Brain dysfunction in COVID-19 and CAR-T therapy: cytokine storm-associated encephalopathy

Abstract

Objective: Many neurological manifestations are associated with COVID-19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID-19 patients. Cytokine storm is also associated with immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T-cell (CAR-T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID-19-related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings.

Methods: Narrative literature review.

Results: Comparisons between COVID-19-related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection-associated encephalopathies.

Interpretation: COVID-19-related encephalopathy and ICANS are characterized by a predominant electro-clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm-associated encephalopathy (CySE), and its diagnostic criteria.

Figure 1

Schematic representation of the mechanisms underlying cytokine‐mediated neuroinflammation. Different triggers, including CAR T‐cell therapy and SARS‐CoV‐2 infection, may lead to a massive release of cytokines via activation of the monocyte/macrophage system. Peripheral cytokines promote blood–brain barrier disruption and microglia/astrocyte activation, which may act synergistically.

Figure 2

The spectrum of Cytokine Storm‐associated Encephalopathy Disorders (CySED). The yellow circle relates to different triggers responsible for cytokine storm disorders (orange circle). Cytokine storm‐associated encephalopathy disorders are shown in the red circle.