key: cord-0746645-np8ls0pe
authors: Finsterer, Josef; Scorza, Fulvio A
title: COVID-19 can be complicated by immune-encephalopathy rather than encephalitis
date: 2021-04-24
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab348
sha: 86f00c029c898be1e67f6dea7fa49b91ff06d787
doc_id: 746645
cord_uid: np8ls0pe

nan

M a n u s c r i p t 2 Letter to the Editor With interest we read the article by Pilotto et al. about a cohort of 13 patients diagnosed with SARS-CoV-2 associated encephalitis ("COVenc") undergoing work-up of the cerebro-spinal fluid (CSF) for immunological/inflammatory parameters. [1] All patients had normal CXCL13 levels but increased neuronal damage markers (NfL, total tau), increased glial-related markers (GFAP, TREM2, YKL-40), and increased cytokines (IL-1β, IL-6, IL-8, TNF-α).*1+ It was concluded that encephalitis in COVID-19 is associated with abnormal neuronal and glial biomarkers and with a specific cytokine pattern suggesting inflammatory-mediated mechanisms underlying SARS-CoV-2associated encephalitis. [1] The study is appealing but raises concerns.

A first shortcoming is that no reference limits were provided, neither in table 1 nor in table 2. [1] According to the results section, a CSF-cell count of 5 was regarded already as pleocytosis. Applying reference limits of our laboratory (cut off 12/3 cells), only 4/13 patients had pleocytosis. Applying our reference limits for CRP (<5mg/L), only 7/13 patients had elevated CRP. Thus, we wonder why all 13 "COVenc" patients were classified as encephalitis.*1+ A further argument against encephalitis is that none of the 13 patients reported headache or hypersensitivity to light/noise. [1] We should be told how many of the 13 patients presented with "meningism" or a positive Brudzinski sign or a positive Kernig sign on neurologic exam.

A further shortcoming is that the provided results of cerebral imaging are insufficient. Of particular interest in patients with encephalitis is the reaction of the brain to contrast medium. Thus, we should know if gadolinium was applied and in how many patients M a n u s c r i p t 3 was there enhancement of the brain or the meningeas. Absence of any gadolinium enhancement would be a further argument against the diagnosis "encephalitis". Missing is the exclusion of sinus venous thrombosis, increasingly recognised as a complication of COVID-19 [2, 3] .

In 4/13 patients (#4, #7, #10, #13) seizures were observed and three patients (two with seizures) were diagnosed with non-convulsive epileptic state (#7, #11, #13). [1] We should be told if these five patients were diagnosed with epilepsy already prior to the SARS-CoV-2 infection, which anti-seizure drugs (ASDs) were applied, and if the ASD treatment resulted in reduction of seizure frequency respectively discontinuation of the epileptic states.

Four of 13 patients died. [1] We should be told about the cause of death in these patients and if an autopsy was carried out. Did these patients die from respiratory compromise, from cardiac involvement, or from CNS involvement? Since three of these patients (#7, #11, #13) had an epileptic state and one of them seizures, it is crucial to know if the ASD regimen was effective or not in these patients and if follow-up EEG-recordings documented discontinuation of the epileptic state. We should know if the three patients with focal epileptiform discharges on EEG also manifested with seizures. The discrepancy between the results (only 3 patients with epileptiform discharges on EEG) and 

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