To Örebro University

Introduction: Epstein-Barr virus (EBV) infection may be a pre-condition  for  the development  of  multiple  sclerosis  (MS).  EBV  antibodies, predominantly anti-EBNA1, develop in the presymp-tomatic phase of virtually all MS patients. Using material from a serum repository, studies in advance of MS onset indicated that EBV  seropositivity  preceded  the  first  expression  of  incipient  axonal lesions, serum Neurofilament Light (sNFL) .

Objectives: To  determine  the  onset  and  individual  order  of  appearance  of EBV  seroreactivity  and  the  serum  neuroaxonal  injury marker neurofilament light (sNfL) in a wide age spectrum of presymptomatic MS patients.

Aims: To  characterize  the  presymptomatic  appearance  of  anti-bodies against an intranuclear (EBNA1) and a surface EBV anti-gen (gp350) and sNfL.Methods:  A nested  case-control  study  in  669  pre-symptomati-cally acquired blood samples from persons who later received an MS diagnosis, and from 1:1 matched control persons. Serum lev-els of EBNA1, VCA and gp350 IgG antibodies and sNFL (n=519) were   measured   in   individual   presymptomatic   samples   and   expressed  as delta  scores  with  matched  controls  in  relation  to  time until MS onset.

Results: Serum levels expressed as delta scores for anti EBV and NfL IgG showed an incipient increase for anti EBNA1 and gp350 from  15-20  years  before  MS debut.  Significant  (p=0.001  and  p=0.002) from 10-15 years, with consistent delta-scores succes-sively closer to MS onset. These findings contrasted to the level of sNfL which increasingly diverged from matched controls from 5-10 years before the onset of MS. None of the individual sam-ples  negative  for  both EBNA1 and  VCA  IgG  antibodies  in  the  pre-MS group (n = 36) showed any elevation of the sNfL level.

Conclusions: In  a  pre-MS  material,  the  seroreactivity  against  EBNA1  was followed  by  VCA  and  gp350,  before  increased  sNFL appeared, indicating incipient axonal injury. Together with its biological characteristics this temporal order confirms the role of EBV as a trigger of MS.