Neurologic Manifestations of COVID-19 May Involve Cytokine Release Syndrome

coronavirus structure
Neurologic disturbances in patients with coronavirus disease 2019 were accompanied by evidence of cytokine release syndrome.

Neurologic disturbances in patients with coronavirus disease 2019 (COVID-19) were accompanied by evidence of cytokine release syndrome (CRS), and treatment with corticosteroids resulted in the recovery of these neurologic symptoms in some patients, according to findings published in the European Journal of Neurology.

Study researchers sought to investigate the neurologic manifestations of COVID-19 and the pathophysiology thereof, especially with respect to the role of CRS. This longitudinal study included 5 patients with COVID-19 with neurologic manifestations who were admitted to a renal unit at a French hospital between March 9 and April 9, 2020. Patients were between 51 and 71 years old.

The patients underwent an extensive clinical work-up to identify causes of neurologic impairment other than COVID-19. None of the patients had a known history of neurologic disease or manifestations.

Neurologic presentation consisted of the following symptoms: confusion (n=5), tremor (n=5), cerebellar ataxia (n=5), behavioral alterations (n=5), aphasia (n=4), pyramidal syndrome (n=4), coma (n=2), cranial nerve palsy (n=1), and central hypothyroidism (n=3). Out of the 5 patients, a 71-year-old woman died of coma and secondary infection. In 3 patients, neurologic manifestations occurred at or around the same time as CRS serum markers peaked.

Serum levels of S100B, an astroglial protein, were elevated when CRS occurred and returned to their reference range following the regression of both neurologic symptoms and hyperinflammation. According to the researchers, this is associated with increased permeability of the blood-brain barrier. Additionally, the presence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was undetectable in patients who underwent reverse transcription polymerase chain reaction testing of cerebrospinal fluid (CSF).

Findings on brain magnetic resonance imaging provided evidence of acute leukoencephalitis (n=3), cytotoxic edema mimicking ischemic stroke (n=1), or normal results (n=2). In 2 cases, treatment with corticosteroids and/or intravenous immunoglobulins was associated with rapid recovery from neurologic disturbances.

The study is limited by its small case-series design, as well as the performance of lumbar puncture during the second phase of COVID-19. The study researchers suggested that the latter may have resulted in failure to detect SARS-CoV-2 RNA with CSF analysis.

“Clinical manifestations [of COVID-19] were chiefly driven by peripheral CRS, absent direct CNS invasion by SARS-CoV-2,” concluded the researchers. They added that depending on future confirmation, the “data indicate that corticosteroids aimed at tackling CRS and [intravenous immunoglobulins] may be effective to control severe neurological disturbances in patients with COVID-19.”


Perrin P, Collongues N, Baloglu S, et al. Cytokine release syndrome-associated encephalopathy in patients with COVID-19. Eur J Neurol. Published online August 27, 2020. doi: 10.1111/ene.14491