Synaptic and Neuronal Autoantibody-Associated Psychiatric Syndromes: Controversies and Hypotheses

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.

Keywords: autoimmune diseases of the nervous system; bipolar disorder; blood–brain barrier disruption; glutamatergic neurotransmission; immunotherapy; major depression; mild encephalitis; schizophrenia.

Figure 1

(A) Patients with isolated psychiatric symptoms and a detectable neural surface antibody can be characterized as having a “synaptic and neuronal autoantibody-associated psychiatric syndrome,” abbreviated to “SNAps.” This distinguishes these patients from the majority of patients with autoimmune encephalitis (AE), which is normally a multi-symptom disorder with specific associated clinical and paraclinical features: diagnostic criteria for AE have been outlined in a recent position paper (14). Some patients with isolated psychiatric symptoms will also meet criteria for AE—these patients are here referred to as SNAps-AE and are clinically atypical for AE by virtue of their monosymptomatic presentation. (B) The distinction between an isolated symptomatic presentation and a polysymptomatic AE presentation can usefully be extended to non-psychiatric presentations. This scheme recognizes that there will be areas of overlap where a monosymptomatic presentation meets paraclinical criteria for AE e.g. imaging, electroencephalogram, or cerebrospinal fluid parameters. Here ‘md’ stands for movement disorder, ‘cog’ is cognitive disorder, and ‘epi’ is epilepsy.

Figure 2

Experimentally testable hypotheses relating to the pathogenicity of neural surface antibodies (NSAbs) in synaptic and neuronal autoantibody-associated psychiatric syndromes (SNAps).

Figure 3

Relationship between severe mental illness (SMI) and the neural surface antibody (NSAb) seropositivity iceberg: psychiatrists will see both autoimmune encephalitis (AE), and synaptic and neuronal autoantibody-associated psychiatric syndromes (SNAps), and overlap areas. In practice, this means that all first-episode SMI with a subacute onset should be regarded as a yellow flag for AE and should be screened for relevant NSAbs (see Figure 4). If these cases have red flag clinical features, then there should be a low threshold for further investigations and liaison with neurology colleagues (see Figure 5). Screening cases of SMI with a longer onset or treatment resistance will yield cases with NSAbs; however, the management of these cases is less certain. There is an imperative for further well-designed research studies to characterize the biology and immunotherapy responsiveness of these cases.

Figure 4

Initial serum neural surface antibody panel recommended in subacute onset first-episode severe mental illness, at risk for autoimmune encephalitis, and to consider in cases with longer onset.

Figure 5

Suggested algorithm for neural surface antibody (NSAb) testing and further management in the context of severe mental illness (SMI).