The long-term neurological symptoms such as “brain fog” that some patients with COVID-19 experience 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 of patients who died with COVID-19 in which large cells resembling megakaryocytes were identified in cortical capillaries. Immunohistochemistry then confirmed their megakaryocyte identity.
They point out that the finding is important since – to their knowledge – megakaryocytes have not been found in the brain before.
The observations are detailed in a research letter published online Feb. 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 brain changes, such as encephalopathy, and since neurological symptoms are commonly reported in COVID-19, I was curious to see if similar effects were seen in post-mortem brain samples from patients who had died of the infection,” said Nauen.
In 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 totally amazed; I couldn’t figure out what they were. Then I realized that these cells were megakaryocytes from the bone marrow. I’ve never seen these cells in the brain. I’ve asked several colleagues and none of them.” also had neither. After extensive literature search, I could find no evidence that megakaryocytes were present in the brain, “noted Nauen.
Megakaryocytes, he explained, are “very large cells, and the brain capillaries are very small – just big enough for red blood cells and lymphocytes to pass through. It is extremely unusual to see these very large cells in such blood vessels causing occlusions. ”
By occluding flow through individual capillaries, these large cells can cause an ischemic change in a distinct pattern, possibly resulting in an atypical form of neurological damage, the authors suggest.
“This could alter hemodynamics and put pressure on other blood vessels, possibly contributing to the increased risk of stroke reported in COVID-19,” said Nauen. Although, he reported, none of the samples he examined were from patients with COVID-19 who had had a stroke.
Aside from the presence of megakaryocytes in the capillaries, the brain looked normal, he said. He has now examined samples from 15 brains from patients with COVID-19 and megakaryocytes have been found in the brain capillaries in five cases.
New neurological complication
Classical encephalitis found with other viruses has not been reported in post-mortem brain exams of patients who had COVID-19, Nauen noted.
“The cognitive problems such as dizziness associated with COVID-19 indicate problems with the cortex, but this has not been documented. This occlusion of a multitude of small blood vessels by megalokaryocytes may provide some explanation for the cognitive problems. This is a new kind of vascular seizure seen in pathology, suggesting a new kind of neurological complication, ”he added.
The big question is what these megakaryocytes do 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 that goes into 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 what part of the COVID inflammatory response causes this. happen, ”said Nauen.
The authors suggest there is a possibility that altered endothelial or other signaling may recruit megakaryocytes into the circulation and somehow pass them through the lungs.
“We have to try to understand if there is anything distinctive about these megakaryocytes – which proteins they express, which could explain why they behave so unusually,” Nauen said.
He noted that many patients with severe COVID-19 have problems with clotting and that megakaryocytes are part of the coagulation system, and speculated that some sort of aberrant message is being sent to these cells.
“It is noteworthy that in 33% of the cases studied we found megakaryocytes in cortical capillaries. Because the standard sections of brain autopsy were randomly sampled. [are] only a small fraction of the cortical volume, finding these cells suggests that the total load could be significant, “the authors write.
Nauen added that this is, to his knowledge, the first report of such observations, and the next step is to look for similar findings in larger samples.
JAMA Neurol. Published online February 12, 2021. Research letter
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