Alien Cells May Explain COVID ‘Brain Fog’

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The long-term neurologic symptoms such as “brain fog” experienced by some patients with COVID-19 may be caused by a unique pathology — the occlusion of brain capillaries by large megakaryocyte cells, a new report suggests.

The authors report five separate post-mortem cases from patients who died with COVID-19 in which large cells resembling megakaryocytes were identified in cortical capillaries. Immunohistochemistry subsequently confirmed their megakaryocyte identity.

They point out that the finding is of interest as — to their knowledge — megakaryocytes have not been found in the brain before.

The observations are described in a research letter published online February 12 in JAMA Neurology.

Bone Marrow Cells in the Brain

Lead author David Nauen, MD, PhD, a neuropathologist from Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News he identified these cells in the first analysis of post-mortem brain tissue from a patient who had COVID-19.

“Some other viruses cause changes in the brain such as encephalopathy, and as neurologic symptoms are often reported in COVID-19, I was curious to see if similar effects were seen in brain post-mortem samples from patients who had died with the infection,” Nauen said.

On his first analysis of the brain tissue of a patient who had COVID-19, Nauen saw no evidence of viral encephalitis, but he observed some “unusually large” cells in the brain capillaries.

“I was taken aback; I couldn’t figure out what they were. Then I realized these cells were megakaryocytes from the bone marrow. I have never seen these cells in the brain before. I asked several colleagues and none of them had either. After extensive literature searches, I could find no evidence of megakaryocytes being in the brain,” Nauen noted.

Megakaryocytes, he explained, are “very large cells, and the brain capillaries are very small — just large enough to let red blood cells and lymphocytes pass through. To see these very large cells in such vessels is extremely unusual. It looks like they are causing occlusions.”  

By occluding flow through individual capillaries, these large cells could cause ischemic alteration in a distinct pattern, potentially resulting in an atypical form of neurologic impairment, the authors suggest.

“This might alter the hemodynamics and put pressure on other vessels, possibly contributing to the increased risk of stroke that has been reported in COVID-19,” Nauen said. Although, he reported, none of the samples he examined came from patients with COVID-19 who had had a stroke.

Other than the presence of megakaryocytes in the capillaries, the brain looked normal, he said. He has now examined samples from 15 brains of patients who had COVID-19 and megakaryocytes have been found in the brain capillaries in five cases.

New Neurologic Complication

Classic encephalitis found with other viruses has not been reported in brain post-mortem examinations from patients who had COVID-19, Nauen noted.

“The cognitive issues such as grogginess associated with COVID-19 would indicate problems with the cortex but that hasn’t been documented. This occlusion of a multitude of tiny vessels by megalokaryocytes may offer some explanation of the cognitive issues. This is a new kind of vascular insult seen on pathology, and suggests a new kind of neurologic complication,” he added.

The big question is what these megakaryocytes are doing in the brain.

“Megakaryocytes are bone marrow cells. They are not immune cells. Their job is to produce platelets to help the blood clot. They are not normally found outside the bone marrow, but they have been reported in other organs in COVID-19 patients.”

“But the big puzzle associated with finding them in the brain is how they get through the very fine network of blood vessels in the lungs. The geometry just doesn’t work. We don’t know which part of the COVID inflammatory response makes this happen,” said Nauen.

The authors suggest one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs.

“We need to try and understand if there is anything distinctive about these megakaryocytes — which proteins are they expressing that may explain why they are behaving in such an unusual way,” said Nauen.

Noting that many patients with severe COVID-19 have problems with clotting, and megakaryocytes are part of the clotting system, he speculated that some sort of aberrant message is being sent to these cells.

“It is notable that we found megakaryocytes in cortical capillaries in 33% of cases examined. Because the standard brain autopsy sections taken sampled at random [are] only a minute portion of the cortical volume, finding these cells suggests the total burden could be considerable,” the authors write.

Nauen added that to his knowledge, this is the first report of such observations, and the next step is to look for similar findings in larger sample sizes.

JAMA Neurol. Published online February 12, 2021. Research Letter

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