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SARS-CoV-2 -- viral RNA, viral protein, or both -- was detected in brain tissue of more than 50% of patients who died with COVID-19, a post-mortem case series in Germany showed.

However, the presence of SARS-CoV-2 was not associated with the severity of pathological changes in the brain, reported Markus Glatzel, MD, of University Medical Center Hamburg-Eppendorf, and co-authors in .

"In this case series, we show that the virus gains access to the brainstem, and we were able to pinpoint the presence of viral proteins to structures such as cranial nerves in some patients," Glatzel said.

"We did not see more severe neuropathological changes in patients with high viral loads when compared to those with no presence of virus, yet the immune reaction to the virus in the brain -- which we start to define in this study -- is there," Glatzel told MedPage Today. "This makes us think that the neuroimmune reaction may be a key factor explaining some of the neurological symptoms seen in COVID-19 patients."

This is the most comprehensive report of neuropathological findings in patients who died from COVID-19, the researchers noted.

"The emerging evidence, including the current study, shows that neuropathological alterations in the brains of patients who die from COVID-19 are relatively mild, although the virus is able to gain access to the brain," they wrote. "The neuropathological alterations are most likely to be immune-mediated, and there does not seem to be fulminant virus-induced encephalitis nor direct evidence for SARS-CoV-2-caused central nervous system damage."

The case series looked at brain tissue from 43 people in Hamburg who died in hospitals, nursing homes, or at home with COVID-19 from March 13 to April 24.

Patients were 51 to 94 years old, with a median age of 76. All had positive SARS-CoV-2 tests: 40 patients had samples to detect SARS-CoV-2 by immunohistochemistry, and 27 patients had samples to detect SARS-CoV-2 by quantitative RT-PCR.

Nearly two-thirds (63%) of patients were men. Almost all patients (93%) had relevant pre-existing chronic medical conditions, mainly cardiorespiratory problems; 30% had pre-existing neurological diseases, including neurodegenerative disease or epilepsy. Cause of death was attributed mainly to the respiratory system, with viral pneumonia as the underlying condition in most cases. Most patients (74%) died in the hospital.

Overall, SARS-CoV-2 RNA or proteins were detected in brain tissues of 21 (53%) of 40 investigated patients; both were detected in eight patients. SARS-CoV-2 viral proteins were found in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem.

A variable degree of astrogliosis was seen in all patients, and 86% had astrogliosis in all regions assessed. "Because astrogliosis occurs in a variety of pre-existing medical conditions, and because critical illness also contributes to astrogliosis, a causal connection to SARS-CoV-2 cannot be drawn at present," the researchers said.

Activation of microglia and infiltration by cytotoxic T lymphocytes was most pronounced in the brainstem and cerebellum. Meningeal cytotoxic T lymphocyte infiltration was seen in 79% of patients. The olfactory bulb showed a high degree of astrogliosis and microgliosis, but only minor infiltration by cytotoxic T lymphocytes. In addition, the researchers detected fresh territorial ischemic lesions in six patients.

"In the American biographical crime film 'Catch Me If You Can,' FBI agent Carl Hanratty goes all out to catch the notorious impostor and check counterfeiter Frank Abagnale Jr.," noted Stephan Frank, PhD, of the University of Basel in Switzerland, in an . "Hanratty's dogged pursuit of the culprit bears striking resemblance to current COVID-19 research efforts to find evidence of changes that SARS-CoV-2 infection might leave in the brain."

In this case series, Glatzel and colleagues detected SARS-CoV-2 protein expression in brain tissue of a substantial portion of patients, he pointed out. "While the replicative and infective potential of the viral RNA remains unclear, the in-situ detection of SARS-CoV-2 proteins is an important finding, as it confirms the presence of the virus in the brain," Frank wrote.

"Of note, the authors found virus protein expression to be confined to the medulla oblongata and to cranial nerves originating from the lower brainstem (most likely glossopharyngeal or vagal nerve)," he added. "Considering the capability of SARS-CoV-2 to infect human gut enterocytes as well as pneumocytes, this finding is of particular interest, warranting future investigations of vagal nerve tissue as a potential viral central nervous system access route in COVID-19."

The study has several limitations, notably its descriptive nature and the absence of age- and sex-matched controls. The researchers assessed only a small number of post-mortem specimens, and selected regions might not fully represent the whole brain. In addition, they did not have systematically validated clinical data and could not establish conclusive clinical and pathological correlations.

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