Encephalitis (EC) and encephalopathy (EP) share common pathological features, such as increased blood-brain barrier permeability, intracerebral migration of immune cells, and cerebral edema. EP often lacks findings in routine MRI and CSF, and as a result, during epidemics such as COVID-19, EP tends to be perceived as a despicable manifestation. 

CSF and serum from individuals with encephalitis (n=10), encephalopathy (n=30), and controls (n=32) were compared among each other to identify differences in a 45-cytokine and in a 6-neurological biomarker multiplex panel, controlling for time of sampling when needed. We used non-parametric tests for comparisons, considering p-values <0.05.

Serum LIF, IL-5, IL-7, IL-8, Eotaxin, IL-1RA, HGF, MIP-1β, IFN-α, MCP-1, IL-18, and VEGF-A were elevated in EC and EP versus control. Serum IL-1β, IL-2, IP-10, IL-10, IL-17A, IFN-γ, TNF-α, and IL-1α were upregulated in EC. In EP, serum IL-31, GM-CSF, TNF-β, and PDGF-BB were upregulated, while RANTES and IL-23 were downregulated. After time adjustment, IL-10 and MCP-1 remained different between EC and EP, being higher in EC. CSF patterns were all different from serum. In the CSF, no cytokine differences were observed after time adjustment between EC and EP, while UCHL1 and total Tau were higher in EC.

Similarities between EC and EP in serum and CSF point to common inflammatory mechanisms, affected mostly by time of clinical evolution. After adjustment, EP findings suggest a process of sustained inflammation, supporting that significant pathological alterations are present in EP, regardless of routine CSF and MRI normality. Differences in UCHL1, total Tau, IL-10 and MCP-1 are possibly related to different severity of EC over EP. Our findings may be also used to corroborate the sustained neurological symptoms of what is still being defined as long-COVID.