Clinically Definite Multiple Sclerosis Research Articles

Soluble CD40 ligand derived from serum is not correlated with early MS

BackgroundSoluble CD40 ligand (sCD154) is a proinflammatory and prothrombotic ligand belonging to the tumor necrosis factor family. It has been shown by a variety of studies that sCD154 is elevated in the serum of patients afflicted with system autoimmune diseases. The aim of our study was to address whether sCD154 is increased in disease affected by Multiple Sclerosis (MS). MethodsTwenty MS patients who have been newly diagnosed as clinically definite multiple sclerosis (CDMS) along with twenty age and sex matched healthy individuals were recruited for this study. Serum cCD154 was measured by Enzyme-Linked Immunosorbent Assay (ELISA). ResultsThe results showed no statistically meaningful difference between newly diagnosed MS patients (3.07ng/ul±0.66) and control group (2.95ng/ul±0.79; p=0.62) ConclusionRegarding our study, it seems that soluble CD40 ligand derived from serum is not correlated with early stage of MS disease.

The 11-year long-term follow-up study from the randomized BENEFIT CIS trial.

Objective:To assess outcomes for patients treated with interferon beta-1b immediately after clinically isolated syndrome (CIS) or after a short delay.Methods:Participants in BENEFIT (Betaferon/Betaseron in Newly Emerging MS for Initial Treatment) were randomly assigned to receive interferon beta-1b (early treatment) or placebo (delayed treatment). After conversion to clinically definite multiple sclerosis (CDMS) or 2 years, patients on placebo could switch to interferon beta-1b or another treatment. Eleven years after randomization, patients were reassessed.Results:Two hundred seventy-eight (59.4%) of the original 468 patients (71.3% of those eligible at participating sites) were enrolled (early: 167 [57.2%]; delayed: 111 [63.1%]). After 11 years, risk of CDMS remained lower in the early-treatment arm compared with the delayed-treatment arm (p = 0.0012), with longer time to first relapse (median [Q1, Q3] days: 1,888 [540, not reached] vs 931 [253, 3,296]; p = 0.0005) and lower overall annualized relapse rate (0.21 vs 0.26; p = 0.0018). Only 25 patients (5.9%, overall; early, 4.5%; delayed, 8.3%) converted to secondary progressive multiple sclerosis. Expanded Disability Status Scale scores remained low and stable, with no difference between treatment arms (median [Q1, Q3]: 2.0 [1.0, 3.0]). The early-treatment group had better Paced Auditory Serial Addition Task–3 total scores (p = 0.0070). Employment rates remained high, and health resource utilization tended to be low in both groups. MRI metrics did not differ between groups.Conclusions:Although the delay in treatment was relatively short, several clinical outcomes favored earlier treatment. Along with low rates of disability and disease progression in both groups, this supports the value of treatment at CIS.ClinicalTrials.gov identifier:NCT01795872.Classification of evidence:This study provides Class IV evidence that early compared to delayed treatment prolongs time to CDMS in CIS after 11 years.

Should the symptomatic region be included in dissemination in space in MRI criteria for MS?

To investigate whether inclusion of lesions in the symptomatic region influences the performance of dissemination in space (DIS) criteria for a diagnosis of clinically definite multiple sclerosis (CDMS) in patients with a clinically isolated syndrome (CIS). We studied 30 patients with CIS with brainstem/cerebellar and spinal cord syndromes who had MRI scans at the time of CIS and were followed up for the development of CDMS. We retrospectively applied the McDonald 2010 DIS criteria (excluding all lesions in the symptomatic region) to baseline MRI scans and 2 modified DIS criteria: (1) the inclusion of asymptomatic lesions in the symptomatic region in DIS, and (2) the inclusion of any lesion in the symptomatic region in DIS. The performance of the McDonald 2010 DIS criteria and the 2 modified criteria for the development of CDMS was compared. The sensitivity, specificity, and accuracy of the DIS criteria was, respectively, 73%, 73%, and 73% for the McDonald 2010 criteria, 80%, 73%, and 77% when asymptomatic lesions in the symptomatic region were included, and 87%, 73%, and 80% when any lesion in the symptomatic region was included in DIS. Including lesions in the symptomatic region in DIS increases the sensitivity of MRI criteria for diagnosing multiple sclerosis without compromising specificity. These findings may help inform future revisions of the diagnostic criteria for multiple sclerosis. This study provides Class II evidence that for patients with CIS, including lesions in the symptomatic region as part of the criteria for DIS does not significantly increase the accuracy for predicting the development of CDMS. The study lacks the precision to detect an important change in accuracy.

Increased expression of Tbet in CD4(+) T cells from clinically isolated syndrome patients at high risk of conversion to clinically definite MS.

BackgroundThe ability to identify clinically isolated syndrome (CIS) patients at high risk of progression to clinically definite multiple sclerosis (CDMS) would be clinically beneficial. The initiation of T cell mediated autoimmune diseases such as multiple sclerosis (MS) requires the initial inappropriate activation and differentiation of auto-reactive CD4+ T cells. The quiescence of naive T cells is actively maintained by molecules such as TOB1, which control the threshold of activation. Upon activation, CD4+ T cells can differentiate into various subsets depending on the milieu present. Th1 and Th17 cells are strongly implicated in MS, while regulatory T (Treg) cells constrain autoimmune inflammation and prevent autoimmunity.FindingsWe therefore investigated the expression of TOB1, CD44 and Treg, Th1 and Th17 transcription factors in relation to CIS progression. The expression of TOB1, CD44, FOXP3, TBX21 and RORC genes were measured in CD4+ T cells from 10 healthy controls, 20 CIS patients within 3 months of initial clinical presentation and 10 relapsing remitting MS patients sampled within 2 months of relapse. CIS patients were subsequently grouped into those who converted to CDMS within 1 year and those who remained CIS. No differences in the expression of TOB1, CD44, FOXP3 and RORC were observed. There was a significant increase in the expression of the Th1 transcription factor Tbet, encoded by TBX21, in CIS patients that converted within 1 year compared with those who did not.ConclusionThis pilot data suggests a role for Th1 cells in CIS progression and warrants further evaluation in a larger cohort.

Should patients with optic neuritis be treated with steroids?

Optic neuritis is the most common cause of optic neuropathy in young adults. High-dose intravenous corticosteroids (IVCS) were established as the standard of treatment for acute optic neuritis via the Optic Neuritis Treatment Trial (ONTT), with its first findings published more than 20 years ago. Subsequent studies have further clarified the role of corticosteroids in the treatment of acute optic neuritis. Recent clinical research has confirmed existing knowledge of the efficacy and limitations of corticosteroids in the treatment of optic neuritis. Recent studies have examined the role of race, route of administration and combination of IVCS with other therapies. Current evidence continues to support high-dose IVCS as the cornerstone of treatment of acute optic neuritis. High-dose IVCS are effective in hastening visual recovery in acute typical optic neuritis, but do not affect the final visual outcome. In optic neuritis patients, IVCS may delay progression to clinically definite multiple sclerosis (CDMS) at 2 years, but not at 5 or 10 years. It is reasonable to recommend high-dose IVCS for acute optic neuritis patients with significant vision loss, severe pain and/or white matter lesions on brain MRI in whom the potential for benefit outweighs the risks.

Lesion Activity on Brain MRI in a Chinese Population with Unilateral Optic Neuritis.

Longitudinal studies have shown that brain white matter lesions are strong predictors of the conversion of unilateral optic neuritis to multiple sclerosis (MS) in Caucasian populations. Consequently brain MRI criteria have been developed to improve the prediction of the development of clinically definite multiple sclerosis (CDMS). In Asian populations, optic neuritis may be the first sign of classical or optic-spinal MS. These signs add to the uncertainty regarding brain MRI changes with respect to the course of unilateral optic neuritis. The aim of this study was to examine the association between brain lesion activity and conversion to CDMS in Chinese patients with unilateral optic neuritis. A small prospective cohort study of 40 consecutive Chinese patients who presented with unilateral optic neuritis was conducted. Brain lesion activity was recorded as the incidence of Gd-enhanced lesions and new T2 lesions. Brain lesions on MRI that were characteristic of MS were defined according to the 2010 revisions of the McDonald criteria. The primary endpoint was the development of CDMS. We found that nineteen patients (48%) had brain lesions that were characteristic of MS on the initial scan. One of these patients (3%) had Gd-enhanced brain lesions. A significantly lower percentage of the patients (10%, p<0.001) presented with new T2 brain lesions on the second scan. During a median of 5 years of follow-up, seven patients (18%) developed CDMS. There was no significant difference in the conversion rate to CDMS between patients with and without brain lesions that were characteristic of MS (4/19 and 3/21, respectively; Fisher exact test, one-sided, p = 0.44). We conclude that brain lesions characteristic of MS are common in Chinese patients with unilateral optic neuritis; however, these patients exhibit low lesion activity. The predictive value of brain lesion activity for CDMS requires investigation in additional patients.

Clinical significance of the number of oligoclonal bands in patients with clinically isolated syndromes

CSF oligoclonal bands (OCBs) in patients with clinically isolated syndromes (CIS) are a risk factor for clinically definite multiple sclerosis (CDMS). We aimed to address the relevance of the number of OCBs in the prognosis of CIS patients. 219 CIS patients were included in the study, and 42% of them developed the disease during follow-up (median: 5.04years). Patients with a high number of CSF OCBs (third quartile, 8–12 OCBs) had 2.5-fold increase in CDMS risk, while no further increase in the HR of disease was observed for patients with more than 12 OCBs. The results did not change after adjustment for additional correlates of CDMS development. This association may be due to the epitope-spreading phenomenon and may reflect the stage of the disease at the time of the examination.

Use of multiple biomarkers to improve the prediction of multiple sclerosis in patients with clinically isolated syndromes

Background: The early identification of patients at high risk of Clinically Definite Multiple Sclerosis (CDMS) represents the main purpose of diagnostic criteria and of clinicians in everyday clinical practice. Objective: To investigate whether the incorporation of different biomarkers in a model with established MRI criteria improves the prediction of MS. Methods: We evaluated baseline clinical data as well as MRI, multimodal evoked potentials and cerebrospinal fluid (CSF) data of patients with a first demyelinating episode. We used discrimination and calibration characteristics and reclassification of risk categories to assess incremental utility of different biomarkers for CDMS prediction. Results: During follow-up (median 7.2 years), 127 of the 243 participants in our study (mean age 31.6 years) developed a second clinical attack (CDMS). In 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 within 2 and 5 years. The C-statistic increased significantly when the three biomarkers were incorporated into a model with established MRI criteria, both at 2 years (C-statistic with biomarkers vs. without biomarkers, 0.74 vs. 0.69) and at 5 years (0.66 vs. 0.70). The use of multiple biomarkers led to a 29% net-reclassification improvement at 2 years (p < 0.001) and 30% at 5 years (p < 0.001). Conclusions: The simultaneous addition of several biomarkers improves the risk stratification for MS in patients with clinically isolated syndromes beyond that of a model that is based only on MRI criteria.

The effect of disease-modifying therapies on brain atrophy in patients with clinically isolated syndrome: a systematic review and meta-analysis.

Brain atrophy is associated with cognitive deficits in patients with clinically isolated syndrome (CIS) and can predict conversion to clinical definite multiple sclerosis. The aim of the present meta-analysis was to evaluate the effect of disease-modifying drugs (DMDs) on brain atrophy in patients with CIS. Eligible placebo-control randomized clinical trials of patients with CIS that had reported changes in brain volume during the study period were identified by searching the MEDLINE, SCOPUS, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. This meta-analysis adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses. Three eligible studies were identified, comprising 1362 patients. The mean percentage change in brain volume was found to be significantly lower in DMD-treated patients versus placebo-treated subgroups (standardized mean difference [SMD]: = -0.13, 95% confidence interval [CI]: -0.25, 0.01; p = 0.04). In the subgroup analysis of the two studies that provided data on brain-volume changes for the first (0-12 months) and second (13-24 months) year of treatment, DMD attenuated brain-volume loss in comparison with placebo during the second year (SMD = -0.25; 95% CI: -0.43, -0.07; p < 0.001), but not during the first year of treatment (SMD = -0.01; 95% CI: -0.27, 0.24; p = 0.93). No evidence of heterogeneity was found between estimates, while funnel-plot inspection revealed no evidence of publication bias. DMDs appear to attenuate brain atrophy over time in patients with CIS. The effect of DMDs on brain-volume loss is evident after the first year of treatment.

Clinically isolated syndrome — Rethinking the diagnosis

A diagnostic lacuna in clinically isolated syndrome (CIS) is the prognostic uncertainty of approximately 20% of patients who do not meet the radiological criteria based on magnetic resonance imaging (MRI) of the brain. A study by Tintore et al. noted that 23% of patients who had normal MRI findings but had oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) developed clinically definite multiple sclerosis (CDMS), compared with 4% who had normal MRI findings but no OCBs in CSF (Tintore et al. 2008). Since a diagnosis of CIS cannot be made if MRI data are equivocal, the opportunity for early treatment is lost if non-radiological data are not taken into diagnostic consideration. In this article, a case for inclusion of cerebrospinal fluid data in the diagnosis of CIS is made, and a distinction is drawn in certain patient cohorts based on ethnicity, that demands urgent research. Certain ethnic cohorts such as African Americans (AAs) may have a higher risk of delayed diagnosis if CSF data are ignored. At the current time, the diagnosis of CIS continues to favor clinical and radiological evidence and this article aims to change that perspective.

Update on clinically isolated syndrome

Optic neuritis, myelitis and brainstem syndrome accompanied by a symptomatic MRI T2 or FLAIR hyperintensity and T1 hypointensity are highly suggestive of multiple sclerosis (MS) in young adults. They are called "clinically isolated syndrome" (CIS) and correspond to the typical first multiple sclerosis (MS) episode, especially when associated with other asymptomatic demyelinating lesions, without clinical, radiological and immunological sign of differential diagnosis. After a CIS, the delay of apparition of a relapse, which corresponds to the conversion to clinically definite MS (CDMS), varies from several months to more than 10 years (10-15% of cases, generally called benign RRMS). This delay is generally associated with the number and location of demyelinating lesions of the brain and spinal cord and the results of CSF analysis. Several studies comparing different MRI criteria for dissemination in space and dissemination in time of demyelinating lesions, two hallmarks of MS, provided enough substantial data to update diagnostic criteria for MS after a CIS. In the last revision of the McDonald's criteria in 2010, diagnostic criteria were simplified and now the diagnosis can be made by a single initial scan that proves the presence of active asymptomatic lesions (with gadolinium enhancement) and of unenhanced lesions. However, time to conversion remains highly unpredictable for a given patient and CIS can remain isolated, especially for idiopathic unilateral optic neuritis or myelitis. Univariate analyses of clinical, radiological, biological or electrophysiological characteristics of CIS patients in small series identified numerous risk factors of rapid conversion to MS. However, large series of CIS patients analyzing several characteristics of CIS patients and the influence of disease modifying therapies brought important information about the risk of CDMS or RRMS over up to 20 years of follow-up. They confirmed the importance of the initial MRI pattern of demyelinating lesions and of CSF oligoclonal bands. Available treatments of MS (immunomodulators or immunosuppressants) have also shown unequivocal efficacy to slow the conversion to RRMS after a CIS, but they could be unnecessary for patients with benign RRMS. Beyond diagnostic criteria, knowledge of established and potential risk factors of conversion to MS and of disability progression is essential for CIS patients' follow-up and initiation of disease modifying therapies.

Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis

Objective: To investigate glial and neuronal biomarkers in cerebrospinal fluid (CSF) samples from patients with relapsing–remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), and to evaluate their ability to predict conversion from CIS to clinically definite MS (CDMS) and also disability progression in MS. Methods: CSF levels of neurofilament light protein (NFL), t-tau, p-tau, glial fibrillary acidic protein (GFAP), S-100B, human chitinase 3-like 1 protein (YKL-40), monocyte chemoattractant protein-1 (MCP-1), α-sAPP and β-sAPP; and Aβ38, Aβ40 and Aβ42, were analyzed in 109 CIS patients and 192 RRMS patients. The mean follow-up time of these 301 patients was 11.7 ± 6.4 years. Results: High levels of NFL were associated with early conversion from CIS to CDMS (hazard ratio (HR) with 95% confidence interval (CI): 2.69 (1.75 – 4.15); p < 0.0001). High levels of YKL-40 and GFAP were associated with earlier progression in the Expanded Disability Status Scale (EDSS), score 3: YKL-40 (HR (95% CI): 2.78 (1.48 – 5.23); p = 0.001) and GFAP (HR (95% CI): 1.83 (1.01 – 3.35); p = 0.04). High levels of YKL-40 were associated with earlier progression to EDSS 6 (HR (95% CI): 4.57 (1.01 – 20.83); p = 0.05). Conclusions: CSF levels of NFL in CIS patients are an independent prognostic marker for conversion to CDMS. Whereas, CSF levels of YKL-40 and GFAP are independent prognostic markers for disability progression in MS.

Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis

Background: Cerebrospinal fluid (CSF) biomarkers have been suggested to predict multiple sclerosis (MS) after clinically isolated syndromes, but studies investigating long-term prognosis are needed. Objective: To assess the predictive ability of CSF biomarkers with regard to MS development and long-term disability after optic neuritis (ON). Methods: Eighty-six patients with ON as a first demyelinating event were included retrospectively. Magnetic resonance imaging (MRI), CSF leukocytes, immunoglobulin G index and oligoclonal bands were registered. CSF levels of chitinase-3-like-1, osteopontin, neurofilament light-chain, myelin basic protein, CCL2, CXCL10, CXCL13 and matrix metalloproteinase-9 were measured by enzyme-linked immunosorbent assay. Patients were followed up after 13.6 (range 9.6–19.4) years and 81.4% were examined, including Expanded Disability Status Scale and MS functional composite evaluation. 18.6% were interviewed by phone. Cox regression, multiple regression and Spearman correlation analyses were used. Results: Forty-six (53.5%) developed clinically definite MS (CDMS) during follow-up. In a multivariate model MRI (p=0.0001), chitinase 3-like 1 (p=0.0033) and age (p=0.0194) combined predicted CDMS best. Neurofilament light-chain predicted long-term disability by the multiple sclerosis severity scale (p=0.0111) and nine-hole-peg-test (p=0.0202). Chitinase-3-like-1 predicted long-term cognitive impairment by the paced auditory serial addition test (p=0.0150). Conclusion: Neurofilament light-chain and chitinase-3-like-1 were significant predictors of long-term physical and cognitive disability. Furthermore, chitinase-3-like-1 predicted CDMS development. Thus, these molecules hold promise as clinically valuable biomarkers after ON as a first demyelinating event.

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Disease-related determinants of quality of life 10 years after clinically isolated syndrome.

The main clinical determinants of quality of life (QOL) 5 years after clinically isolated syndrome (CIS) are Expanded Disability Status Scale (EDSS) score and conversion to clinically definite multiple sclerosis (CDMS). The aim of this study was to determine the demographic, clinical, and magnetic resonance imaging (MRI) factors associated with QOL 10 years after CIS. Controlled High Risk Avonex® Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance (CHAMPIONS) 10-year patients were assessed for CDMS, EDSS score, MRI T2 activity, brain parenchymal fraction, and patient-reported QOL. Associations were evaluated using analysis of variance models. A second clinical event consistent with CDMS and higher EDSS scores at years 5 and 10 were associated with lower 36-item Short Form Health Status Survey (SF-36) Physical Component Summary scores at year 10 (P < .01). Patients with earlier onset of CDMS had worse patient-reported Physical Component Summary, SF-36 Mental Component Summary, fatigue, and pain scores at year 10 than patients with later or no onset of CDMS. Neither initial randomization group nor any MRI metrics assessed at baseline or during follow-up were associated with QOL at 10 years. These results support the development of therapies for patients with CIS that significantly reduce the risk of conversion to CDMS and the progression of physical disability to milestones as low as EDSS scores of 2.0.

Treatment of Multiple Sclerosis – Relationship between Vitamin D and Interferon β-1b

There are many reports suggesting an association between vitamin D status and both the development of multiple sclerosis (MS) and its course. This relationship and the effects of vitamin D and interferon β-1b (IFNβ-1b) in the treatment of patients are reviewed in the BEtaferon/ Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) and the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose in multiple sclerosis (BEYOND) studies. In the BENEFIT study the average serum 25-hydroxyvitamin D (25[OH]D) levels strongly predicted MS disease activity and progression. The probability of clinically definite MS (CDMS) and magnetic resonance imaging (MRI) activity was lower in these clinically isolated syndrome (CIS) patients with 25(OH)D levels ≥50 nmol/L and in those starting with IFNβ -1b. Furthermore, there was a beneficial effect on relapse rate, occurrence of new active MRI lesions and disease progression for a 50 nmol/L increase in 25(OH)D levels. Similarly, in relapsing-remitting (RR) MS patients from the BEYOND study serum 25(OH)D levels were inversely associated with MRI markers of MS activity. Genetic analysis of patients from these studies indicated that there may be a benefit in monitoring and managing vitamin D levels in early MS patients treated with IFNβ-1b and a cumulative number of risk alleles predict lower 25(OH)D levels in CIS and RRMS patients. Further studies have suggested that some of the IFNβ-1b therapeutic effects on relapse could be mediated through modulation of vitamin D metabolism. Thus, there seems to be a benefit on clinical and MRI measures if patients are treated with both vitamin D and IFNβ-1b. There is a need to further evaluate this effect in clinical trials. The relationship between vitamin D and MS disease activity along with the effects of vitamin D and IFNβ-1b in the treatment of MS patients is reviewed.

Predicting outcome in clinically isolated syndrome using machine learning.

We aim to determine if machine learning techniques, such as support vector machines (SVMs), can predict the occurrence of a second clinical attack, which leads to the diagnosis of clinically-definite Multiple Sclerosis (CDMS) in patients with a clinically isolated syndrome (CIS), on the basis of single patient's lesion features and clinical/demographic characteristics.Seventy-four patients at onset of CIS were scanned and clinically reviewed after one and three years. CDMS was used as the gold standard against which SVM classification accuracy was tested. Radiological features related to lesional characteristics on conventional MRI were defined a priori and used in combination with clinical/demographic features in an SVM. Forward recursive feature elimination with 100 bootstraps and a leave-one-out cross-validation was used to find the most predictive feature combinations.30 % and 44 % of patients developed CDMS within one and three years, respectively. The SVMs correctly predicted the presence (or the absence) of CDMS in 71.4 % of patients (sensitivity/specificity: 77 %/66 %) at 1 year, and in 68 % (60 %/76 %) at 3 years on average over all bootstraps. Combinations of features consistently gave a higher accuracy in predicting outcome than any single feature.Machine-learning-based classifications can be used to provide an “individualised” prediction of conversion to MS from subjects' baseline scans and clinical characteristics, with potential to be incorporated into routine clinical practice.

Validation of semaphorin 7A and ala-β-his-dipeptidase as biomarkers associated with the conversion from clinically isolated syndrome to multiple sclerosis.

BackgroundIn a previous proteomics study using pooled cerebrospinal fluid (CSF) samples, we proposed apolipoprotein AI, apolipoprotein AIV, vitronectin, plasminogen, semaphorin 7A, and ala-β-his-dipeptidase as candidate biomarkers associated with the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes (CIS). Here, we aimed to validate these results in individual CSF samples using alternative techniques.MethodsIn a first replication study, levels of apolipoproteins AI and AIV, vitronectin, and plasminogen were measured by ELISA in CSF and serum of 56 CIS patients (29 patients who converted to CDMS (MS converters) and 27 patients who remained with CIS during follow-up (MS non-converters)) and 26 controls with other neurological disorders. Semaphorin 7A and ala-β-his-dipeptidase levels were determined by selected reaction monitoring (SRM) in CSF of 36 patients (18 MS converters, 18 non-converters) and 20 controls. In a second replication study, apolipoprotein AI levels were measured by ELISA in CSF of 74 CIS patients (47 MS converters, 27 non-converters) and 50 individual controls, and levels of semaphorin 7A and ala-beta-his-dipeptidase were determined by SRM in 49 patients (24 MS converters, 25 non-converters) and 22 controls.ResultsCSF levels of apolipoprotein AI were increased (P = 0.043) and levels of semaphorin 7A and ala-β-his-dipeptidase decreased (P = 4.4 × 10−10 and P = 0.033 respectively) in MS converters compared to non-converters. No significant differences were found in serum levels for apolipoproteins AI and AIV, vitronectin, and plasminogen. Findings with semaphorin 7A and ala-β-his-dipeptidase were also validated in the second replication study, and CSF levels for these two proteins were again decreased in MS converters versus non-converters (P = 1.2 × 10−4 for semaphorin 7A; P = 3.7 × 10−8 for ala-β-his-dipeptidase). Conversely, apolipoprotein AI findings were not replicated and CSF levels for this protein did not significantly differ between groups. Furthermore, CSF semaphorin 7A levels were negatively associated with the number of T2 lesions at baseline and one-year follow-up.ConclusionsThese results validate previous findings for semaphorin 7A and ala-β-his-dipeptidase, and suggest that these proteins play a role as CSF biomarkers associated with the conversion to CDMS in CIS patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0181-8) contains supplementary material, which is available to authorized users.

CIS diagnostics and predictors of conversion to CDMS

Clinically isolated syndrome (CIS) is a term used to define an episode suggestive of central nervous system (CNS) inflammatory demyelination. The majority of CIS will evolve to multiple sclerosis (MS), a chronic disease characterised by further relapses and accumulation of disability. Current evidence suggests that disease modifying treatment (DMT) should be started at early stages since it is likely to have a significant impact on the evolution of the disease. Thus, accurately identifying which patients will remain as CIS or which will develop MS and, above all, determining the degree of disability they could develop over the mid- to long term is considered crucial for a more individualized treatment. Natural history studies have shown that a younger age at disease onset is related to a higher risk of conversion to clinically definite MS (CDMS) and that male gender is associated to a higher disability accumulation as measured by the Kurtzke Expanded Disability Status Scale (EDSS). Among clinical factors, CIS patients presenting with an optic neuritis have been related to a lower risk of developing both MS and disability accumulation in comparison to CIS affecting other topographies. Regarding biological factors, a recent meta-analysis showed that presence of IgG oligoclonal bands (OB) increases both the risk of having a second attack and the risk of disability accumulation. To date, brain MRI remains the most reliable prognostic marker for developing MS or disability. It has been demonstrated that a higher number of brain T2 lesions or Barkhof criteria (BC) on baseline MRI increases the risk of developing MS and disability in the mid- to long term. However, although the abovementioned natural history studies are indeed based on large multicentre cohorts with long follow-up, they have a number of limitations: they usually comprised data obtained both retrospectively and prospectively, which could lead to information bias. Baseline and follow-up visits do not follow a standardized protocol, compromising the homogenization among the different centres of the data acquired. Absence of MRI data is frequent and when present, a systematic MRI protocol is lacking. These limitations often result in the fact that MRI and OB have not been taken into account as joint covariates in the models. Finally, quantification of patients lost to follow-up and its causes are not registered, leading to survival bias. On the other hand, the longitudinal MRI cohorts have a small sample size, follow-up is not regular, and optic neuritis is frequently over-represented, deeming subgroup analyses impossible. Overcoming some of these limitations, I will present the Barcelona inception cohort study on 1000 CIS. We have tried to identify and stratify which baseline demographic, clinical, radiological or biological factors predict MS development and disability accumulation in a unique multivariate approach on a large prospective cohort.

Ten-year follow-up of the ‘minimal MRI lesion’ subgroup from the original CHAMPS Multiple Sclerosis Prevention Trial

Background: Patients with clinically isolated syndrome (CIS) and characteristic magnetic resonance imaging (MRI) lesions are at high risk for multiple sclerosis (MS). However, patients with a minimal MRI lesion burden (a low T2-hyperintense [low T2] lesion count) may have borderline formal diagnostic criteria, presenting a clinical management challenge. Objective: Compare the 10-year disease progression of patients with low and higher T2 lesion counts treated over most intervals. Methods: CIS patients from the original CHAMPS MS trial were retrospectively assigned to low-T2 (first quartile; 2–8 lesions) or higher-T2 (second through fourth quartiles; ≥ 9 lesions) groups using baseline T2 lesion counts. The 5- and 10-year open-label extension of CHAMPS (CHAMPIONS) evaluated conversion to clinically definite MS (CDMS), MRI activity, relapses, and disability. Results: The vast majority of patients showed new disease activity by MRI and/or clinical criteria at 10 years (low-T2 86%; higher-T2 98%). Fewer low-T2 than higher-T2 patients developed CDMS (40% vs. 63%; p = 0.013); low-T2 patients also had fewer new brain lesions, less brain volume loss, and less disability progression. Conclusion: CIS patients with low T2 lesion counts show continued disease activity. However, all assessments of disease progression over 10 years indicated a significantly less severe disease course for low-T2 patients.