Abstract
Autoimmune encephalitis (AE) mediated by antibodies against synaptic and neuronal surface targets frequently presents with a psychiatric syndrome. In these patients, removal of autoantibodies treats the disease and outcomes are closely linked to early intervention. The discovery of these autoantibodies in isolated psychiatric syndromes has raised the possibility that these patients may derive similar benefits from immunotherapy, a potentially transformational approach to the treatment of mental illness. Although open-label case series suggest impressive therapeutic outcomes, the pathological relevance of these autoantibodies outside of canonical presentations is debated. The advent of diagnostic criteria for AE attempts to facilitate its prompt identification but risks prematurely neglecting the potential scientific and clinical significance of isolated syndromes that do not satisfy these criteria. Here, we propose using a syndrome-level taxonomy that has occasional, but not necessary, overlap with AE: synaptic and neuronal autoantibody-associated psychiatric syndromes or “SNAps”. This will prevent confusion with AE and act heuristically to promote active investigation into this rare example of psychopathology defined on a molecular level. We suggest that this concept would have application in other autoantibody-associated syndromes including seizure, cognitive, and movement disorders, in which similar issues arise. We review putative direct and indirect mechanisms and outline experimentally testable hypotheses that would help to determine prospectively in whom autoantibody detection is relevant, and as important, in whom it is not. We summarize a pragmatic approach to autoantibody testing and management in severe mental illness in order to promptly diagnose AE and advocate a research-orientated experimental medicine paradigm for SNAps, where there is greater equipoise. We conclude that SNAps remains a nascent area of clinical neuroscience with great potential and in ongoing need of psychiatry-led basic and clinical research.
Highlights
The serum of patients with functional psychoses contains abnormal globulins
neural surface antibodies (NSAbs) found in isolated psychiatric syndromes, which are currently considered of research interest and potential clinical relevance, would be scientifically neglected or “orphaned.” The reality that cerebrospinal fluid (CSF) is often difficult to obtain in these patients, and multiple assay methods to evaluate serum are rarely available outside specialist centers, compounds this issue
It is possible to make a diagnosis of NMDAR-Autoimmune encephalitis (AE) if an isolated psychiatric syndrome of subacute onset is associated with CSF NMDAR (NR1) antibody or in serum if a cell-based assays (CBAs) result is confirmed by testing on neuronal cultures or immunohistochemistry
Summary
The serum of patients with functional psychoses contains abnormal globulins. I have previously suggested that an autoimmune mechanism might be involved ... any interpretation of their meaning is completely speculative and must be approached with the greatest caution. Antibodies that bind to cell surface neuronal, glial, or synaptic targets, collectively known as neural surface antibodies (NSAbs), have attracted significant attention in neurology and psychiatry [2] Their detection in a patient presenting with psychiatric symptoms raises the possibility both of a causal or disease-modifying role and of clinical improvement with immunotherapy (IT). This would represent a major step forward from current largely symptom-targeted psychotropic medications and has been met by clinicians and researchers with enthusiasm. We discuss the controversies in applying knowledge of autoimmune encephalitis (AE) to such psychiatric disorders and suggest experiments by which these controversies may be resolved
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