A First In Medical History! John Hopkins Study Finds That SARS-CoV-2 Causes Megakaryocyte Cells To Be Found In Brain Cells Resulting In COVID Brain Fog

COVID Brain Fog: According to a new study by researchers from John Hopkins University, the typical ‘COVID brain fog; symptom experienced by many infected by the SARS-CoV-2 coronavirus could be due to the occlusion of brain capillaries by large megakaryocyte cells.


 
According to the study abstract, “Evidence suggests brain involvement in the COVID-19 disease. Manifestations in acutely ill individuals often include confusion and alteration of consciousness. After this phase, many patients experience continued neurologic symptoms such as dysexecutive syndrome or “COVID brain fog.” However, in autopsies from patients with COVID-19 who had neurologic abnormalities, investigations have largely not identified the chronic inflammation or marked neural changes typically associated with viral infection, and viral genetic material has been minimal or absent. It has been difficult to reconcile the experience of patients and clinicians that COVID-19 is altering cognition with tissue studies that show no evidence of encephalitis involving higher brain centers. The study team hypothesized that histopathology might provide insight. The team reports here a finding that may contribute in some cases, identified by analysis of brain tissue from patients who died of COVID-19.”
 
The study findings showed that in 5 cases, in cortical capillaries, the study team identified large cell nuclei morphologically consistent with megakaryocytes. To further characterize these cells, the study team performed immunohistochemistry for CD61 and CD42b, markers of platelets and megakaryocytes. CD61 labels these cells, as does CD42b, confirming their megakaryocyte identity. The cells were distinct from platelet clusters, which were found in postmortem intravascular precipitates. However evaluation of the cortex of 2 patients who tested negative for COVID-19 who had hypoxic brain changes demonstrated no megakaryocytes on CD61.
 
The study findings were published in the peer reviewed journal: JAMA
https://jamanetwork.com/journals/jamaneurology/fullarticle/2776455
 
According to the study team, the long-term neurologic symptoms such as "brain fog" experienced by some patients with COVID-19 may be caused by a unique pathology ie the occlusion of brain capillaries by large megakaryocyte cells.
 
The study team 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.
 
The team points out that the finding is of interest as to their knowledge megakaryocytes have not been found in the brain before.
 
Dr David Nauen, MD, PhD, a neuropathologist from Johns Hopkins University and lead author of the study said that he identified these cells in the first analysis of post-mortem brain tissue from a patient who had COVID-19.
 
Dr Nauen told Thailand Medical News, "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 simil ar effects were seen in brain post-mortem samples from patients who had died with the infection."
 
Interestingly 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.
 
Dr Nauen added, "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.”
 
He explained, “Megakaryocytes, 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."  
 
It was observed that 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 study team suggests.
 
Dr Nauen further added, "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."
 
Though, he reported, none of the samples he examined came from patients with COVID-19 who had had a stroke.
 
Importantly other than the presence of megakaryocytes in the capillaries, the brain looked normal, according to the study team.
 
The study team 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.
 
The team noted that classic encephalitis found with other viruses has not been reported in brain post-mortem examinations from patients who had COVID-19.
 
Dr Nauen added, "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.”
 
However the key question is what these megakaryocytes are doing in the brain.
 
The study team commented, "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."
 
Dr Nauen said, "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."
 
The study team suggests one possibility is that altered endothelial or other signaling is recruiting megakaryocytes into the circulation and somehow permitting them to pass through the lungs.
 
Dr Nauen stressed, "We need to try and understand if there is anything distinctive about these megakaryocytes like which proteins are they expressing that may explain why they are behaving in such an unusual way."
 
Observing 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.
 
The study team added, "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 study team added that to their knowledge, this is the first report of such observations, and the next step is to look for similar findings in larger sample sizes.
 
The team also stressed that it is important to understand how the SARS-CoV-2 virus is affecting the signaling and cellular pathways that result in this manifestation of megakaryocytes cells in the brain’s capillaries.
 
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