Neuropathology associated with SARS-CoV-2 infection - Authors' reply.

We welcome the opportunity to respond to the comments about our Correspondence. To increase the availability of data, we reported our findings, which were produced by a team that included an experienced neuropathologist and was subjected to the The Lancet's peer-review process. The three responses are similar as they all challenge our interpretation of the findings presented. Striking is the fact that the three responses disagree among themselves, with each offering yet another interpretation.

To analyse our findings, we consulted a standard neuropathology textbook, coauthored by one of our critics. In the textbook, one reads that glial cells indeed can be differentiated from non-glial cells, and that hypoxic neurons can be distinguished from dark neurons based on classical haematoxylin and eosin staining.

In the absence of specific morphological alterations, shrinking is often the only indication of necrosis or apoptosis. Aware of the hypoxic origin of similar morphological alterations, we used the general level of hypoxic injury to vulnerable CA1 areas of the hippocampus and Purkinje cells in the cerebellum as a baseline. Because we did not observe hypoxic injury in these areas, we do not attribute the observed morphological alterations to hypoxia.We concede that the term pan-encephalitis was poorly chosen. In the neuropathological literature, pan-encephalitis refers to a fulminant necrotic disease, which we clearly did not observe. However, both MacLean Nasrallah and colleagues and a more recent report point out that patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit signs of the observed disseminated encephalitis as well as aseptic meningitis. Whether this observation is a general feature of SARS-CoV-2 infection should be established through extensive studies of a larger set of patients.

It is suggested that we over-interpreted petechial haemorrhage. We agree that petechial haemorrhages are a common finding in autopsies of terminally ill patients, although they are most often localised in the occipital lobe and basal ganglia. In our group of patients, petechial haemorrhaging was located in the frontal and high parietal area and pronounced in the white matter (purpura cerebri-like). Beside the fact that reports of petechial bleeding in the brains of SARS-Cov-2 fatalities are mounting, a fact also alluded to by Nasrallah and colleagues, the massive haemorrhaging observed in our group of patients is certainly not an over-interpretation.3, 4, 5, 6, 7

Considering the ongoing global pandemic, we are happy that our Correspondence has generated a lively discussion and can only hope that the various hypotheses discussed in this exchange will be subjected to systematic rigorous analysis in a larger sample.