Neuropathology associated with SARS-CoV-2 infection
Authors: Markus Glatzel, Christian Hagel, Jakob Matschke, Jan Sperhake, Nikolaus Deigendesch, Alexandar Tzankov, Stephan Frank
Journal: The Lancet (2021)

We read with interest the Correspondence by Claus Hann von Weyhern and colleagues,1von Weyhern CH Kaufmann I Neff F Kremer M Early evidence of pronounced brain involvement in fatal COVID-19 outcomes.Lancet. 2020; 395: e109Summary Full Text Full Text PDF PubMed Scopus (212) Google Scholar in which they report pronounced CNS involvement with pan-encephalitis in six patients with COVID-19 who were on invasive ventilation, some of whom were also receiving extracorporeal membrane oxygenation. Of these, three patients were further reported to have "massive intracranial" and "diffuse petechial haemorrhage in the entire brain".1von Weyhern CH Kaufmann I Neff F Kremer M Early evidence of pronounced brain involvement in fatal COVID-19 outcomes.Lancet. 2020; 395: e109Summary Full Text Full Text PDF PubMed Scopus (212) Google Scholar These changes are then attributed directly or indirectly to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Having neuropathologically assessed brains of more than 41 patients with COVID-19, and having investigated the neurotropism of SARS-CoV-2, we do not concur with the conclusion that pan-encephalitis and CNS haemorrhage are common complications of COVID-19.2Puelles VG Lütgehetmann M Lindenmeyer MT et al.Multiorgan and renal tropism of SARS-CoV-2.N Engl J Med. 2020; 383: 590-592Crossref PubMed Scopus (1288) Google Scholar, 3Matschke J Lütgehetmann M Hagel C et al.Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.Lancet Neurol. 2020; 19: 919-929Summary Full Text Full Text PDF PubMed Scopus (849) Google Scholar We do not observe pan-encephalitis, nor do we see massive intracranial haemorrhage or excessive and diffuse petechial haemorrhage in any of the brains of patients with COVID-19 that we have investigated (appendix). It is well known that long-term intensive care involving invasive ventilation, and especially extracorporeal membrane oxygenation, can lead to intracranial haemorrhagic lesions and diffuse neuroimmune activation.4Le Guennec L Cholet C Huang F et al.Ischemic and hemorrhagic brain injury during venoarterial-extracorporeal membrane oxygenation.Ann Intensive Care. 2018; 8: 129Crossref PubMed Scopus (86) Google Scholar Additionally, immune activation should not be confused with encephalitis, and petechial haemorrhage routinely observed in brains of critically ill patients should not be over-interpreted as CNS haemorrhage. Moreover, other neuropathological studies of COVID-19 brains have not found any evidence of encephalitis or intracranial haemorrhage.5Schaller T Hirschbühl K Burkhardt K et al.Postmortem examination of patients with COVID-19.JAMA. 2020; 323: 2518-2520Crossref PubMed Scopus (417) Google Scholar Neuropathological assessment of patients with COVID-19, especially those dying under intensive care treatment, is an expert task and all observed changes must be carefully interpreted in the context of comorbidities and therapeutic interventions to avoid misinterpretation. MG reports grants from the German Federal Ministry of Education and Research (Defeat Pandemics) and by the state of Hamburg with Landesforschungsförderung. AT received funding from the Botnar Research Centre for Child Health. All other authors declare no competing interests. Download .pdf (.18 MB) Help with pdf files Supplementary appendix Early evidence of pronounced brain involvement in fatal COVID-19 outcomesThe first cases of COVID-19 in Germany were confirmed in the greater Munich area and isolated in our hospital. Subsequently, more than 690 patients were admitted for inpatient care, 103 of whom were transferred to the intensive care unit (ICU). 63 patients died in hospital. 587 patients recovered and were discharged. Full-Text PDF Neuropathology associated with SARS-CoV-2 infectionWe believe that many of the key findings described in the Correspondence by Claus Hann von Weyhern and colleagues1 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. Full-Text PDF Neuropathology associated with SARS-CoV-2 infectionClaus Hann von Weyhern and colleagues1 describe autopsy findings of six patients who died of COVID-19. Better understanding of the central effects of COVID-19 is crucial, and we read with great interest their findings that included pan-encephalitis and meningitis in all six patients, regardless of whether cause of death was due to cardiorespiratory failure, pulmonary embolism, or intracranial haemorrhage. However, the images provided in the appendix of the Correspondence1 do not clearly show meningitis or encephalitis. Full-Text PDF Neuropathology associated with SARS-CoV-2 infection – Authors' replyWe welcome the opportunity to respond to the comments about our Correspondence.1 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. Full-Text PDF