CSF-Neurofilament Light Chain Levels in NMDAR and LGI1 Encephalitis: A National Cohort Study

Abstract

Background and ObjectivesThe two most common autoimmune encephalitides (AE), N-methyl-D-Aspartate receptor (NMDAR) and Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis, have been known for more than a decade. Nevertheless, no well-established biomarkers to guide treatment or estimate prognosis exist. Neurofilament light chain (NfL) has become an unspecific screening marker of axonal damage in CNS diseases, and has proven useful as a diagnostic and disease activity marker in neuroinflammatory diseases. Only limited reports on NfL in AE exist. We investigated NfL levels at diagnosis and follow-up in NMDAR and LGI1-AE patients, and evaluated the utility of CSF-NfL as a biomarker in AE.MethodsPatients were included from the National Danish AE cohort (2009-present) and diagnosed based upon autoantibody positivity and diagnostic consensus criteria. CSF-NfL was analyzed by single molecule array technology. Clinical and diagnostic information was retrospectively evaluated and related to NfL levels at baseline and follow-up. NMDAR-AE patients were subdivided into: idiopathic/teratoma associated or secondary NMDAR-AE (post-viral or concomitant with malignancies/demyelinating disease).ResultsA total of 74 CSF samples from 53 AE patients (37 NMDAR and 16 LGI1 positive) were included in the study. Longitudinal CSF-NfL levels was measured in 21 patients. Median follow-up time was 23.8 and 43.9 months for NMDAR and LGI1-AE respectively. Major findings of this study are: i) CSF-NfL levels were higher in LGI1-AE than in idiopathic/teratoma associated NMDAR-AE at diagnosis; ii) CSF-NfL levels in NMDAR-AE patients distinguished idiopathic/teratoma cases from cases with other underlying etiologies (post-viral or malignancies/demyelinating diseases) and iii) Elevated CSF-NfL at diagnosis seems to be associated with worse long-term disease outcomes in both NMDAR and LGI1-AE.DiscussionCSF-NfL measurement may be beneficial as a prognostic biomarker in NMDAR and LGI1-AE, and high CSF-NfL could foster search for underlying etiologies in NMDAR-AE. Further studies on larger cohorts, using standardized methods, are warranted.

Life after autoantibody-mediated encephalitis: optimizing follow-up and management in recovering patients

“…These findings build upon a prior longitudinal study showing that higher CSF concentrations of neurofilament light chain (NfL) - a marker of neuroaxonal injury - were associated with worse long-term clinical outcomes in NMDAR AME patients [44]. Similarly, higher CSF NfL levels at diagnosis were associated with higher mRS at follow-up in patients with NMDAR or LGI1 AME [45]. Collectively, these findings suggest that CSF biomarkers may be used to stratify patients based on disease activity.…”

“…Beyond autoantibody levels, biomarkers of neuronal and synaptic injury may provide a more direct measure of the neural processes that drive outcomes in AME. In a recent multicenter study including data from 46 ]. Moreover, in the subset of patients with available longitudinal clinical data, markers of neuroinflammation and synaptic dysfunction at presentation associated with 1-year functional outcomes [44 & ].…”

Philosophical Approach to Neural Autoantibodies in Psychiatric Disease—Multi-Systemic Dynamic Continuum from Protective to Harmful Autoimmunity in Neuronal Systems

“…Anomalies in one cognitive system can affect other cognitive systems. Autoantibodies can enter the brain and induce a severe inflammation that can also trigger transient or persistent focal brain damage, such as hippocampal damage in LGI1 autoantibody-associated disease [ 4 ] or unspecific axonal brain damage indicated by elevated neurofilament light chains in the cerebrospinal fluid in LGI1 and NMDAR encephalitis [ 35 ]. Harmful autoimmunity, compared to regulatory or protective autoimmunity, is more relevant for diagnostics, as in conditions of harmful autoimmunity brain damage or brain inflammation can be found.…”

CHI3L1 in the CSF is a potential biomarker for anti-leucine-rich glioma inactivated 1 encephalitis

“…Autoimmune encephalitis is often accompanied by inflammatory cell activation and cytokineproduction during pathogenesis ( 15 , 16 ). Anti-LGI1 encephalitis patients have elevated neurofilament light chain protein, glial fibrillary acidic protein and chemokine ligand 13 levels and reduced Visinin-like protein 1, Synaptosomal Associated Protein-25 (SNAP-25) and neurogranin levels in the serumand CSF ( 17 – 21 ). However, none of these biomarkers reflect microglia activation.…”