Background and Objectives Reliable biomarkers for autoimmune encephalitis (AE) are limited, and emerging CSF markers are not incorporated into current diagnostic criteria. Prognostic tools remain insufficient, highlighting the need for biomarkers that support both early diagnosis and assessment of disease severity and prognosis. Methods In this multicenter prospective cohort study, we analyzed clinical data and paired CSF-serum samples from adults with definite AE enrolled in the German Network for Research on Autoimmune Encephalitis registry and the CSF biobank of Hannover Medical School. Of 2,330 screened individuals, 92 patients with anti–N-methyl-d-aspartate receptor (NMDAR, n = 53), anti–leucine-rich glioma-inactivated 1 (LGI1, n = 20), or anti–contactin-associated protein-like 2 (CASPR2, n = 19) encephalitis were included and followed longitudinally for a median of 38 months. Control groups comprised patients with relapsing multiple sclerosis, varicella-zoster virus encephalitis, and noninflammatory neurologic conditions (each n = 30), as well as antibody-positive patients without AE (n = 15), with the groups frequency-matched for age and sex. Kappa free light chain (KFLC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and cytokines were measured in paired CSF-serum samples obtained at baseline and during follow-up. Disease severity and disability were assessed using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score and the modified Rankin Scale (mRS). Results Intrathecal synthesis of KFLC was detected in 94% of anti-NMDAR, 50% of anti-LGI1, and 53% of anti-CASPR2 encephalitis cases, demonstrating higher diagnostic sensitivity than CSF-restricted oligoclonal bands or pleocytosis. Diagnostic specificity across pooled control groups was moderate at 44% but reached 90% when compared with noninflammatory neurologic controls. CSF NfL z-score levels were strongly associated with baseline disease severity, with each 1-standard deviation increase corresponding to an approximately 10-point higher CASE score, independent of clinical covariates (β = 0.61). Longitudinal changes in NfL concentrations in CSF and serum were associated with disease severity and neurologic disability at follow-up (CASE score: adjusted R2 = 0.401; mRS score: adjusted R2 = 0.203). GFAP and cytokines showed limited diagnostic or prognostic utility. Discussion Intrathecal KFLC synthesis represents a highly sensitive CSF marker that supports early suspicion of autoimmune encephalitis and prompts antibody testing. NfL provides robust biochemical information on baseline disease severity and longitudinal changes that may aid prognostic assessment across AE subtypes.
F. Konen, E. Bucak, F. Bachhuber et al.· Neurology(R) neuroimmunology...· 0 citations
Importance
Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation.
Objective
To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA).
Design, Setting, and Participants
This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements).
Exposures
Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months.
Main Outcomes and Measures
Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC).
Results
The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively.
Conclusions and Relevance
In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.
M. Einsiedler, S. Sandgren, S. Schaedelin et al.· JAMA Neurology· 0 citations
ZUSAMMENFASSUNG Serum-Neurofilament-Leichtkette (sNfL) ist ein Biomarker für neuroaxonalen Schaden und korreliert mit klinischer und bildgebender Krankheitsaktivität, Hirnatrophie und Behinderungsprogression, ist jedoch nicht krankheitsspezifisch. Diese Übersichtsarbeit fasst aktuelle Aspekte der Messmethodik, Präanalytik und Interpretation von sNfL zusammen. Besondere Bedeutung haben zentrale Einflussfaktoren wie Alter, Body-Mass-Index beziehungsweise Verteilungsvolumen, Nierenfunktion sowie andere Einflussfraktoren. Für die klinische Anwendung ist daher eine standardisierte Bewertung anhand alters- und BMI-korrigierter Referenzdaten, etwa über Z-Scores oder Perzentile, entscheidend. Klinisch kann sNfL die initiale Risikostratifizierung und Therapieplanung unterstützen, im Verlauf als Frühwarnsignal für subklinische Krankheitsaktivität dienen, die Abgrenzung von Schub und Pseudoschub erleichtern, progrediente Verläufe ergänzend charakterisieren und Entscheidungen in besonderen Situationen wie Schwangerschaft, höherem Lebensalter oder Deeskalation begleiten. Dabei sind serielle Messungen einzelnen Bestimmungen überlegen. Zukünftige Prioritäten sollten in der Harmonisierung der Assays sowie in prospektiven Studien zu NfL-gestützten, multimodalen Entscheidungsstrategien liegen.
Hernan Inojosa, Katja Akgün, L. Masanneck et al.· Fortschritte der Neurologie...· 0 citations
A review of current evidence on established and emerging fluid biomarkers in NMOSD and MOGAD, with emphasis on analytical performance, biological relevance, and clinical utility, and outlines priorities for future research.
S. Mariotto, Á. Cobo-Calvo, Michael Khalil et al.· Neurology(R) neuroimmunology...· 0 citations
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