined the second patient described in the paper.

"He had been in an eyes-closed coma for nearly six weeks post-injury," Dr. Schiff recalled. "I examined him three times. He had been off sedation for weeks, with burst suppression on the EEG. I couldn't get any response. It was inconceivable to me that this patient could have a significant recovery, as it was for Dr. Devinsky. We were absolutely certain that this person would never recover. We counseled the family strongly that they withdraw care."

A few weeks later, however, a friend of the patient happened to see Dr. Schiff on the street who told him that the patients did not die and was following commands. Remarkably, Dr. Shiff said, the patient eventually returned to his cognitive baseline.

"These patients invite us to understand better how a low-functioning state of neurons can endure for long periods of time and then recover," Dr. Schiff said. "It's exciting and largely unknown territory, and it tells us we can't give up on these COVID-19 patients too soon."

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