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.

Autoimmune encephalitis with psychosis: Warning signs, step-by-step diagnostics and treatment

“…It should be noted that there is no single standard for the diagnosis of autoimmune encephalitis. We rely on an expert consensus of neuroimmunologists; see Tables 2 and 3: (Graus et al 2016) and its reception by English psychiatrists (Al-Diwani et al 2017), a recent opinion article (Ehrenreich 2017), the above mentioned retrospective study at the Charit e (Herken and Pr€ uss 2017) and our previously published German review paper on this topic ). This includes: a rapid progression of psychotic and/or affective symptoms despite psychopharmacotherapy, consciousness/orientation/memory impairment catatonia speech dysfunction neurological deficits, epileptic seizures autonomic dysfunction or hyponatremia.…”

Psychosis: an autoimmune disease?

“…) . Although NMDAR‐antibody encephalitis has an abrupt onset and a distinctive psychiatric phenotype, and usually progresses to frank neurological features, some features of an encephalopathy including catatonia, disorientation and more traditional cognitive deficits are not uncommon in primary psychotic disorders, and are probably under‐recognized . Estimates of NSAb prevalence in primary psychotic disorders have varied largely with symptom duration and assay approaches, but generally studies looking at patients early in their illness with live cell‐based assays have detected NMDAR‐IgG antibodies at higher rates than controls, whereas those looking at more chronic presentations with commercial fixed cell‐based assays have been negative .…”

N-Methyl-D-Aspartate(NMDA) Receptor and Voltage-Gated Potassium Channel (VGKC) Antibody-Associated Encephalitides Presenting as First Episode Acute Psychosis

“…These patients have antibodies directed against N-methyl-D-aspartate (NMDA) receptor, voltage-gated potassium channel (VGKC) complex, and its subunits, leucinerich glioma inactivated 1 (LGI1) and contactin-associated protein like 2 (CASPR2), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and gamma-aminobutyric acid (GABA) receptor. Their presence raises the possibility both of a causal or disease-modifying role and of clinical improvement with immunotherapy (6).…”

“…Most cases go on to develop neurological symptoms which would then trigger an evaluation for non-psychiatric illness, including infectious, autoimmune, neurodegenerative, and metabolic disorders which may cause psychotic symptoms. An important clinical challenge is identifying these patients in the course of their illness early, so that the selection of those requiring comprehensive evaluation can be rationalized (6,17). There have been studies examining the prevalence and incidence of autoimmune encephalitis in Western populations.…”