Updating the mild encephalitis hypothesis of schizophrenia

Abstract

Emerging evidence indicates that low level neuroinflammation (LLNI) may not occur infrequently. Many infectious agents with low overall pathogenicity are risk factors for psychoses including schizophrenia and for autoimmune disorders. According to the mild encephalitis (ME) hypothesis, LLNI represents the core pathogenetic mechanism in a schizophrenia subgroup that has syndromal overlap with other psychiatric disorders. ME may be triggered by infections, autoimmunity, toxicity, or trauma. A ‘late hit’ and gene–environment interaction are required to explain major findings about schizophrenia, and both aspects would be consistent with the ME hypothesis. Preliminary criteria for subgrouping neurodevelopmental, genetic, ME, and other types of schizophrenias were provided. Considering recent investigations of CSF, the ME schizophrenia subgroup may constitute approximately 40% of cases. LLNI may involve dysfunction of the blood–brain barrier, the blood–CSF barrier of CNS-endogenous immunity in part mediated by the volume transmission mode involving CNS-extracellular-fluid and CSF signaling. Both together could represent a common pathogenetic link for the distributed brain dysfunction observed in schizophrenia. However, CSF signaling may even extend along nerves into peripheral tissues via the CSF outflow pathway and explain peripheral topologies of dysfunctions/lesions found (dysautonomia, muscle lesions). In general, CSF signaling including at the PCOP could play an underestimated role in neuroinflammatory disorders.