Reader Response: Acute Necrotizing Encephalopathy with SARS-CoV-2 RNA Confirmed in Cerebrospinal Fluid

Virhammar et al.1 present a case of acute necrotizing encephalopathy (ANE) in a patient with COVID-19 diagnosed by nasopharyngeal swab PCR1. SARS-CoV-2 PCR testing on 2 CSF specimens performed on days 9 and 12 after symptom onset was negative, whereas a third CSF specimen tested positive at a cycle threshold (Ct) of 34.29 at 21 days. Although interesting, these results do not indicate that SARS-CoV-2 is neurotropic. First, most experts consider Ct counts >40 to represent a negative test, and counts >34 may not represent meaningful disease.2 Because PCR testing can amplify contaminants, this result may be a false positive, particularly with negative initial CSF testing. Second, because ANE is typically a postinfectious disease, a biologically plausible causal link with a weakly positive CSF PCR at 21 days is not established. Third, a large series of patients with COVID-19 who had neurologic symptoms found SARS-CoV-2 PCR was negative in the CSF in 100% of patients.3 Although one study reportedly detected SARS-CoV-2 in a brain autopsy,4 no immunohistochemistry studies were performed, and rough endoplasmic reticulum may be mistaken for virions. Larger brain autopsy series using immunohistochemistry have not detected primary viral CNS invasion.5 Direct neurotropism of SARS-CoV-2 has yet to be definitively established.