The prognostic role of cerebrospinal fluid molecular biomarkers determined in early pathogenic stages of multiple sclerosis has yet to be defined. In the present study, we aimed to investigate the prognostic value of chitinase 3 like 1 (CHI3L1), neurofilament light chain, and oligoclonal bands for conversion to clinically isolated syndrome and to multiple sclerosis in 75 patients with radiologically isolated syndrome. Cerebrospinal fluid levels of CHI3L1 and neurofilament light chain were measured by enzyme-linked immunosorbent assay. Uni- and multivariable Cox regression models including as covariates age at diagnosis of radiologically isolated syndrome, number of brain lesions, sex and treatment were used to investigate associations between cerebrospinal fluid CHI3L1 and neurofilament light chain levels and time to conversion to clinically isolated syndrome and multiple sclerosis. Neurofilament light chain levels and oligoclonal bands were independent risk factors for the development of clinically isolated syndrome (hazard ratio = 1.02, P = 0.019, and hazard ratio = 14.7, P = 0.012, respectively) and multiple sclerosis (hazard ratio = 1.03, P = 0.003, and hazard ratio = 8.9, P = 0.046, respectively). The best cut-off to classify cerebrospinal fluid neurofilament light chain levels into high and low was 619 ng/l, and high neurofilament light chain levels were associated with a trend to shorter time to clinically isolated syndrome (P = 0.079) and significant shorter time to multiple sclerosis (P = 0.017). Similarly, patients with radiologically isolated syndrome presenting positive oligoclonal bands converted faster to clinically isolated syndrome and multiple sclerosis (P = 0.005 and P = 0.008, respectively). The effects of high neurofilament light chain levels shortening time to clinically isolated syndrome and multiple sclerosis were more pronounced in radiologically isolated syndrome patients with ≥37 years compared to younger patients. Cerebrospinal fluid CHI3L1 levels did not influence conversion to clinically isolated syndrome and multiple sclerosis in radiologically isolated syndrome patients. Overall, these findings suggest that cerebrospinal neurofilament light chain levels and oligoclonal bands are independent predictors of clinical conversion in patients with radiologically isolated syndrome. The association with a faster development of multiple sclerosis reinforces the importance of cerebrospinal fluid analysis in patients with radiologically isolated syndrome.

1st Pavlov Saint Petersburg State Medical University Saint Petersburg Russia

Center of Neuroimmunology Service of Neurology Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi Sunyer Barcelona Spain

Department of Neurology Charles University Prague 1st Faculty of Medicine Prague Czech Republic

Department of Neurology Medical University of Lublin Lublin Poland

Department of Neurology Neuroimmunological Section University of Rostock Rostock Germany

Departments of Neurology and Immunology Hospital Universitario Ramón y Cajal Instituto Ramón y Cajal de Investigacion Sanitaria Madrid Spain

Hospital Clínico San Carlos Servicio de Neurología Instituto de Investigación Sanitaria del Hospital Clínico San Carlos Madrid Spain

Medical University of Innsbruck Department of Neurology Innsbruck Austria

MS Center Saint Petersburg Russia 1st Pavlov Saint Petersburg State Medical University Saint Petersburg Russia

Neuroimmunology Unit Hospital Universitario Puerta de Hierro Madrid Spain

Neurology Clinic Clinical Centre of Serbia Belgrade Serbia

Servei de Neurologia Neuroimmunologia Centre d'Esclerosi Múltiple de Catalunya Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona Barcelona Spain

Unitat d'Estadística i Bioinformàtica VHIR Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona Barcelona Spain Genetics Microbiology and Statistics Department Universitat de Barcelona Barcelona Spain

Unitat de Neuroimmunologia i Esclerosi Múltiple Servei de Neurologia Hospital Universitari Dr Josep Trueta Institut d'Investigació Biomèdica de Girona Girona Spain

University of Milan Fondazione Ca' Granda IRCCS Ospedale Policlinico Milan Italy

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$a Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome / $c C. Matute-Blanch, LM. Villar, JC. Álvarez-Cermeño, K. Rejdak, E. Evdoshenko, G. Makshakov, V. Nazarov, S. Lapin, L. Midaglia, A. Vidal-Jordana, J. Drulovic, A. García-Merino, AJ. Sánchez-López, E. Havrdova, A. Saiz, S. Llufriu, R. Alvarez-Lafuente, I. Schroeder, UK. Zettl, D. Galimberti, L. Ramió-Torrentà, R. Robles, E. Quintana, H. Hegen, F. Deisenhammer, J. Río, M. Tintoré, A. Sánchez, X. Montalban, M. Comabella,

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$a The prognostic role of cerebrospinal fluid molecular biomarkers determined in early pathogenic stages of multiple sclerosis has yet to be defined. In the present study, we aimed to investigate the prognostic value of chitinase 3 like 1 (CHI3L1), neurofilament light chain, and oligoclonal bands for conversion to clinically isolated syndrome and to multiple sclerosis in 75 patients with radiologically isolated syndrome. Cerebrospinal fluid levels of CHI3L1 and neurofilament light chain were measured by enzyme-linked immunosorbent assay. Uni- and multivariable Cox regression models including as covariates age at diagnosis of radiologically isolated syndrome, number of brain lesions, sex and treatment were used to investigate associations between cerebrospinal fluid CHI3L1 and neurofilament light chain levels and time to conversion to clinically isolated syndrome and multiple sclerosis. Neurofilament light chain levels and oligoclonal bands were independent risk factors for the development of clinically isolated syndrome (hazard ratio = 1.02, P = 0.019, and hazard ratio = 14.7, P = 0.012, respectively) and multiple sclerosis (hazard ratio = 1.03, P = 0.003, and hazard ratio = 8.9, P = 0.046, respectively). The best cut-off to classify cerebrospinal fluid neurofilament light chain levels into high and low was 619 ng/l, and high neurofilament light chain levels were associated with a trend to shorter time to clinically isolated syndrome (P = 0.079) and significant shorter time to multiple sclerosis (P = 0.017). Similarly, patients with radiologically isolated syndrome presenting positive oligoclonal bands converted faster to clinically isolated syndrome and multiple sclerosis (P = 0.005 and P = 0.008, respectively). The effects of high neurofilament light chain levels shortening time to clinically isolated syndrome and multiple sclerosis were more pronounced in radiologically isolated syndrome patients with ≥37 years compared to younger patients. Cerebrospinal fluid CHI3L1 levels did not influence conversion to clinically isolated syndrome and multiple sclerosis in radiologically isolated syndrome patients. Overall, these findings suggest that cerebrospinal neurofilament light chain levels and oligoclonal bands are independent predictors of clinical conversion in patients with radiologically isolated syndrome. The association with a faster development of multiple sclerosis reinforces the importance of cerebrospinal fluid analysis in patients with radiologically isolated syndrome.

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