Discussion
We could not demonstrate any value of CSF IgG index and presence of OCGBs at a mean of 8.9 ± 3.8 years of follow-up for prognosis of disability in MS, which contrasts with previous studies but is in line with a recent study. Older age at disease onset (≥50 years) and initial PP course of MS were predictors of worsening disability. In contrast with other studies, gender was not a prognostic factor.
In recent years, several studies have suggested the prognostic value of OCGBs in MS, showing good correlation between disability and presence of OCGBs, as well as IgG index. CSF OCGBs are stable over time, which allowed us to consider it for subjects with late lumbar puncture, as a reflection of the value of this factor at diagnosis. However, whether CSF total protein level and IgG index at the time of lumbar puncture actually reflects their values at diagnosis is uncertain.
Many studies have investigated the prognosis of MS in terms of biological markers. Most studies have focused on the RR form of MS. The absence of OCGBs and low baseline T2-weighted lesions found on MRI were favourable prognostic factors influencing the clinical response to interferon β treatment in patients with RR MS. Age at disease onset and number of MS attacks during the first 2 years of MS were predictors of the evolution of the disability. Blood levels of gene markers, CSF IgM oligoclonal bands, the association of intrathecal Ig synthesis and cortical lesions, simple detection of intrathecal IgG synthesis and initial relapse of RR MS have been studied as prognosis markers of RR MS. Other studies have focused on imaging and motor-evoked potentials or the secondary progressive phase of MS.
Another recent study found that the presence of OCGBs and elevated total CSF IgG and protein levels moderately were associated with PP MS but not disease progression. As in our study, for patients who had undergone multiple lumbar punctures, only the earliest puncture was considered, and we found the same percentages for the RR form (85.7%) and PP form (14.3%). However, the study differed from ours in a higher number of subjects, different biological technique for CSF analysis, smaller time from MS onset to lumbar puncture and no multivariate analysis.
In patients with clinically isolated syndromes, the presence of lesions as determined by T2-weighted baseline magnetic resonance imaging (MRI) of the brain or medullar tract increases chances of developing multiple sclerosis. The degree of long-term disability from multiple sclerosis correlates with the volume increase of the lesions seen on the brain MRI in the first five years only In our study, the change in volume over time was not taken into account. Therefore, the absence of a prognostic role of baseline MRI considering only the Barkhof-Tintore criteria is not surprising.
For an early prognostic perspective, we entered only covariates assessed at the time of MS onset in the regression model. Compared with the other studies, we were interested in the well-known prognostic markers and new data at MS onset.
End of the 90's was a milestone in the support of MS. As noted earlier, the biological techniques to detect OCGBs have evolved over time, especially after the 1990s, which must be considered in interpreting results. In recent years, the isoelectric focusing technique of CSF with IgG immunoassays was allowed for detecting chronic inflammatory CSF, especially MS. Here, percentage of OCB negative patients is higher (12.9% for RR and 13.8 for PP) than in previous works where percentage oscillated between 3–5%, with maximum 10.6% in Siritho's work in 2009. It was reported a tendency for lower prevalences in CSF from MS patients in countries in southern of Europe compared to MS patients in northern countries. Although not available in our study, information about the origin of our patients might contribute to explain this atypical result. Finally, the first eligible criterion, minimal time from disease onset for at least 5 years, considerably decreased the number of patients with CSF test results, because in recent years, the database has had more complete data from CSF tests.
The strengths of our study are that first, we conducted multivariate analysis unlike most studies evaluating the predictive value of routine CSF biological data which used only bivariate analysis and included a low number of patients (<100), except for two studies. Furthermore, only 2 studies claimed they used adjustment for variables. Yet, with our relatively large sample size (n = 407), our results did not show the predictive value of these biological markers. Such differences might explain the previous contradictory results. Second, patients were followed for a median of 8.7 years (6.2–11.0), a long period as compared with other studies.
Our study contains some limitations. The main difficulty was the number of missing data relating to CSF, which has several explanations. First, some neurologists believe that CSF data are not important in the diagnosis of MS, particularly if the clinical and radiological criteria leave no doubt. On another hand, for some patients living far from major care center, it was not always possible to perform lumbar puncture. Second, the information might be available but not yet complete for some patients, which led to our excluding data for some patients. Therefore, our cohort of 407 patients could have been even larger, with higher statistical power. Third, we had an exhaustive database, the Lorraine MS register, with data for about 4,700 patients. From the overall register population, patients who did and did not meet the eligibility criteria were comparable in demographic characteristics. Regarding the quality of the data, patient records in the register are regularly updated when patients see their neurologist. However, although they were identified in the register, patients retained in the sample were likely more severe since more frequently diagnosed at hospital center, as our team reported in a previous paper. But as a reflection of the recruitment from the register, there was more heterogeneity in clinical profile, in routine biological markers and in treatments.