Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis

Jakob Theorell,Patrick Waters,Sophie Erhardt,Ruby Harrison,Leslie Jacobson,Melanie Ramberger,Carl M Sellgren,Sarosh R Irani,Simon Cervenka,Fredrik Piehl,Victor Mgbachi

doi:10.1038/s41398-021-01701-3

Abstract

Patients with autoimmune encephalitides, especially those with antibodies to the N-methyl-d-aspartate receptor (NMDAR), often present with prominent psychosis and respond well to immunotherapies. Although most patients progress to develop various neurological symptoms, it has been hypothesised that a subgroup of patients with first-episode psychosis (FEP) suffer from a forme fruste of autoimmune encephalitis. Without accurate identification, this immunotherapy-responsive subgroup may be denied disease-modifying treatments. Thirty studies addressing aspects of this hypothesis were identified in a systematic review. Amongst other shortcomings, 15/30 reported no control group and only 6/30 determined cerebrospinal fluid (CSF) autoantibodies. To ourselves address these—and other—limitations, we investigated a prospectively ascertained clinically well-characterised cohort of 71 FEP patients without traditional neurological features, and 48 healthy controls. Serum and CSF were tested for autoantibodies against seven neuronal surface autoantigens using live cell-based assays. These identified 3/71 (4%) patient sera with weak binding to either contactin-associated protein-like 2, the NMDAR or glycine receptor versus no binding from 48 control samples (p = 0.28, Fisher’s test). The three seropositive individuals showed no CSF autoantibodies and no differences from the autoantibody-negative patients in their clinical phenotypes, or across multiple parameters of peripheral and central inflammation. All individuals were negative for CSF NMDAR antibodies. In conclusion, formes frustes of autoimmune encephalitis are not prevalent among FEP patients admitted to psychiatric care. Our findings do not support screening for neuronal surface autoantibodies in unselected psychotic patients.

Highlights

In recent years, a group of immunotherapy-responsive autoimmune encephalitis (AE) syndromes have been discovered, which are associated with autoantibodies that target the extracellular domains of neuronal surface proteins [1,2,3]
In this study, potentially pathogenic serum immunoglobulin G (IgG) autoantibodies against neuronal surface proteins were found in serum, but not cerebrospinal fluid (CSF), from 4% of first-episode psychosis patients who lacked overt neurological features
Phenotypes and parameters fundamental to encephalitis and neuroinflammation were not enriched in seropositive first-episode psychosis patients, suggesting that these autoantibodies do not indicate the presence of mild encephalitis, and may represent clinically irrelevant results

Summary

Introduction

A group of immunotherapy-responsive autoimmune encephalitis (AE) syndromes have been discovered, which are associated with autoantibodies that target the extracellular domains of neuronal surface proteins [1,2,3]. This characteristic enables autoantibody binding to neurons and glia in vivo and confers their likely pathogenicity. Patients typically present with more classically neurological features such as headache, disorientation, catatonia, hyperkinesis and speech deficits [2, 5,6,7], the existence of formes frustes of AE has been proposed, especially in patients who display exclusive psychiatric symptoms [8, 9]. Such patients could be misdiagnosed with primary psychiatric illnesses and denied effective immunotherapies

Methods

Results

Conclusion