Editors' Note: Neurofilament Light Chain Levels in Anti-NMDAR Encephalitis and Primary Psychiatric Psychosis

Abstract

Dr. Guasp et al. assessed the performance of serum neurofilament light chain (NfL) testing in differentiating anti-NMDA receptor encephalitis (NMDARe) from psychiatric causes of a first episode of psychosis (pFEP) in an observational study of 118 patients with NMDARe (33 of whom had isolated psychosis at presentation), comparing them with 45 patients with pFEP, 36 patients with herpes simplex encephalitis (HSV), and 36 healthy controls. They found that young patients with first episode psychosis and serum NfL ≥15 pg/mL had a 120 times higher chance of having NMDARe than pFEP, with this cutoff correctly classifying 96% of patients with pFEP and 85% of patients with NMDARe and isolated psychosis. Notably, all patients with HSV also had serum NFL≥15 pg/mL. The authors concluded that patients with first episodes of psychosis of unclear etiology and serum NfL ≥15 pg/mL should undergo testing for NMDAR antibodies in the CSF. In response, Dr. Vale notes that the presence of NMDAR antibodies is not essential for diagnosing autoimmune encephalitis, given that other autoantibodies can cause psychotic presentations, and that elevations of NfL may reflect comorbidities causing central or peripheral neuroaxonal damage. Dr. Vale argues that given the severity of first episodes of psychosis, all such patients should be considered for CSF examinations, as was the historical practice for concerns of neurosyphilis. Responding to these comments, the authors agree that CSF studies should be reincorporated in the evaluation of patients with new onset psychosis, but note that they restricted their study to the identification of NMDARe, given that this condition can almost perfectly mimic psychiatric causes of first episodes of psychosis, in contrast to other autoimmune encephalitides, which typically have other concurrent neurologic features. They argue that the usefulness of serum NfL testing seen in their study is a relevant finding, regardless of any other underlying contributors to NfL elevation. This exchange highlights the importance of ongoing research into noninvasive markers of neurologic causes of psychosis. It is the editors' opinion that in practice, routine CSF testing for all patients with first episodes of psychosis is unlikely to be feasible in all psychiatric facilities, and as such, screening using serum markers will likely complement clinical examination-guided autoantibody testing in the future. Dr. Guasp et al. assessed the performance of serum neurofilament light chain (NfL) testing in differentiating anti-NMDA receptor encephalitis (NMDARe) from psychiatric causes of a first episode of psychosis (pFEP) in an observational study of 118 patients with NMDARe (33 of whom had isolated psychosis at presentation), comparing them with 45 patients with pFEP, 36 patients with herpes simplex encephalitis (HSV), and 36 healthy controls. They found that young patients with first episode psychosis and serum NfL ≥15 pg/mL had a 120 times higher chance of having NMDARe than pFEP, with this cutoff correctly classifying 96% of patients with pFEP and 85% of patients with NMDARe and isolated psychosis. Notably, all patients with HSV also had serum NFL≥15 pg/mL. The authors concluded that patients with first episodes of psychosis of unclear etiology and serum NfL ≥15 pg/mL should undergo testing for NMDAR antibodies in the CSF. In response, Dr. Vale notes that the presence of NMDAR antibodies is not essential for diagnosing autoimmune encephalitis, given that other autoantibodies can cause psychotic presentations, and that elevations of NfL may reflect comorbidities causing central or peripheral neuroaxonal damage. Dr. Vale argues that given the severity of first episodes of psychosis, all such patients should be considered for CSF examinations, as was the historical practice for concerns of neurosyphilis. Responding to these comments, the authors agree that CSF studies should be reincorporated in the evaluation of patients with new onset psychosis, but note that they restricted their study to the identification of NMDARe, given that this condition can almost perfectly mimic psychiatric causes of first episodes of psychosis, in contrast to other autoimmune encephalitides, which typically have other concurrent neurologic features. They argue that the usefulness of serum NfL testing seen in their study is a relevant finding, regardless of any other underlying contributors to NfL elevation. This exchange highlights the importance of ongoing research into noninvasive markers of neurologic causes of psychosis. It is the editors' opinion that in practice, routine CSF testing for all patients with first episodes of psychosis is unlikely to be feasible in all psychiatric facilities, and as such, screening using serum markers will likely complement clinical examination-guided autoantibody testing in the future.