Alien cells may explain COVID’s ‘brain fog’

Long-term neurological symptoms, such as “brain fog” that some COVID-19 patients experience, may be caused by a unique pathology: occlusion of brain capillaries by large megakaryocyte cells, a new report suggests.

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

They note that the finding is of interest since, to their knowledge, megakaryocytes have not been found in the brain before.

The observations are described in an investigative letter published online February 12 at JAMA Neurology.

Bone marrow cells in the brain

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

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

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

“I was surprised; I couldn’t figure out what they were. Then I realized that these cells were megakaryocytes from the bone marrow. I had never seen these cells in the brain before. I asked several colleagues and none of them either. After extensive searches In the literature, I could not find evidence of megakaryocytes in the brain, “Nauen noted.

Megakaryocytes, he explained, are “very large cells, and the brain capillaries are very small, large enough to let red blood cells and lymphocytes pass through. Seeing these cells so large in such vessels is extremely unusual. They appear to be causing occlusions. “.

By occluding flow through individual capillaries, these large cells could cause ischemic disturbance in a distinct pattern, which could result in an atypical form of neurological impairment, the authors suggest.

“This could alter 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 COVID-19 patients who had had a stroke.

Aside from the presence of megakaryocytes in the capillaries, the brain appeared normal, he said. Now he has examined samples from 15 brains of patients who had COVID-19 and megakaryocytes have been found in the brain capillaries in five cases.

New neurological complication

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

“Cognitive problems, such as lightheadedness associated with COVID-19, would indicate problems with the cortex, but that has not been documented. This occlusion of a multitude of tiny vessels by megalokaryocytes may offer some explanation for the cognitive problems. This is a new one. type of vascular damage seen in pathology, and suggests a new type of neurological complication, “he added.

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

“Megakaryocytes are cells in the bone marrow. 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- patients. 19 “.

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

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

“We have to try to understand if there is something distinctive about these megakaryocytes, what proteins are they expressing that might explain why they behave in such an unusual way,” Nauen said.

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

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

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

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

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