Epstein-Barr virus antibodies in serum and DNA load in saliva are not associated with radiological or clinical disease activity in patients with early multiple sclerosis

OBJECTIVE: To investigate the association of Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) and viral capsid antigen (VCA) immunoglobulin (Ig)G antibodies in serum as well as EBV DNA load in saliva with radiological and clinical disease activity in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS). METHODS: EBNA-1 and VCA immunoglobulin (Ig)G antibodies were determined in serum of 100 patients with CIS/early RRMS and 60 healthy controls. EBV DNA load was measured in saliva of 48 patients and 50 controls. Patients underwent clinical assessment with the Expanded Disability Status Scale (EDSS) and 3 Tesla magnetic resonance imaging at baseline and after a median of 20 months of follow-up (n = 63 for MRI, n = 71 for EDSS). The association of EBV parameters with occurrence of a second relapse, indicating conversion to clinically definite MS (CDMS), was evaluated over a median of 35 months of follow-up after the first clinical event (n = 89). RESULTS: BNA-1 IgG antibody frequency (p = 0.00005) and EBNA-1 and VCA IgG antibody levels (p<0.0001 for both) were higher in patients than in controls. EBV DNA load in saliva did not differ between groups. Neither EBV antibody levels nor DNA load in saliva were associated with baseline or follow-up number or volume of T2-weighted (T2w) or contrast enhancing lesions, number of Barkhof criteria or the EDSS, or with the number of new T2w lesions, T2w lesion volume change or EDSS change on follow-up. Likewise, levels of EBV IgG antibodies in serum and DNA load in saliva were not associated with conversion to CDMS. CONCLUSIONS: While these findings confirm the association of EBV infection with early MS, neither EBNA-1 nor VCA IgG antibodies in serum nor EBV DNA load in saliva were associated with radiological or clinical disease activity in patients with CIS/early RRMS. These data are compatible with the concept that EBV may be a trigger for MS acting very early during the development of the disease

Retinal imaging and axonal degeneration in later onset multiple sclerosis

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease of the CNS typically affecting younger adults and resulting in neuro-axonal degeneration already at early stages of the disease. Less is known about the effects of a later disease onset (LOMS, onset >50years of age). Analysis of retinal layers by optical coherence tomography (OCT) is a non-invasive method to investigate retinal and neuro-axonal degeneration. We applied OCT to detect differences in retinal damage depending on a later disease manifestation. METHODS: 14 LOMS patients, 14 age- and 14 disease duration-matched normal onset (NOMS) patients with a relapsing remitting disease course and 15 healthy controls (HC) were included. OCT measurement of peripapillary retinal nerve fiber layer (RNFL), total macular volume (TMV), combined ganglion cell/inner plexiform layer (GCIPL), inner nuclear layer (INL) and outer retinal layers (ORL) was conducted. Furthermore, analysis of clinical features and of effects of previous optic neuritis (ON) was performed RESULTS: In a GEE based analysis of age- and disease duration matched NOMS, LOMS patients show no significant differences in retinal layer thickness whereas ON significantly reduced thickness of retinal layers. All MS groups display lower retinal layer thickness as compared to HC independently of type of onset. DISCUSSION: Our LOMS findings are well in line with published OCT data of normal onset MS. As the degree of retinal layer thinning was similar in MS subgroups, retinal neurodegeneration in MS may occur independently of time of disease onset

Intrathecal IgM production is a strong risk factor for early conversion to multiple sclerosis

OBJECTIVES: To evaluate intrathecal immunoglobulin M (IgM) production, as compared to previously established risk factors, as risk factor for conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) and to explore the association of intrathecal IgM production with onset age and radiologic and CSF findings in CIS/early MS. METHODS: Comprehensive CSF data, including oligoclonal immunoglobulin G (IgG) bands (OCB) and calculated intrathecal IgM and IgG production, were collected in a prospective study of 150 patients with CIS/early MS with regular clinical and MRI assessments. RESULTS: Intrathecal IgM production >0% occurred in 23.2% (33/142) of patients, who were on average 5 years younger at disease onset (p = 0.013) and more frequently had infratentorial lesions (18/32, 56.3%) than patients without intrathecal IgM production (33/104, 31.7%, p = 0.021). In multivariable Cox regression analyses, intrathecal IgM production in patients with a CIS (n = 93, median clinical and MRI follow-up 24 and 21 months) was strongly associated with conversion to MS according to the McDonald 2010 criteria (hazard ratio [95% confidence interval] 3.05 [1.45-6.44], p = 0.003) after adjustment for age (0.96 [0.93-1.00], p = 0.059), OCB (0.92 [0.33-2.61], p = 0.879), intrathecal IgG production (0.98 [0.48-1.99], p = 0.947), and radiologic evidence of dissemination in space (2.63 [1.11-6.22], p = 0.028). CONCLUSION: Intrathecal IgM production is a strong independent risk factor for early conversion to MS and may thus represent a clinically meaningful marker for predicting future disease activity in patients with a CIS

Association of serum Epstein-Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis

Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection. A characteristic feature of MS is an intrathecal synthesis of immunoglobulin (Ig)G. In 90 patients with clinically isolated syndromes/early relapsing-remitting MS, serum antibodies to Epstein-Barr nuclear antigen-1, but not to EBV viral capsid antigen, rubella, or varicella zoster virus, were higher (p=0.03) in those with than those without a calculated intrathecal IgG synthesis >0% and correlated with the percentage (r=0.27, p=0.009) and concentration (r=0.27, p=0.012) of intrathecally produced IgG. These findings suggest a link between EBV infection and the events leading to intrathecal IgG synthesis in patients with MS