Epilepsy-related psychosis: a role for autoimmunity?

Postictal psychosis (PIP) is a serious psychiatric complication of epilepsy that occurs in approximately 6% of patients following multiple complex partial or generalized seizures. The psychosis is classically described as having a pleomorphic phenomenology, including paranoid, grandiose, and religious delusions as well as multimodal hallucinations with prominent affective changes and agitation. Little is understood about the pathophysiology of the condition. There has been a recent increase in interest in the relevance of autoimmunity to the pathogenesis of both epilepsy and psychosis. Studies have demonstrated the presence of antibodies directed against synaptic autoantigens (such as the N-methyl-d-aspartate receptor or the voltage-gated potassium channel complex) in approximately 10% of cases of sporadic epilepsy. These same autoantibodies are known to cause encephalopathy syndromes which feature psychiatric symptoms, usually psychosis, as a prominent part of the phenotype as well as other neurological features such as seizures, movement disorders, and autonomic dysfunction. It is beginning to be asked if these antibodies can be associated with a purely psychiatric phenotype. Here, we hypothesize that PIP may be an autoimmune phenomenon mediated by autoantibodies against synaptic antigens. More specifically, we outline a potential mechanism whereby long or repeated seizures cause short-lived blood-brain barrier (BBB) dysfunction during which the brain becomes exposed to pathogenic autoantibodies. In essence, we propose that PIP is a time-limited, seizure-dependent, autoantibody-mediated encephalopathy syndrome. We highlight a number of features of PIP that may be explained by this mechanism, such as the lucid interval between seizures and onset of psychosis and the progression in some cases to a chronic, interictal psychosis.