Reply to the Letter “COVID‐19‐Associated Encephalopathy and Cytokine‐Mediated Neuroinflammation”

Cerebrospinal fluid in COVID-19: A systematic review of the literature

“…There were 28 patients who had CSF IL-6 measured, 21 (75%) of whom had an increased concentration based on the author’s reported normal; 11/21 patients with increased CSF IL-6 concentration had serum IL-6 concentration measured, and this was elevated for all 11 patients [ 10 , 30 , 31 , 98 , 111 , 128 , 135 , 149 , 165 , 182 , 191 , 205 , 215 , 217 , 236 ]. Keller et al measured IL-6 in the CSF and serum of 5 patients (2 with hemiparesis, 1 who was comatose, 1 who was encephalopathic and 1 who had seizures) and found it was elevated in 4/5 patients, but was lower than it was in serum [ 182 ].…”

“…In addition to that patient, there were 16 other patients who had CSF IL-8 measured, 16/17 (94%) of whom had elevated CSF IL-8; 6 patients with elevated CSF IL-8 had serum IL-8 measured, all of whom had elevated serum concentrations too [ 10 , 31 , 98 , 111 , 135 , 149 , 165 , 205 , 217 ]. In comparison to historical controls with normal cognition and no viral illness, Benameur et al found that 3 patients with CSF SARS-CoV-2 antibodies who were comatose or profoundly encephalopathic had increased levels of CSF IL-6, IL-8, interleukin-10 (IL-10), interferon gamma-induced protein-10 (IP-10) and TNF-α [ 31 ].…”

“…IL-8 was elevated in CSF for all three patients, and was higher than it was in serum (42.6 pg/mL in CSF and 17.8 pg/mL in serum; 96 pg/mL in CSF and 55 pg/mL in serum; and 22.7 pg/mL in CSF and 20 pg/mL in serum). Pilotto et al evaluated CSF cytokines in a 60-year-old man who presented with five days of encephalopathy, fever and cough, who was found to have lymphocytic pleocytosis (WBC count of 18 cells/μL) and hyperproteinorrachia (127.2 mg/dL) [ 10 , 217 ]. He had a negative CSF SARS-CoV-2 PCR and no evidence of intrathecal antibody synthesis, oligoclonal bands or autoimmune antibodies.…”

“…β2 microglobulin, a biomarker for monocytic activation in the CNS, was increased in the CSF of 6/7 patients [ 10 , 119 , 157 , 217 ]. Pilotto et al found that CSF β2 microglobulin was increased in a patient with encephalopathy (3.06 mg/L; no reference range provided) [ 10 , 217 ].…”

“…β2 microglobulin, a biomarker for monocytic activation in the CNS, was increased in the CSF of 6/7 patients [ 10 , 119 , 157 , 217 ]. Pilotto et al found that CSF β2 microglobulin was increased in a patient with encephalopathy (3.06 mg/L; no reference range provided) [ 10 , 217 ]. Eden et al found elevated CSF and serum β2 microglobulin in 5/5 patients with encephalopathy (3 of whom had an initial CSF SARS-CoV-2 PCR result as indeterminate (Ct 37-40), prompting retesting which did not detect SARS-CoV-2 RNA) [ 157 ].…”