Abstract
Circulating and cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels represent a reliable indicator of disease activity and axonal damage in different neuroinflammatory conditions. Recently, high CSF NfL levels have been detected in active autoimmune encephalitis, as opposed to significant lower levels after clinical improvement. The aim of the present study was to evaluate serum and CSF NfL concentration in patients with autoimmune encephalitis and to analyse the association between NfL levels and clinical, MRI, and CSF data. We retrospectively included 25 patients with neurological syndromes associated with autoantibodies to neuronal cell surface antigens and we collected clinical, MRI, CSF, and follow-up data. Using an ultrasensitive method (Simoa, Quanterix), we measured NfL levels in serum and CSF samples of all patients and in 25 sera of healthy controls. Serum NfL levels were higher in all cases, including 20 patients with inflammatory MRI/CSF features and 5 non-inflammatory cases (median 16.9 pg/ml, range 4.5–90) than in controls (median 6.9 pg/ml, range 2.7–12.8; p < 0.001). A correlation between serum and CSF NfL levels was found (r = 0.461, p = 0.023), whereas no significant association was observed between NfL levels and clinical, MRI/CSF inflammatory burden, and antibody type. In the 13 available follow-up samples, correlation between disease activity and NfL values was also observed. In conclusion, NfL levels are significantly increased in the serum of patients with antibody-mediated encephalitis, independently of the MRI/CSF inflammatory profile. These findings support the presence of ongoing axonal damage and suggest the co-occurrence of different mechanisms for neuronal/axonal involvement in antibody-associated CNS syndromes.
Similar content being viewed by others
References
Gaiottino J, Norgren N, Dobson R, Topping J, Nissim A, Malaspina A, Bestwick JP, Monsch AU, Regeniter A, Lindberg RL, Kappos L, Leppert D, Petzold A, Giovannoni G, Kuhle J (2013) Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One 8:e75091
Rossi D, Volanti P, Brambilla L, Colletti T, Spataro R, La Bella V (2018) CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis. J Neurol 265:510–521
Byrne LM, Rodrigues FB, Blennow K, Durr A, Leavitt BR, Roos RAC, Scahill RI, Tabrizi SJ, Zetterberg H, Langbehn D, Wild EJ (2017) Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington’s disease: a retrospective cohort analysis. Lancet Neurol 16:601–609
Meeter LHH, Vijverberg EG, Del Campo M, Rozemuller AJM, Donker Kaat L, de Jong FJ, van der Flier WM, Teunissen CE, van Swieten JC, Pijnenburg YAL (2018) Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum. Neurology 90:e1231–e1239
Rohrer JD, Woollacott IO, Dick KM, Brotherhood E, Gordon E, Fellows A, Toombs J, Druyeh R, Cardoso MJ, Ourselin S, Nicholas JM, Norgren N, Mead S, Andreasson U, Blennow K, Schott JM, Fox NC, Warren JD, Zetterberg H (2016) Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology 87:1329–1336
Gille B, De Schaepdryver M, Goossens J, Dedeene L, De Vocht J, Oldoni E, Goris A, Van Den Bosch L, Depreitere B, Claeys KG, Tournoy J, Van Damme P, Poesen K (2018) Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. https://doi.org/10.1111/nan.12511
Donker Kaat L, Meeter LH, Chiu WZ, Melhem S, Boon AJW, Blennow K, Zetterberg H, van Swieten JC (2018) Serum neurofilament light chain in progressive supranuclear palsy. Parkinsonism Relat Disord 56:98–101
Mariotto S, Farinazzo A, Monaco S, Gajofatto A, Zanusso G, Schanda K, Capra R, Mancinelli C, Bonora A, Bombardi R, Reindl M, Ferrari S (2017) Serum neurofilament light chain in NMOSD and related disorders: comparison according to aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies status. Mult Scler J Exp Transl Clin 3:2055217317743098
Kuhle J, Barro C, Disanto G, Mathias A, Soneson C, Bonnier G, Yaldizli Ö, Regeniter A, Derfuss T, Canales M, Schluep M, Du Pasquier R, Krueger G, Granziera C (2016) Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity. Mult Scler 22:1550–1559
Kuhle J, Nourbakhsh B, Grant D, Morant S, Barro C, Yaldizli Ö, Pelletier D, Giovannoni G, Waubant E, Gnanapavan S (2017) Serum neurofilament is associated with progression of brain atrophy and disability in early MS. Neurology 88:826–831
Novakova L, Zetterberg H, Sundström P, Axelsson M, Khademi M, Gunnarsson M, Malmeström C, Svenningsson A, Olsson T, Piehl F, Blennow K, Lycke J (2017) Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology 89:2230–2237
Disanto G, Barro C, Benkert P, Naegelin Y, Schädelin S, Giardiello A, Zecca C, Blennow K, Zetterberg H, Leppert D, Kappos L, Gobbi C, Kuhle J, Swiss Multiple Sclerosis Cohort Study Group (2017) Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol 81:857–870
Håkansson I, Tisell A, Cassel P, Blennow K, Zetterberg H, Lundberg P, Dahle C, Vrethem M, Ernerudh J (2017) Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing-remitting multiple sclerosis. Eur J Neurol 24:703–712
Siller N, Kuhle J, Muthuraman M, Barro C, Uphaus T, Groppa S, Kappos L, Zipp F, Bittner S (2018) Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis. Mult Scler. https://doi.org/10.1177/1352458518765666
Varhaug KN, Barro C, Bjørnevik K, Myhr KM, Torkildsen Ø, Wergeland S, Bindoff LA, Kuhle J, Vedeler C (2017) Neurofilament light chain predicts disease activity in relapsing-remitting MS. Neurol Neuroimmunol Neuroinflamm 5:e422
Constantinescu R, Krýsl D, Bergquist F, Andrén K, Malmeström C, Asztély F, Axelsson M, Menachem EB, Blennow K, Rosengren L, Zetterberg H (2016) Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outcome in patients with autoimmune encephalitis. Eur J Neurol 23:796–806
Constantinescu R, Krýsl D, Andrén K, Asztély F, Bergquist F, Zetterberg H, Andreasson U, Axelsson M, Menachem EB, Jons D, Mahamud U, Malmeström C, Rosengren L, Blennow K (2017) Cerebrospinal fluid markers of neuronal and glial cell damage in patients with autoimmune neurologic syndromes with and without underlying malignancies. J Neuroimmunol 306:25–30
Dalmau J, Geis C, Graus F (2017) Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 97:839–887
Höftberger R (2015) Neuroimmunology: an expanding frontier in autoimmunity. Front Immunol 6:206
Dalmau J, Graus F (2018) Antibody-mediated encephalitis. N Engl J Med 378:840–851
Finke C, Kopp UA, Scheel M, Pech LM, Soemmer C, Schlichting J, Leypoldt F, Brandt AU, Wuerfel J, Probst C, Ploner CJ, Prüss H, Paul F (2013) Functional and structural brain changes in anti-N-methyl-d-aspartate receptor encephalitis. Ann Neurol 74:284–296
Irani SR, Bera K, Waters P, Zuliani L, Maxwell S, Zandi MS, Friese MA, Galea I, Kullmann DM, Beeson D, Lang B, Bien CG, Vincent A (2010) N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133:1655–1667
Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7:1091–1098
Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12:157–165
Bien CG, Vincent A, Barnett MH, Becker AJ, Blümcke I, Graus F, Jellinger KA, Reuss DE, Ribalta T, Schlegel J, Sutton I, Lassmann H, Bauer J (2012) Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135:1622–1638
Tüzün E, Zhou L, Baehring JM, Bannykh S, Rosenfeld MR, Dalmau J (2009) Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol 118:737–743
Barro C, Benkert P, Disanto G, Tsagkas C, Amann M, Naegelin Y, Leppert D, Gobbi C, Granziera C, Yaldizli Ö, Michalak Z, Wuerfel J, Kappos L, Parmar K, Kuhle J (2018) Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain 141:2382–2391
Funding
This work was supported by the Ministry of Health (RF-2011-0234-7955).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
Sa.Ma. was sponsored by Merck for attending a scientific meeting. AG received research support funding from Merck. Sa.Mo. received honoraria from Biogen. S.F. was sponsored by Shire for attending a scientific meeting. The other authors declare that they have no conflict of interest.
Ethics standards
All human studies have been performed in accordance with the ethical standards laid down in the 1964 declaration of Helsinki and its later amendments.
Informed consent
We collected consented to diagnostic procedures and biological sample storage at the referring laboratory for research use from all patients or legal representatives.
Rights and permissions
About this article
Cite this article
Mariotto, S., Gajofatto, A., Zuliani, L. et al. Serum and CSF neurofilament light chain levels in antibody-mediated encephalitis. J Neurol 266, 1643–1648 (2019). https://doi.org/10.1007/s00415-019-09306-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-019-09306-z