Neuropathology associated with SARS-CoV-2 infection.

We believe that many of the key findings described in the Correspondence by Claus Hann von Weyhern and colleagues should be interpreted differently. The exact nature of CNS involvement in COVID-19 is not only of fundamental importance for our understanding of the disease, but might have substantial consequences in directing clinical efforts to achieve better patient management in the future. Thus, observations about CNS inflammation as described by von Weyhern and colleagues will cause a great stir among biomedical scientists and clinicians if proven to be correct. However, we feel obliged to express our sincere reservations about the conclusions drawn from these data given the potentially wide-ranging consequences.

We particularly feel that the main conclusion, namely that “in addition to viral pneumonia, a pronounced CNS involvement with pan-encephalitis, meningitis, and brainstem neuronal cell damage were key events”, are possibly the consequence of a misinterpretation of histological findings. Although it is conceivable that hypoxic-ischaemic neuronal damage could occur as part of COVID-19, the depicted neuronal changes characterised by contracted, intensely stained neurons do not represent hypoxic, but rather suggest dark neurons. Dark neurons are frequent histological artifacts usually caused by post-mortem manipulation of the brain before fixation, and differ from dying or degenerating neurons.

Furthermore, we find the data illustrating the inflammatory involvement of the CNS in patients with COVID-19 unconvincing. Although we agree that a possible direct or indirect CNS involvement in the context of severe acute respiratory syndrome coronavirus 2 infection merits investigation, we cannot support the diagnosis made by the authors of pan-encephalitis or meningitis on the basis of the provided data and histological photomicrographs provided. We acknowledge the modest perivascular T-cell population depicted by immunohistochemistry by CD3 staining. However, such minimal lymphocytic CNS infiltrates are quite commonly seen in patients with multisystem failure (who required treatment in the intensive care unit), and we feel that these are non-specific changes whose clinical relevance is debatable. In our opinion, the histological findings have been over-interpreted as pan-encephalitis or meningitis. We would also highlight Solomon and colleagues' findings, which are in line with our assessment (and also our observations of CNS COVID-19 autopsies performed at our centres), namely that encephalitis is not a general feature of COVID-19.

Although the global COVID-19 pandemic is a public health emergency and presents us with the need to find out as much as we can about the disease as rapidly as possible, we believe that hastily publishing such findings without adequate peer review should be challenged. Especially in times of description of a new disease, much care should be taken to obtain expert review of the findings and any conclusions need to be substantiated by appropriate evaluations and inclusion of controls. Although this literature draw attention to the important question of CNS involvement of COVID-19, the data presented by von Weyhern and colleagues are likely to cause confusion and possibly misdirect future clinical efforts.