PracticeUpdate: You have done significant work on the effects of COVID-19 on the brain at the NIH. How would you characterize our knowledge of COVID and the brain at this point?
Dr. Nath: What we know most of are the acute manifestations of the infection whereby patients have had respiratory dysfunction and which results in admission of these patients. But what has not been recognized until recently is that the brain can be affected independent of the respiratory complications, and they can occur acutely in hospitalized patients, or it can be weeks after recovery from the infection itself that new manifestations can emerge.
COVID-19 and the Loss of Smell
I'll first describe the parainfectious complications which occur during the phase of active viral replication. These patients can often present with loss of smell. And although it was originally thought that maybe the virus is affecting the olfactory nerve itself, it turns out that the virus replicates in the supporting cells in the nasal mucosa called sustentacular cells. And because of that, there are secondary effects on the olfactory nerve resulting in loss of smell. Most people will recover from the loss of smell, but there was a small subset of individuals in whom the smell does not recover. And then some when they do recover their smell, they can develop parosmia, which is they get a weird smell sensation. For example, if they were to smell coffee, they might smell some burnt toast or something like that.
The taste can similarly be altered at the same time.
COVID-19 and Encephalopathy
Patients who get hospitalized, about a third of those individuals will have encephalopathy. Two thirds of them at the time of discharge are unable to manage their activities of daily living, and the mortality rate of individuals who have encephalopathy is about six times compared to those that do not. There's a very significant toll of the infection on the brain. These symptoms seem to be more dominant in males and in older individuals, and it's independent of the degree of respiratory involvement.
Clinical Features of COVID-19 Encephalopathy
If you look at the brains of these patients, they often times have diffused encephalopathy. It's called a leukoencephalopathy: a critical illness. Some patients may have punctate white matter lesions. There's a group from Spain that had patients in the ICU for over two months, and they had all kinds of cognitive impairment, and they decided to treat them with plasma exchange and IVIG. What they found was that three of the patients out of five had excellent recovery and two did not. The ones that did not, had much more diffused white matter changes, suggesting that there is an important immune-mediated process that involves these manifestations and that patients may benefit from immune therapy, even several months after the initial manifestations.
We had an opportunity to look at the brains of individuals who had died suddenly from the infection. We had 11 such individuals who were in the acute phase because they were positive for the virus by PCR from the nasal mucosa, but were found dead either at home or one person was found dead in the subway.
Another individual was just playing with a sister and just dropped dead at that time. These individuals didn't have symptoms that would have warranted attention by a physician, and they did not seek any medical attention. But when we looked at the brain, almost all of them had pathology in the brain to varying degrees. What was most predominant was a leakage from the blood-brain barrier: the multifocal breakdown of the blood brain barrier throughout the brain with leakage of fibrinogen in the surrounding parenchyma and perivascular inflammation. When we looked at the neurons, we found that particularly in the brainstem, there was normal damage from surrounding macrophages and microglia, a phenomenon that is called neuronophagia. In some patients, we also found inflammation within the olfactory bulb; however, we failed to find any virus in the brain.
That seems to be a consistent observation from other groups that have studied the pathology. Except for one group in Germany that claimed they found some virus within the brain, but in very small subset of individuals, and the viral load was also extremely low. This suggests that the virus itself does not invade the brain, yet it causes a breakdown of the blood-brain barrier and inflammation within the brain. One possibility is that it's the viral proteins that may be responsible for this damage and not the virus itself.