Multiple biomarkers improve the prediction of multiple sclerosis in clinically isolated syndromes.
1, Dalla Costa G
1, Messina MJ
2, Di Maggio G
1, Sangalli F
1, Moiola L
1, Rodegher M
2, Colombo B
1, Furlan R
3, Leocani L
4, Falini A
5, Comi G
Since its introduction, MRI had a major impact on the early and more precise diagnosis of multiple sclerosis (MS), and the 2010 diagnostic criteria even allow a diagnosis to be made just after a single attack if stringent MRI criteria are met. Several other clinical and paraclinical markers have been reported to be associated with an increased risk of MS independently of MRI in patients with clinically isolated syndromes (CIS), but the incremental usefulness of adding them to the current criteria has not been evaluated. In this study, we determined whether multiple biomarkers improved the prediction of MS in patients with CIS in a real-world clinical practice.
MATERIALS AND METHODS:
This was a retrospective study involving patients with CIS admitted to our department between 2000 and 2013. We evaluated baseline clinical, MRI, neurophysiological, and cerebrospinal fluid (CSF) data.
During follow-up (median, 7.2 years), 127 of 243 participants (mean age, 31.6 years) developed MS. Cox proportional-hazards models adjusted for established MRI criteria, age at onset, number of T1 lesions, and presence of CSF oligoclonal bands significantly predicted the risk of developing MS at 2 and 5 years. The use of multiple biomarkers led to 29% net reclassification improvement at 2 years (P<.001) and 30% at 5 years (P<.001).
The simultaneous addition of several biomarkers significantly improved the risk stratification for MS in patients with CIS beyond that of a model based only on established MRI criteria.
The Blind Men and the Elephant, John Godfrey Saxe (1816-1887)
In my mind both MRI research and CSF research have contributed equally to our understanding of MS. It may at times seem that these two developments are disparate, with the McDonald MRI criteria taking centre stage and CSF being less favoured owing to the discomfort of lumbar punctures. However, it would be a mistake to assume that MRI alone formally legitimizes and rationalises the whole picture that is MS. Like beauty, it’s in the eye of the beholder.
In this paper, Martinelli et al. identified 272 PwMS; of which 52% developed clinically definite MS (21% in the first year and 32% within the 2nd year). At 5y 56% had converted. A diagnosis of clinically definite MS (CDMS) was made when new symptoms or signs occurred after at least 1 mth from the onset of the first event (CIS).
In terms of parameters that helped to predict those who’d developed CDMS, they found that the fulfilment of the dissemination in time (DIS, i.e. more than one lesion in the nervous system) was the single best predictor of developing MS (3.5 fold increase in CDMS risk). The presence of oligoclonal bands (OCBs) follows this with 2.87 fold increase in risk. Moreover, the addition of age at onset, T1 MRI lesions, and OCBs provided incremental value to the existing McDonald 2010 MRI criteria at 2 years and 5 years. What this suggests is that all three (age, T1 lesions and OCBs) are ongoing risk factors in developing MS after the initial period (29% net reclassification improvement at 2 years and 30% at 5 years).
The current MAGNIMS guidelines, which will eventually replace the 2010 McDonald criteria only recommends lumbar punctures for OCBs in atypical PPMS cases, and yet the findings presented in this paper are in line with previous work concluding that the inclusion of OCBs and other CSF biomarkers improve predictive accuracy. The science, therefore, may not readily fit into current thinking, but rest assured ignoring it or placing it at the bottom of the pile whilst you decide what to do with it isn’t helping matters one jot!