A small postmortem study that scrutinized the brains of people who died from COVID-19 did not find a lot of direct SARS-CoV-2 virus impact in brain tissue, researchers reported at the 2021 virtual AAN Annual Meeting.
“Our major finding was a lack of evidence for direct SARS-CoV-2 infection of the brain," said Erica Normandin, a PhD candidate in systems biology at Harvard University School of Medicine.
“This suggests that, at least in these fatal cases, non-central nervous system organ dysfunction is the more likely cause of the neurologic symptoms that we observe. Histopathology of brain specimens revealed hypoxia with limited evidence of direct viral damage, including no viral protein. Concordantly, although SARS-CoV-2 was detected in some sections of the autopsied brains, viral load was low and did not correlate with other pathological features."
In the study, Normandin and colleagues scrutinized the brains of 18 consecutive patients who died from complications of SARS-CoV-2 infection. They examined brain tissue specimens from 10 standard areas of the brain that had been fixed in formalin and stained with hematoxylin and eosin for histopathological analysis. They conducted SARS-CoV-2 immunohistochemistry tests and reverse transcription-quantitative polymerase chain reaction on 10 brain sections from two subjects and two sections—the medulla and frontal lobe with olfactory nerve—from the remaining 16 subjects.
“We do have details on the patient history and clinical course, including pre-existing conditions, treatment interventions, and specific symptoms, Normandin said. “Some of the subjects in our study had neurologic symptoms, including myalgia, headache, and decreased taste. These symptoms are among the most common for COVID-19; more severe sequelae such as altered mental status, stroke, and encephalopathy are also frequently observed."
In this study, three patients had complained of myalgia, two patients had reported headaches, and one person reported a decreased sense of taste, she said. The patients' median age was 62 years, and 14 of the 18 patients were men.
Normandin said the autopsy results determined that acute hypoxic injury was detected in the cerebrum, hippocampus, and cerebellum in all patients; rare foci of perivascular lymphocytes were observed in two patients' brains, and focal leptomeningeal inflammation was detected in one patient.
“There was little evidence of SARS-CoV-2 viral RNA," she said. “In 10 unique specimens from two subjects, results were equivocal—viral load of less than 5.0 copies/mm3 in four and five sections. In the remaining 16 patients, the medulla sections and three frontal lobe and olfactory sections were positive—5.0 to 59.4 copies/mm3—while the rest were equivocal or negative."
Normandin said that SARS-CoV-2 viral load did not correlate with the interval between the onset of symptoms and death or histopathological findings. Immunohistochemical staining for SARS-CoV-2 nucleocapsid protein was negative in neurons, glia, endothelium, and immune cells, she reported.
Commenting on the study, Richard Temes, MD, director of Northwell Health's Center for Neurocritical Care at North Shore Hospital in Manhasset, NY, told Neurology Today At the Meetings, “This study actually raises more questions than answers. It is not the definitive work on the subject. We need more of these studies, and I think we will begin to see them."
The virus-brain injury hypothesis, he said, arises from two theories. “First is a direct invasion of the central nervous system from the virus," he said. “Initially even in the first few cases of COVID in the United States, we were able to observe virus growing from the spinal fluid with patients who had abnormal MRI imaging. That you can grow a virus from the spinal fluid suggests that you could have a direct invasion of the virus into the central nervous system. It has been postulated that the virus infects the nervous system through the nose and the olfactory tracts."
“The second mechanism is due to an autoimmune phenomenon where the body produces antibodies to the virus in response to the infection, and in attacking the virus, the antibodies also attack the brain," Dr. Temes added.
Dr. Temes suggested that because most patients with COVID die due to respiratory inflammation, the finding by Normandin and her colleagues that hypoxic brain injury was seen in most of the autopsies is not surprising. “The brain injury, hypoxia, is a sequelae of the virus infection in other organs of the body."
He noted that COVID-19 patients often have seizures which can cause hypoxia in the brain; they have a tendency to develop clots that can block brain arteries and cause strokes and hypoxia in that fashion. It can also cause clots in the heart and kidneys.
Normandin has received research support from Howard Hughes Medical Institute and the National Institutes of Health. Dr. Temes had no disclosures.
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AAN Abstract S 31.003: Normandin E, Bhattacharyya S, Mukerji S, et al. Neuropathological features of COVID-19.