Neurofilament Light Chain Levels in Anti-NMDAR Encephalitis and Primary Psychiatric Psychosis

Abstract

Introduction:An important challenge in diagnosing anti-NMDAR encephalitis (NMDARe) is differentiating it from a first episode of psychosis (FEP) caused by a psychiatric disease (pFEP). CSF antibody testing distinguishes these diseases, but spinal taps are difficult to obtain in psychiatric facilities. A separate problem is the lack of biomarkers of NMDARe severity and outcome. Here we assessed the performance of neurofilament light chain (NfL) testing in these settings.Methods:In this observational study, NfL were determined with Single molecule array (SiMoA) in patients with NMDARe, pFEP, herpes simplex encephalitis (HSE), and healthy subjects (HC), the latter two groups used as controls. Receiver operating characteristic (ROC) analyses were performed to assess the prediction accuracy of serum NfL (sNfL) levels for NMDARe and pFEP, and to obtain clinically useful cutoffs.Results:118 patients with NMDARe (33 with isolated psychosis at presentation), 45 pFEP, 36 HSE, and 36 HC were studied. NMDARe patients with seizures/status epilepticus, ICU admission, CSF pleocytosis (>20 WBC/µL), and without early immunotherapy were more likely to have higher sNfL than NMDARe without these features. NfL levels at diagnosis of NMDARe did not correlate with outcome at 1 year follow-up assessed with the modified Ranking Scale (mRS). NMDARe patients had significantly higher NfL than pFEP and HC, and lower than HSE patients. ROC analysis of sNfL between NMDARe with isolated psychosis and pFEP provided an AUC of 0.93 (95% CI 0.87-0.99) and a sNfL cutoff ≥15 pg/mL to distinguish these disorders (sensitivity 85%, specificity 96%, positive likelihood ratio 19.3). Forty-three/45 (96%) pFEP had sNfL<15pg/mL whereas only 5/33 (15%) NMDARe with isolated psychosis were below this cutoff (risk estimation NMDARe vs pFEP: odds ratio 120.4 [95% CI 21.8-664], p<0.001). None of the HSE and 35/36 (97%) HC had sNfL<15pg/mL.Discussion:NfL measured at diagnosis of NMDARe associated with features of disease severity but not with long-term outcome. Young patients with FEP and sNfL≥15pg/mL had 120 times higher chance of having NMDARe than pFEP. This cutoff correctly classified 96% of pFEP and 85% of NMDARe with isolated psychosis. Patients with FEP of unclear etiology and sNfL≥15pg/mL should undergo CSF NMDAR-antibody testing.

Advances in Potential Cerebrospinal Fluid Biomarkers for Autoimmune Encephalitis: A Review

“…Kammeyer et al (117) collected 26 plasma and 14 CSF samples of patients with autoimmune neurological disorders, compared to the control group, and patients with active AE show an elevated level of plasma Nfl, implying that it may act as a minimally-invasive biomarker for CNS injury during AE development. Another study also confirmed the opinion that the Nfl level is closely related to disease severity during diagnosis (118).…”

NMDAR autoantibodies in psychiatric disease - An immunopsychiatric continuum and potential predisposition for disease pathogenesis

“…2 ). It seems relevant if neurodegeneration markers such as neurofilament light chains are elevated and exceed 15 pg/ml in patients experiencing their first psychotic episode, if those patients develop NMDARE [ 41 ]. Another issue seems to be the presence of CSF-NMDAR antibodies, as such CSF-NMDAR autoantibodies are associated with a higher percentage of patients suffering from psychiatric symptoms [ 42 ].…”

“…In such cases other tools might help identify patients with a potential NMDAR-antibody associated encephalitis, like quantitative EEGs with a fast-slow ratio index as a very sensitive early sign of NMDAR encephalitis [ 49 ]. There are other markers of neuronal damage in the same context that might help identify first-episode psychosis patients with NMDAR antibodies as neurofilament light chains is a particular marker of disease severity in first-episode psychosis, but not a long-term disease marker, as a recent study by Guasp et al [ 41 ] showed. Old and novel biomarkers could thus help us interrupt the autoimmune continuum of NMDAR pathogenicity from psychiatric diseases associated with NMDAR autoantibodies and NMDARE ( Fig.…”

The clinical relevance of serum versus CSF NMDAR autoantibodies associated exclusively with psychiatric features: a systematic review and meta-analysis of individual patient data

“…Given the current lack of availability of lumbar puncture facilities in most mental healthcare settings, further research using prospective methods is urgently needed to investigate the feasibility of developing a clinical tool that captures the complex psychopathology associated with NMDAR-antibody mediated disorders. In addition, alternative biomarkers that do not require CSF sampling, such as neurofilament light chain, may have clinical utility in identifying patients with NMDARE[ 13 ]. Such approaches would help clinicians identify which patients are in greatest need of CSF antibody testing [ 1 ].…”