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Testing for antibodies in the cerebrospinal fluid (CSF) may confirm that COVID-19 has invaded the brain.

A case series of three patients attending an inner city US hospital who had severe, laboratory-confirmed COVID-19 and encephalitis shows that while only one had abnormal white blood cells or protein present in CSF, all had evidence of immunoglobulin (IgM) antibodies.

"What was novel about our study was that we were able to show IgM, the acute phase reactant against COVID, in the spinal fluid of these patients, which is a direct indicator they had COVID in their brain," lead author Karima Benameur, MD, a neurologist and associate professor, Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, told Medscape Medical News.

Benameur added that just because CSF testing indicates normal levels of inflammatory proteins, it doesn't mean the virus has not entered the brain and, therefore, to confirm this, she recommends CSF IgM testing, if possible.

The paper was published online June 2 in Emerging Infectious Diseases.

COVID-19 is typically characterized by respiratory illness and viral pneumonia with fever, cough, shortness of breath, and, in severe cases, progression to acute respiratory distress syndrome.

However, there have been few detailed investigations of neurologic complications in COVID-19 infection.

The documented cases include a 31-year-old woman with sickle cell disease who had a recent pulmonary embolus; a 34-year-old man with hypertension and signs of fever, shortness of breath, and cough; and a 64-year-old man also with hypertension and showing typical signs of the virus.

In addition to assessing CSF IgM, researchers analyzed CSF inflammatory proteins and performed molecular testing for SARS-CoV-2 using reverse transcription polymerase chain reaction (PCR).

Two of the patients had normal white blood cell counts and protein levels. "The only reason we could actually diagnose them with COVID encephalitis is because we were able to measure the IgM in their spinal fluid," said Benameur.

Neurologists ordering spinal taps on patients may incorrectly assume there's no brain involvement if the spinal fluid is normal, said Benameur.

Benameur emphasized, "just because the PCR in CSF is negative, this does not mean that the virus has not made it into the brain."

The PCR test is a good test for some viruses, including the herpes virus, but is a poor test for this new coronavirus, she said.

While all three patients had encephalitis, the female patient also developed encephalomyelitis as indicated by inflammation in her brain and spinal cord.

All patients had symptoms affecting cortical and brainstem function at the peak of neurologic illness.

It's not clear how the virus invades the brain, said Benameur. Some speculate it could be through the olfactory nerve, which might explain why some patients lose their sense of taste and/or smell.

Benameur noted that animal research shows that when the virus is injected into nose fibers, it can travel to the brain.

Experts don't know what percentage of COVID patients have the virus in the brain, said Benameur.

In addition, although all of the patients in the current case series were African American, the sample is too small to determine if neurological involvement is more prevalent in this population of COVID patients, said Benameur.

"Overall, having a poor prognosis has been reported to be more frequent in African Americans, but we don't know about neurologic complications. There are not enough subjects for us to be able to do that statistical analysis."

While the three cases were relatively young patients, again, this is not a large enough sample to determine if brain involvement is more likely in younger patients, said Benameur. She noted that she has data from additional patients and there is a wide range of ages.

The two male patients in the current series recovered and were released from hospital. The female patient died.

Her sickle cell disease may have complicated her outcome. Having hypoxia from a condition like pneumonia, in addition to sickle cell disease, may make it more difficult to get oxygen to tissues, said Benameur.

She urged all clinicians seeing COVID patients in clinics, including those without classic symptoms, to "ask them about their cognition."

Commenting for Medscape Medical News, Andrew Wilner, MD, associate professor of neurology, University of Tennessee Health Science Center, Memphis, said reports of neurological complications associated with COVID-19 "continue to multiply" as clinicians gain more experience treating these patients.

"To date, most, if not all, of the neurological complications can be explained by inflammatory changes such as thrombosis or cytokine storm as well as post-infectious causes such as antibody-related Guillain-Barre," said Wilner.

Other complications appear "nonspecific" and "related to acute, severe systemic illness such as hypoxic ischemic encephalopathy due to respiratory failure" as was the case with these three cases, he said.

"Whether unusual symptoms such as loss of olfactory sense are due to direct neuronal injury or inflammation has not been determined."

Wilner noted that although antibodies to the SARS-CoV-2 virus were present in the CSF of the current cases, SARS-CoV-2 RNA was not detected in the CSF.

"As such, this paper is consistent with prior observations that suggest the SARS-CoV-2 virus may cause neurologic injury by secondary mechanisms, but is not specifically neurotropic. Research on this important question is ongoing."

Wilner reports being medical adviser for CVS/Health and receiving royalties from "The Locum Life: A Physician's Guide to Locum Tenens."

Emerg Infect Dis. Published online June 2, 2020. Full text

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Does CSF Antibody Testing Confirm Coronavirus in the Brain? - Medscape