Article In Brief
From past experiences with other viruses with neurologic symptoms, these neurovirologists glean what can be applied (or not) to understanding COVID-19.
Lessons learned from prior outbreaks of respiratory viruses may help clinicians and scientists understand the potential neurologic impact of novel SARS CoV-2, which causes COVID-19.
Hints of how CoV-2 may directly or indirectly cause neurologic complications can be gleaned from experiences with previously known coronaviruses as well as influenza, respiratory syncytial virus, metapneumovirus and enteroviruses. Such viruses have been associated with a long list of neurologic complications, both in the acute phase and longer term, according to a review of the medical literature that was published in the April issue of Critical Care Explorations.
The paper's perspective on the neurologic aspects of CoV-2 comes as global confirmed cases of COVID-19 approach two million, with nearly 125,000 people deaths, including more than 25,000 in the United States. While attention has mostly been on the severe respiratory toll, anecdotal reports and small studies are emerging that possible neurologic manifestations of COVID-19 illness can include loss of taste and smell, headache, impaired consciousness, neuromyopathy, and stroke.
What History Teaches
As the COVID-19 outbreak grew earlier this year, Christopher P. Robinson, DO, assistant professor of neurology and neurosurgery at University of Florida, thought it would be useful to look at what could be learned about neurologic complications from other respiratory viral illnesses.
Dr. Robinson and his colleague Katharina M. Busl, MD, MS, reviewed known evidence on severe acute respiratory syndrome coronavirus (SARS Co-V), Middle Eastern respiratory syndrome coronavirus (MERS), influenza, respiratory syncytial virus, human metapneumovirus and enteroviruses D 68 and 71.
They found reports of an array of neurologic complications related to those viral illnesses, including seizures, status epilepticus, encephalitis, critical illness neuropathy, acute disseminated encephalomyelitis, acute necrotizing encephalitis, Guillain-Barré syndrome, transverse myelitis, and acute flaccid myelitis.
Dr. Robinson told Neurology Today that while the neurologic picture for CoV-2 is still unclear, there is reason for neurologists and other clinicians to be vigilant.
“We have to be aware of any and all complications that come with a novel illness,” whether in the initial phase or months afterwards, he said. “While it is likely that CoV-2 could, based on the experience of SARS and MERS, invade the central nervous system, that has not been determined with CoV-2.”
Dr. Robinson said it is likely that the many of the neurologic complications being reported with COVID-19 are secondary to the virus's assault on the respiratory system and the systemic inflammatory response mounted by the body.
Dr. Robinson said he has received several reports of COVID-19 patients with diffuse muscle weakness and encephalitis, suggesting a direct link between SARS CoV-2 and neuropathology. He predicts that neurologists may see a wave of patients after the pandemic who present with neurologic complications such as Guillain-Barré and post-infectious demyelinating disorders secondary to having had COVID-19.
New Report from China
A report published April 10 in JAMA Neurology (which was first published earlier in March in a preprint server) reviewed neurological symptoms among 214 consecutive hospitalized patients at three designated COVID-19 care centers in Wuhan, China. The retrospective review of electronic medical records found that 36.4 percent of patients (78) had neurologic manifestations, with the sickest patients most likely to have neurologic complications. The list of complications ranged from headache and dizziness to, on the more severe end, impaired consciousness, stroke and skeletal muscle injury
The report, by Ling Mao, MD, and colleagues, noted that clinicians should be aware that the rapid deterioration or worsening of COVID-19 patients “could be associated with a neurologic event such as stroke, which could contribute to high mortality rate.”
On the flip side, the report urged clinicians seeing patients who present with a neurologic symptom to “suspect acute respiratory coronavirus 2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent further transmission.”
An accompanying editorial in JAMA Neurology said neurologists may very well turn out to be “on the front lines of the pandemic.”
What's Known, What's Not
Right now, several neurologists with expertise in neuroinfectious disease told Neurology Today, it may be premature to make that prediction.
Carlos A. Pardo, MD, professor of neurology and pathology at Johns Hopkins University, said it is too early to draw any conclusions on the neurologic aspects of CoV-2 based on anecdotal reports and small case studies, which may be lacking peer review if they are in preprint status.
“At the moment the data available doesn't suggest that this virus is either neurotropic or neurovirulent,” he said, referring to its potential to invade and infect neurons and glial cells.
Dr. Pardo cautioned against applying what has been observed with in vitro studies of other respiratory viruses such as MERS and SARS, noting that the results may not apply to “what is happening in real life.” He said severe neurologic complications stemming from respiratory viruses in general are rare; for example, about one in every 100,000 cases with influenza develop paralyzing diseases like Guillan-Barré syndrome.
He said it is likely that the neurologic complications being reported with COVID-19 are secondary effects of the “magnitude of pathophysiologic changes” brought about by the virus not only in the respiratory tract but throughout the body. He said the “cytokine storm,” or intense inflammatory response, being reported could “lead to changes in the central nervous system and the neuromuscular system,” leading to symptoms such as delirium, encephalopathy and myalgias.
“The severity and length these patients stay in the intensive care unit is going to increase the likelihood of neurologic complications,” Dr. Pardo added, including critical illness neuropathies.
“When we see big data from large COVID-19 registries is when we are going to be able to come to some conclusions,” about the full neurologic impact of COVID-19, he said.
Three Categories of Potential Impact
Kenneth L. Tyler, MD, FAAN, Louise Baum Endowed Professor and Chair of Neurology at University of Colorado School of Medicine, said he tends to think of the potential neurologic impacts of CoV-2 as falling into one of three broad categories.
The first category and likely the largest, involves “indirect effects on the nervous system” resulting from COVID19-associated multi-organ system failure and systemic effects such as disseminated intravascular coagulation (DIC) and a hyperinflammatory state. These commonly include encephalopathy and altered mental status, an increased risk for acute cerebrovascular disease, and potentially seizures.
Dr. Tyler said that because many more severely ill coronavirus patients are older and have multiple underlying conditions such as cerebrovascular disease, diabetes, and hypertension, they may be prone to neurologic complications, as was suggested in the case series from China.
The second category of neurologic symptoms, which he described as theoretical for now, would be due to direct involvement of the central nervous system (CNS) with CoV-2. This category requires direct proof of viral invasion of the CNS, which could include a positive CSF RT-PCR for SARS-CoV2, or evidence of viral antigen or nucleic acid in brain tissue obtained at biopsy or autopsy, Dr. Tyler said.
The likely presentation would be as a form of encephalitis with CSF pleocytosis, MRI abnormalities, and focal neurological signs and symptoms in conjunction with depressed or altered consciousness.
He said some rare cases of direct CNS invasion were seen with SARS and MERS and there has been a very recent case report of acute necrotizing encephalitis with CoV-2, but he said the lack of data at this point in the pandemic on brain imaging, spinal fluid sampling, and brain tissue pathology at autopsy make it impossible to know whether direct invasion of the CNS CoV-2 will occur, and if so how frequently and with what specific presentations.
Dr. Tyler said the third category of possible neurologic complications includes post-viral immune-mediated conditions such as acute disseminated encephalomyelitis (ADEM) in the CNS and Guillain-Barré–like syndromes in the peripheral nervous system, both of which were reported in the aftermath of SARS and MERS.
“Will we be seeing anything like that in the setting of CoV-2?” he asked. “The answer will likely take time to emerge.”
Dr. Tyler said neurologists who treat multiple sclerosis and other autoimmune diseases also stand to learn from the data that eventually will emerge from large-scale antibody testing.
“One of the things that will be important for everyone to understand is the key components of protective immunity against this virus,” he said. “That could influence our selection of immune-modifying therapy we might give our patients. You might pick the therapy that preserved the ability of the host to clear SARS-CoV2 while still being effective in treating the patient's primary neurological disease.”
Will the Virus Persist Over Time?
Dennis L. Kolson, MD, PhD, professor of neurology at the University of Pennsylvania Perelman School of Medicine, said one of the reasons why it's important to understand whether SARS-CoV-2 can invade the nervous system is to also understand whether the virus could persist there long-term, like HIV does, and even later cause problems.
“You want to know where the virus is so you can properly assess whether you are eliminating the virus, dealing with a recurrence of symptoms, or a rebound of viral replication,” he said.
He said findings in brain and other tissue obtained at autopsy will be critical to “understanding the pathogenesis in a disease like this [COVID-19].”
Dr. Kolson, who mainly studies HIV, said the convalescent plasma therapy being tried for COVID-19 might not only help patients recover more easily from the viral infection, but it also could help inform the development of an effective vaccine. If, for instance, antibodies present in the serum of recovered patients can neutralize the infectivity of the virus through their binding to specific regions of the spike protein found on the surface of the coronavirus, then that would make those regions of the protein a logical target of a vaccine, he said. If these protein regions are conserved among different virus strains that might emerge in the future, then such a vaccine might be useful in future outbreaks.
Dr. Robinson has received honoraria for serving as an expert legal witness for traumatic brain injury. Drs. Tyler and Busl had no relevant disclosures.