Understanding COVID-19's Neurological Effects

Neurologist Shibani Mukerji, MD, PhD, associate director of the Neuro-Infectious Diseases Unit at Massachusetts General Hospital, and her colleagues are investigating neurologically-related COVID-19 symptoms and their effects on treatment and recovery. Dr. Mukerji works in clinics dedicated to the neurological complications of infectious diseases such as HIV and syphilis, neuro-invasive viruses such as West Nile virus and those immunocompromised after transplantation—and now severe COVID-19 illness. Her team is leveraging learnings from these cohorts to better understand the mechanisms behind short- and long-term neurological sequelae of COVID-19 infection.

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Researchers have gained critical insights into SARS-CoV-2 from studying the pathogenesis of other human coronaviruses, namely severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS-CoV) and human CoV-OC43 (HCoV-OC43). While they are primarily respiratory viruses, they all have neuro-invasive potential as well.

"There have been viral particles found in the brains of patients with SARS-CoV and HCoV-OC43, and a subset will have RNA-identified NCSF, but we await those high-quality confirmatory studies in SARS-CoV-2," says Dr. Mukerji.

Neurological Manifestations of and Resilience to COVID-19

Human coronaviruses can directly affect both the central nervous system (CNS) and the peripheral nervous system (PNS), causing:

• Dizziness
• Dysautonomia
• Headache
• Myalgia
• Myopathy
• Neuropathy
• Stroke

Indirect effects vary widely depending on the host.

"Some individuals recover while others have profound hospital stays," says Dr. Mukerji. "Hypoxia may result, and they may have immune dysregulation. They can be hypercoagulable, and you can have end-organ effects from that. All of those will directly and indirectly affect the central and peripheral nervous system."

Any history of neurological disease can heavily exacerbate symptoms. Neurologically related symptoms, including headache and anosmia, are also known as dominant features of COVID-19 presentation. But initial COVID-19 screening tests did not include a neurological component.

"That's obviously changing, resilience depends on their age—really on a patient's neurological reserve," says Dr. Mukerji. "It's tough for anybody, but it's tougher for those individuals that have a vulnerable brain and COVID-19 infection."

Recovery becomes that much more difficult if neurological comorbidities are present when patients transition from severe COVID-19 infection with supportive oxygen to critical infection with ventilation.

At Mass General, she has seen COVID-19 patients who have been intubated for weeks. The ability to wake up and recover is more challenging for patients without a robust neurological reserve.

"It's a new world for a lot of people," says Dr. Mukerji.

Anticipating COVID-19's Neuropsychiatric Impacts

Dr. Mukerji notes that neuropsychiatric effects from SARS-CoV-2 will be substantial. After the 1918 flu pandemic, which had lower mortality than COVID-19, the resulting encephalopathy was reported to be profound.

"People were left tired, apathetic and confused after that pandemic. There was also a large increase in Parkinsonism and Parkinson's. And we don't even think of influenza as a highly neuro-invasive virus. But we know from all the flu epidemics that there have been neurological effects. Encephalitis is there. SARS had the same thing. SARS-CoV-2 will have it."

But the difference lies in scale, says Dr. Mukerji, given the astronomical nature of the COVID-19 pandemic. A New England Journal of Medicine paper corroborated this hypothesis when it reported that the majority of hospitalized COVID-19 patients have encephalopathy upon discharge—irrespective of whether their treatment teams thought they had a neurological disorder during hospitalization.

"The hypothesis is that there's this virus phase, and then there's this immune dysregulation phase. Is that phase a problem for the brain? It probably doesn't help if a person is older and already on the brink of cognitive impairment or dysfunctional," she says. "And then there's the question of the incidence of being encephalopathic because of related pandemic social factors without having contracted SARS-CoV-2."

Clinicians are only at the beginning stages of seeing and understanding these psychological impacts. "I have a young woman who has migraines and small fiber neuropathy. She's young, eloquent and very reasonable in terms of separating her old neuropathy from what's new. She said very clearly that out of everything, the hardest part is the anxiety," says Dr. Mukerji. "She's scared that she has coronavirus and of infecting her family. She doesn't know when to come into the hospital. She can't go outside to get her own food. And with all of that, she doesn't sleep and her headaches get worse. That story is being played out all over the country. It's sheer anxiety, and people are often cut off from their therapists and friends who can help them through it."

Dr. Mukerji, whose research also involves depression and cognitive impairment in HIV, says that while neurology and psychiatry are often treated separately, they are closely related because of the brain.

"Neuropsychiatric conditions aren't ailments that others can physically see," she says. "From our own experiences with other viruses, we see that most people who have had a viral infection that affected their brain are primarily concerned with neuropsychiatric sequelae. There's no reason why SARS-CoV-2 won't have this issue."

Neurological Consequences of COVID-19 Infection

Frontline experiences and unprecedented collaboration at Mass General are helping provide clear evidence of the neurological effects of COVID-19.

"I don't think I've ever seen this many people collaborating within every department. It's as if every department's walls just came crashing down," says Dr. Mukerji. "The scale of what we're doing to understand SARS-CoV-2 has never been done before. We already know a lot in a very little amount of time, and we're still trying to work through it. But that happens only because people have collaborated."

Mass General's Department of Neurology is heading a number of COVID-19 research initiatives. Investigators seek to identify both the short- and long-term neurological consequences of COVID-19 infection, including encephalopathy, delirium and headaches.

Serological Assay Validation

Many companies touting serological studies haven't proven the basics of sensitivity, specificity and predictive values. Mass General scientists are validating some of these assays. "We have the ability to do it in a very steward fashion, but we are still trying to understand what it means and how that relates to neurological symptoms such as stroke," says Dr. Mukerji.

Neurological COVID-19 Database

Dr. Mukerji and her colleagues in Neurology are closely collaborating with experts in infectious disease, the Mass General Respiratory Illness Clinic (RIC) within the Division of Pulmonary and Critical Care Medicine, and the Athinoula A. Martinos Center for Biomedical Imaging to create a 40,000-person prospective database. The database currently contains demographics, medications, labs and COVID-19 testing results. In the future it will also include serology.

"We want to be able to pull down patient data in a large scale and then prospectively understand neurological manifestation. This would help us separate the signal from the noise because stroke and other neurological symptoms can happen with or without COVID-19," says Dr. Mukerji.

Viral Sequencing of Cerebrospinal Fluid (CSF)

Dr. Mukerji's lab is collecting CSF from patients who have had CSF analysis performed for clinical neurological indications. They are virally sequencing it to address how patients with SARS-CoV-2 present.

"Our data suggest that the vast majority do not have at least polymerase chain reaction (PCR-)positive SARS-CoV-2 in the CSF despite having neurological symptoms that required a lumbar puncture. But I suspect that a few will have it, and we want to know who those people are and why," says Dr. Mukerji. "We know SARS and HCoV-OC43 infect neurons. We suspect the same is also true for SARS-CoV-2."

More data will help solidify the neurological symptoms and syndromes associated with COVID-19 infection and the direct effect of SARS-CoV-2 on the brain, says Dr. Mukerji. "But we're only six months into the virus, and that's such a short period to understand anything. It's just not enough time. The papers defining the neurological impacts of SARS came out a decade later—and they're still coming out. We'll see a lot more in the next year or so."

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