Early evidence of pronounced brain involvement in fatal COVID-19 outcomes
Authors: Claus Hann von Weyhern, Ines Kaufmann, Frauke Neff, Marcus Kremer
Journal: The Lancet (2020)

The 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. Older patients with comorbidities are considered most at risk of death; however, there are reports of rapid decline and subsequent death in younger patients with no known comorbidities. Pulmonary and heart failure are considered the primary causes of COVID-19-associated death, but the precise pathology of disease progression is unknown. Moreover, recent reports describe irregularities in coagulation for a subset of patients.1Kollias A Kyriakoulis KG Dimakakos E Poulakou G Stergiou GS Syrigos K Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action.Br J Haematol. 2020; (published online April 18.)DOI:10.1111/bjh.16727Crossref PubMed Scopus (347) Google Scholar Here we report the findings of autopsies of six patients (four men and two women, aged 58–82 years) who died from COVID-19 in April, 2020. Clinical and pathological findings are summarised in the appendix. The period from onset of symptoms to admission spanned 2–10 days. Five patients were transferred to the ICU within the first 2 days of hospital admission. All patients eventually required ventilation or extracorporeal membrane oxygenation. The cause of death in the older patients (>65 years), all of whom were admitted with multiple comorbidities, was cardiorespiratory failure. By contrast, all patients younger than 65 years died either of massive intracranial haemorrhage or pulmonary embolism, consistent with COVID-19-associated coagulopathy.2Zhang Y Xiao M Zhang S et al.Coagulopathy and antiphospholipid antibodies in patients with COVID-19.N Engl J Med. 2020; 382: e38Crossref PubMed Scopus (1622) Google Scholar These patients exhibited a diffuse petechial haemorrhage in the entire brain. However, both groups showed lymphocytic pan-encephalitis and meningitis. Our histopathological findings are shown in the appendix. Although entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the CNS via endothelial cells has been documented with electron microscopy,3Varga Z Flammer AJ Steiger P et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Summary Full Text Full Text PDF PubMed Scopus (4530) Google Scholar we observed no conspicuous endotheliitis. Abundant experimental and animal model evidence of a neurogenic pathway for SARS CoV-2 via olfactory (CN I), trigeminal nerves (CN V), and the brainstem nuclei led us to look for evidence of localised brainstem alterations.4Román GC Spencer PS Reis J et al.The neurology of COVID-19 revisited: a proposal from Environmental Neurology Specialty Group of the Worlds Federation of Neurology to implement international neurological registries.J Neurol Sci. 2020; 414116884Summary Full Text Full Text PDF PubMed Scopus (166) Google Scholar In all brains examined, we observed localised perivascular and interstitial encephalitis with neuronal cell loss and axon degeneration in the dorsal motor nuclei of the vagus nerve, CN V, nucleus tractus solitarii, dorsal raphe nuclei, and fasciculus longitudinalis medialis, but no territorial infarctions (appendix). We do not attribute these findings to the clinically relevant COVID-19-associated severe hypoxia because morphological alterations of brain areas especially prone to hypoxia were consistent with those commonly observed in autopsied brains. Hypoxic alterations of brains in patients with COVID-19 are listed in the appendix. Whether the observed lesions were a direct consequence of virus infiltration or resulted from an immune response could not be established definitively in this autopsy study and requires further investigations. All patients had severe viral pneumonia, with a simultaneous heterogeneous occurrence of different disease stages, independent of the duration of the disease or ventilation time. The most prominent changes were those of a diffuse alveolar damage with virus-induced epithelial changes, capillaritis, and organising pneumonia without interstitial collagen deposition.3Varga Z Flammer AJ Steiger P et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Summary Full Text Full Text PDF PubMed Scopus (4530) Google Scholar, 5Paniz-Mondolfi A Bryce C Grimes Z et al.Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).J Med Virol. 2020; (published online April 21.)DOI:10.1002/jmv.25915Crossref Scopus (694) Google Scholar, 6Barton LM Duval EJ Stroberg E Ghosh S Mukhopadhyay S COVID-19 autopsies, Oklahoma, USA.Am J Clin Pathol. 2020; 153: 725-733Crossref PubMed Google Scholar Intranuclear inclusion bodies were not observed. It is noteworthy that no cellular damage or angiitis were observed in the heart of any patient. In summary, in addition to viral pneumonia, a pronounced CNS involvement with pan-encephalitis, meningitis, and brainstem neuronal cell damage were key events in all our cases. In patients younger than 65 years, CNS haemorrhage was a fatal complication of COVID-19. We declare no competing interests. Download .pdf (.32 MB) Help with pdf files Supplementary appendix 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 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 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 Neuropathology associated with SARS-CoV-2 infectionWe read with interest the Correspondence by Claus Hann von Weyhern and colleagues,1 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".1 These changes are then attributed directly or indirectly to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Full-Text PDF