Clinically Definite Multiple Sclerosis Research Articles

Serum Biomarker gMS-Classifier2: Predicting Conversion to Clinically Definite Multiple Sclerosis

BackgroundAnti-glycan antibodies can be found in autoimmune diseases. IgM against glycan P63 was identified in clinically isolated syndromes (CIS) and included in gMS-Classifier2, an algorithm designed with the aim of identifying patients at risk of a second demyelinating attack.ObjectiveTo determine the value of gMS-Classifier2 as an early and independent predictor of conversion to clinically definite multiple sclerosis (CDMS).MethodsData were prospectively acquired from a CIS cohort. gMS-Classifier2 was determined in patients first seen between 1995 and 2007 with ≥ two 200 µL serum aliquots (N = 249). The primary endpoint was time to conversion to CDMS at two years, the factor tested was gMS-Classifier2 status (positive/negative) or units; other exploratory time points were 5 years and total time of follow-up.ResultsSeventy-five patients (30.1%) were gMS-Classifier2 positive. Conversion to CDMS occurred in 31/75 (41.3%) of positive and 45/174 (25.9%) of negative patients (p = 0.017) at two years. Median time to CDMS was 37.8 months (95% CI 10.4–65.3) for positive and 83.9 months (95% CI 57.5–110.5) for negative patients. gMS-Classifier2 status predicted conversion to CDMS within two years of follow-up (HR = 1.8, 95% CI 1.1–2.8; p = 0.014). gMS-Classifier2 units were also independent predictors when tested with either Barkhof criteria and OCB (HR = 1.2, CI 1.0–1.5, p = 0.020) or with T2 lesions and OCB (HR = 1.3, CI 1.1–1.5, p = 0.008). Similar results were obtained at 5 years of follow-up. Discrimination measures showed a significant change in the area under the curve (ΔAUC) when adding gMS-Classifier2 to a model with either Barkhof criteria (ΔAUC 0.0415, p = 0.012) or number of T2 lesions (ΔAUC 0.0467, p = 0.009), but not when OCB were added to these models.ConclusionsgMS-Classifier2 is an independent predictor of early conversion to CDMS and could be of clinical relevance, particularly in cases in which OCB are not available.

Impact of cigarette smoking on conversion from clinically isolated syndrome to clinically definite multiple sclerosis

Multiple sclerosis (MS) is known to be influenced by various environmental factors including cigarette smoking. To identify the impact of smoking on conversion from clinically isolated syndrome (CIS) to clinically definite MS (CDMS), 95 consecutive uniformly treated smoker (n = 31) and nonsmoker (n = 64) CIS patients were evaluated retrospectively. The smoker CIS patients did not differ from nonsmokers by means of demographic and clinical findings. In addition, there was no difference between the two groups with respect to rate and time of conversion to CDMS. However, white matter lesions were detected in magnetic resonance imagings (MRIs) of all smoking versus 54 of 64 (63.5%) nonsmoking CIS patients (p = 0.02). Our results show that smoking does not predict conversion from CIS to CDMS. However, smoking may be associated with the appearance of white matter lesions on MRI at CIS onset.

Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome

Background: The placebo-controlled phase of the PreCISe study showed that glatiramer acetate delayed onset of clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome and brain lesions on MRI. Objective: To compare the effects of early versus delayed glatiramer acetate treatment in the open-label phase of PreCISe. Methods: Patients with a clinically isolated syndrome suggestive of MS with unifocal manifestation and ≥2 T2-weighted brain lesions were randomized to receive glatiramer acetate 20 mg/d (early-treatment, n=198) or placebo (delayed-treatment, n=211) for 36 months or until conversion to CDMS, followed by open-label glatiramer acetate treatment for two years. Results: Early glatiramer acetate treatment reduced CDMS conversion risk by 41% (hazard ratio 0.59, 95% confidence interval 0.44–0.80; p=0.0005) versus delayed-treatment, and was associated with a 972-day delay (185%) in conversion to CDMS, less brain atrophy (−28%, p=0.0209), fewer new T2 lesions/year (−42%, <0.0001) and lower T2 lesion volume (−22%, p=0.0005) versus delayed treatment. Adverse events were consistent with the established safety profile of glatiramer acetate. Conclusions: Effects of early glatiramer acetate treatment on the rate of conversion to CDMS and on MRI measures of disease activity and lesion burden support initiating glatiramer acetate treatment soon after the first clinical symptoms suggestive of MS and continuing treatment to sustain benefits.

Spinal cord lesions in patients with clinically isolated syndrome

Spinal cord (SC) lesions are frequently found in multiple sclerosis (MS), but are rare in healthy aging and cerebrovascular patients. Our aim was to analyze the contribution of SC involvement in clinically isolated syndrome (CIS) in diagnosing MS according the McDonald 2010 criteria and in predicting conversion to clinically definite MS (CDMS). We prospectively followed monofocal, relapsing onset CIS patients with either SC or brain symptom onset (including optic neuritis). MRI of the brain and SC were performed shortly after onset and patients were followed for 24 to 119 months (median 64 months). SC MRI findings were assessed for their contribution to the McDonald 2010 diagnostic criteria and their effect on conversion to CDMS. One hundred twenty-one patients were included (63 spinal CIS). Based on the brain scan only, 36 patients fulfilled the McDonald criteria; by including SC findings, 6 additional patients fulfilled these criteria. To diagnose 1 additional nonspinal CIS patient, the number needed to scan is 7. In nonspinal CIS patients that did not fulfill McDonald brain MRI criteria (n = 42), presence of an SC lesion was associated with a higher risk of conversion to CDMS (odds ratio: 14.4; 95% confidence interval: 2.6-80.0) and shorter time to conversion to CDMS (hazard ratio: 51.4; 95% confidence interval: 5.5-476.3). Presence of SC lesions facilitates diagnosing MS and is predictive for conversion to CDMS, especially in patients with nonspinal CIS who do not fulfill brain MRI criteria. We therefore recommend performing an SC scan in patients with nonspinal CIS who do not fulfill McDonald brain MRI criteria.

Updates on Clinically Isolated Syndrome and Diagnostic Criteria for Multiple Sclerosis

Clinically isolated syndrome (CIS) is a central nervous system demyelinating event isolated in time that is compatible with the possible future development of multiple sclerosis (MS). Early risk stratification for conversion to MS helps with treatment decisions. Magnetic resonance imaging (MRI) is currently the most useful tool to evaluate risk. Cerebrospinal fluid studies and evoked potentials may also be used to assess the likelihood of MS. Four clinical trials evaluating the benefits of either interferon β (IFN-β) or glatiramer acetate (GA) within the first 3 months after a high-risk CIS demonstrate decreased rates of conversion to clinically definite MS (CDMS) and a lesser degree of MRI progression with early treatment. In the 3-, 5-, and 10-year extension studies of 2 formulations of IFN-β, the decreased conversion rate to CDMS remained meaningful when comparing early treatment of CIS to treatment delayed by a median of 2 to 3 years. Diagnostic criteria have been developed based on the clinical and MRI follow-up of large cohorts with CIS and provide guidance on how to utilize clinical activity in combination with radiographic information to diagnose MS. The most recent 2010 McDonald criteria simplify requirements for dissemination in time and space and allow for diagnosis of MS from a baseline brain MRI if there are both silent gadolinium-enhancing lesions and nonenhancing lesions on the same imaging study. The diagnostic criteria for MS require special consideration in children at risk for acute disseminated encephalomyelitis (ADEM), in older adults who may have small vessel ischemic disease, and in ethnic groups that more commonly develop neuromyelitis optica (NMO).

Cost-Effectiveness Analysis of Interferon Beta-1b for the Treatment of Patients With a First Clinical Event Suggestive of Multiple Sclerosis

ObjectivesTo assess, from a Swedish societal perspective, the cost effectiveness of interferon β-1b (IFNB-1b) after an initial clinical event suggestive of multiple sclerosis (MS) (ie, early treatment) compared with treatment after onset of clinically definite MS (CDMS) (ie, delayed treatment). MethodsA Markov model was developed, using patient level data from the BENEFIT trial and published literature, to estimate health outcomes and costs associated with IFNB-1b for hypothetical cohorts of patients after an initial clinical event suggestive of MS. Health states were defined by Kurtzke Expanded Disability Status Scale (EDSS) scores. Model outcomes included quality-adjusted life years (QALYs), total costs (including both direct and indirect costs), and incremental cost-effectiveness ratios. Sensitivity analyses were performed on key model parameters to assess the robustness of model results. ResultsIn the base case scenario, early IFNB-1b treatment was economically dominant (ie, less costly and more effective) versus delayed IFNB-1b treatment when QALYs were used as the effectiveness metric. Sensitivity analyses showed that the cost-effectiveness results were sensitive to model time horizon. Compared with the delayed treatment strategy, early treatment of MS was also associated with delayed EDSS progressions, prolonged time to CDMS diagnosis, and a reduction in frequency of relapse. ConclusionEarly treatment with IFNB-1b for a first clinical event suggestive of MS was found to improve patient outcomes while controlling costs.

Correlation between Brain MRI and Health Related Quality of Life in Early Treated MS Patients and Clinically Isolated Syndrome (P03.051)

Objective: To compare brain MRI and health related quality of life (HRQOL) at the initiation of disease modifying therapy (DMD) in patients with clinically isolated syndrome (CIS) and clinically definite multiple sclerosis (CDMS). Background Few studies assessed correlation between MRI and HRQOL. In a previous study, we reported negative correlations between HRQOL, lesion load (LL) and brain parenchymal fraction (BPF) in early treated CDMS patients. Design/Methods: Our prospective study included patients with either CIS fulfilling 2005 McDonald criteria or CDMS. Patients started their first DMD at the inclusion. Annual assessment included clinical data, EDSS score, French version of MSQol-54 questionnaire, and 1.5T conventional brain MRI (T1 with and without gadolinium injection, T2 spin echo, proton density and FLAIR sequences). Images were analysed using the SepINRIA software to obtain T2-LL and BPF. Results: 60 patients were included. Mean age was 32 years (16-49) and F/M sex ratio was 2.2. Mean baseline EDSS was 1 (0-5). CIS patients differed from CDMS group by a lower EDSS score (mean 0.8 vs. 1.7, p=0.003), a lower T2-LL (2.8 vs. 6.5 cc3, p=0.002). BPF was not significantly different between the two groups (91.7% vs 90.5%, p=0.2). At the beginning of DMD, HRQOL was significantly better in CIS group considering total, physical and mental components. In CDMS group, T2-LL was significantly correlated to role limitations-physical (Pearson9s r coefficient: -0.45, p=0.04) and role limitations-emotional (r=-0.44, p=0.05) scores, whereas in CIS group, it was only correlated to role limitations-emotional (r=-0.427, p=0.05), independently of EDSS. Conclusions: Results suggest that alteration of physical dimensions of HRQOL is associated with accumulation of T2 lesions during disease course. Therefore, earlier DMD initiation could prevent degradation of HRQOL during follow-up. Longitudinal study is on going to assess impact of early treatment on HRQOL and potential correlations with brain MRI parameters. Supported by: Grants from Merck Serono and Bayer Schering Pharma. Disclosure: Dr. Cohen has received personal compensation for activities with Schering-Plough Corporation, Biogen Idec, Serono, Inc., Teva Neuroscience, and Sanofi-Aventis Pharmaceuticals, and Novartis. Dr. Brochet has received personal compensation for activities with Bayer HealthCare, Novartis, Merck Serono, and Biogen Idec. Dr. Brochet has received personal compensation in an editorial capacity for LEN. Dr. Brochet has received research support from Merck Serono, Biogen Idec, and Bayer HealthCare. Dr. Clavelou has received personal compensation for activities with Schering-Plough Corporation, Biogen Idec, Serono, Inc., and Sanofi-Aventis Pharmaceuticals, Inc. as a speaker. Dr. Le Page has nothing to disclose. Dr. Vermersch has received personal compensation for activites with Merck Serono, Bayer Schering, Teva-Aventis, Biogen Idec, Allmirall, and Novartis as a consultant and/or speaker. Dr. Tourbah has received personal compensation for activities with Schering AG, Biogen Idec, Serono, Inc. and Sanofi-Aventis Pharmaceuticals, Inc. as a speaker. Dr. Moreau has received research support from Biogen Idec, Sanofi Aventis and Teva Pharma, Bayer Schering, Merck Serono and Novartis. Dr. Lebrun has received personal compensation for activities with Schering, Biogen Idec, Serono and Sanofi as a speaker.Dr. Lebrun has received personal compensation in an editorial capacity for Elsevier.

An Early Disease Activity Composite Can Predict Long-Term Disease Outcome in CHAMPIONS (PD5.010)

Objective: To compare long-term outcomes in groups categorized based on a composite of short-term disease activity parameters in the CHAMPIONS 5-year cohort. Background The ability to use short-term parameters to identify individuals at risk for poor long-term outcomes would help clinicians select optimal treatments for multiple sclerosis (MS) patients. Design/Methods: CHAMPIONS 5-year was an open-label extension study enrolling 203 (53%) of the patients from CHAMPS. In CHAMPS, patients received immediate treatment (IT) or delayed treatment (DT) with intramuscular interferon beta-1a (IM IFNβ-1a). Progression to clinically definite MS (CDMS) and magnetic resonance imaging (MRI) activity within the first 6 months of CHAMPS formed composites that defined therapeutic target achieved (TTA) ( Results: In the IT group, patients who met TTA criteria had better outcomes compared to TTNA patients. Mean Expanded Disability Status Scale (EDSS) change from month 6 to year 5 was -0.17 in TTA patients and 0.80 in TTNA patients (P=0.0009). Mean brain parenchymal fraction change was -0.010 in TTA patients and -0.017 in TTNA patients (P Conclusions: Use of clinical and imaging measures to monitor disease activity early in the disease course may help predict long-term outcomes for patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Kinkel has received personal compensation for activities with Biogen Idec, Inc, Ironwood Pharmaceuticals, and Teva Neuroscience as a consultant. Dr. Kinkel has received personal compensation in an editorial capacity for Neurological Diseases. Dr. Kinkel has received research support from Biogen Idec. Dr. Simon has nothing to disclose. Dr. Waubant has received personal compensation for activities with Teva Neuroscience, Actelion, Sanofi-Aventis Pharmaceuticals, Roche Diagnostics Corporation and Biogen Idec as a speaker and/or consultant. Dr. Waubant has received research support from Biogen Idec and Sanofi-Aventis Pharmaceuticals. Dr. Fisher has received personal compensation for activities with Biogen Idec. Dr. Fisher has received research support from Biogen Idec and Genzyme. Dr. You has received personal compensation for activities with Biogen Idec as an employee.

Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis

Background: Cognitive dysfunction occurs at the earliest stages of multiple sclerosis (MS), including the stage of clinically isolated syndrome (CIS). Methods: We evaluated the impact of interferon beta-1b (IFNβ-1b) 250 µg on cognitive performance during the CIS stage in the BENEFITstudy. Cognition was assessed by Paced Auditory Serial Addition Test-3” (PASAT-3”) scores. Results: Improvement in PASAT-3” score from baseline to year two was greater for IFNβ-1b treatment than placebo in patients not reaching clinically definite MS (CDMS) by year two. The treatment effect was maintained at year five and was statistically significant. Conclusions: To conclude, early IFNβ-1b treatment had a sustained positive effect on PASAT-3” score over the 5-year BENEFIT study.

Clinical Utility of Glatiramer Acetate in the Management of Relapse Frequency in Multiple Sclerosis

Glatiramer acetate (GA) represents one of the most common disease-modifying therapies for multiple sclerosis. GA is currently approved for patients at high risk of developing clinically definite multiple sclerosis (CDMS) after having experienced a well-defined first clinical episode (clinically isolated syndrome or CIS) and for patients with relapsing-remitting multiple sclerosis (RRMS). GA’s efficacy and effectiveness to reduce relapse frequency have been proved in placebo-controlled and observational studies. Comparative trials have also confirmed the lack of significant differences over other choices of treatment in the management of relapse frequency, and long-term studies have supported its effect at extended periods of time. Additionally, RRMS patients with suboptimal response to interferon β may benefit from reduced relapse rate after switching to GA, and those with clinically isolated syndrome may benefit from delayed conversion to CDMS. All these results, together with its proven long-term safety and positive effect on patients’ daily living, support the favorable risk-benefit of GA for multiple sclerosis treatment.

Killer immunoglobulin-like receptor locus polymorphisms in multiple sclerosis

Objective: The objective of this study was to analyze whether inhibitory and activating killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I alleles defined by their KIR binding motifs are associated with multiple sclerosis (MS) susceptibility or severity. Method: We performed a population-based case–control study in 321 patients with clinically isolated syndrome (CIS) and clinically definite MS (CDMS) and 156 healthy blood donors (HD). Inhibitory and activating KIRs and HLA class I alleles were genotyped using polymerase chain reaction (PCR) sequence-specific primers. Allelic frequencies were correlated with prevalence, age of onset, disability and disease duration of CIS and CDMS. Results: The frequency of the inhibitory KIR2DL3 gene was significantly reduced in patients with CIS and CDMS (p = 3.1 × 10−5). KIR2DL3-dependent risk reduction remained significant after elimination of patients carrying MS-associated DRB1*15, DRB1*03, DRB1*01 alleles. In addition, individuals carrying two copies for KIR2DL2/KIR2DS2 but lacking KIR2DL3 were overrepresented in the CIS/CDMS cohort. However, both genes did not affect disease risk in presence of KIR2DL3. We did not detect any association between the presence or absence of KIR genes with clinical disease parameters. Conclusion: Absence of the inhibitory KIR2DL3 gene is associated with the development of CIS/CDMS. These findings, if confirmed in larger cohorts, suggest that KIR-mediated recognition of HLA class I molecules should be further explored as potential disease mechanism in MS.

Assessing the value of spinal cord lesions in predicting development of multiple sclerosis in patients with clinically isolated syndromes

The purpose of this study was to determine the value of spinal cord lesions as a predictive factor for conversion in clinically isolated syndrome (CIS) patients. Patients with CIS and without immunomodulatory treatment were prospectively included. Age at onset, sex, clinical syndrome at onset, oligoclonal bands, and presence, number and location of lesions on brain and spinal MRI were analyzed. Conversion to multiple sclerosis (MS) was the primary endpoint. Cox regression was used to compare outcomes between groups. A total of 75 patients were included: 53 (71%) women, mean age at onset 32.7 years (SD ± 7.5), mean follow-up time 72.5 months (SD ± 9; range 17-104 months). There were 11 (14.6%) patients with one focal spinal cord lesion, while 13 (17%) patients had two or more spinal cord lesions at the first scan during the onset of the disease. Of the 23 patients (30.6%) who converted to clinically definite MS (CDMS), 2 had a normal spinal cord MRI, 8 patients had one spinal cord lesion, and 13 had more than one lesion on MRI (p < 0.001). In multivariable analyses, one focal spinal cord lesion was significantly associated with increased risk of conversion to MS (p = 0.01, HR 3.5, CI 95% 2.1-6.9), while the presence of two or more focal spinal cord lesions was independently associated with a higher risk of conversion to MS (p < 0.001, HR 5.9, CI 95% 3.2-10.8). CIS patients with an abnormal baseline spinal cord MRI have a higher risk for developing clinically definite MS, independent of brain lesions as well as the presence of cerebrospinal fluid oligoclonal banding (OSF-OB) .

Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial

In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event. We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18-50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00404352. 517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p<0·0001, hazard ratio [HR] 0·49 [95% CI 0·38-0·64]; once a week 75·5%, p=0·008, HR 0·69 [0·54-0·87]) versus placebo (85·8%). 2-year rates of conversion to CDMS were lower for both interferon beta-1a dosing regimens (three times a week 20·6%, p=0·0004, HR 0·48 [0·31-0·73]; once a week 21·6%, p=0·0023, HR 0·53 [0·35-0·79]) than for placebo (37·5%). Adverse events were within the established profile for subcutaneous interferon beta-1a. Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study. Merck Serono SA, Geneva, Switzerland.

Clinical Course of Patients With Ophthalmoplegia Caused by Radiographically Detectable Brainstem Demyelination Occurring as a Clinically Isolated Demyelinating Syndrome

Demyelinating brainstem lesions often causing ophthalmoplegia may occur as the first manifestation of a clinically isolated demyelinating syndrome (CIS). CIS could be the initial attack of clinically definite multiple sclerosis (CDMS) should a second symptomatic attack occur. We report a series of patients with ophthalmoplegia occurring as CIS and assess potential factors affecting the clinical course and final outcome. A computer search was performed for patients evaluated in a university academic neurology practice to identify those with the diagnosis of diplopia. Selection was then made of patients who met the criteria for CIS, and these individuals formed the basis of this study. Ten of 327 patients presenting with diplopia fulfilled inclusion criteria. Of these, all had ophthalmoplegia in primary position of gaze or symptomatic internuclear ophthalmoplegia, and all recovered irrespective of brain MRI findings, steroid use, presence of oligoclonal bands, or progression to CDMS. The ophthalmoplegia of CIS tends to improve with time, regardless of later progression to CDMS. More analysis is needed to fully understand this unique presentation of demyelination.

Interferon β-1b–neutralizing antibodies 5 years after clinically isolated syndrome

To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon β-1b (IFNβ-1b). In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 μg IFNβ-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNβ-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer >20 NU/mL was considered NAb-positive, with low (≥20-100 NU/mL), medium (≥100-400 NU/mL), and high (≥400 NU/mL) titer categories. Here we examine early-treated patients, who received IFNβ-1b for up to 5 years. NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers. Although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNβ-1b and may also result from temporal changes in NAb titers and biology.

Evaluation of soluble HLA-G as a biomarker for multiple sclerosis

Human leukocyte antigen G (HLA-G) is a nonclassical HLA class I antigen that stands out for its immune regulatory properties. First recognized as a mediator of tolerance at the feto-maternal interface, HLA-G is considered a key molecule in protecting target tissue from autoaggressive inflammation.1 High serum levels of soluble HLA-G (sHLA-G) were found to predict graft acceptance in allotransplantation, whereas low levels seem to increase the risk of autoimmunity and account for higher disease activity in autoimmune diseases (e.g., rheumatoid arthritis).1 To evaluate its potential use as a biomarker in multiple sclerosis (MS), we analyzed sHLA-G serum protein in a large cohort of patients with clinically isolated syndrome (CIS) who developed MS during the 5-year observation period of the Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) trial.2 ### Methods. BENEFIT was a placebo-controlled phase III trial of interferon-β (IFNβ)–1b in patients with CIS.2 The study design and outcomes of BENEFIT have been reported elsewhere.2 All patients underwent Expanded Disability Status Scale (EDSS) assessment and brain MRI on a regular basis. The present study focused on patients who reached clinically definite MS (CDMS) during the trial (n = 209). From these patients, a total of 555 serum samples and 435 MRI scans were analyzed. Quantification of sHLA-G was performed using a commercially available ELISA kit (Exbio, Prague, Czech Republic). Nonparametric tests and Cox proportional hazards regression were used in the statistical analysis. A 2-sided p value < 0.05 was considered significant. ### Results. The analysis of “basal” sHLA-G serum levels in untreated patients yielded a highly heterogeneous result (figure 1A). While sHLA-G was undetectable in 22.1% of patients, 12.7% had excessive amounts of sHLA-G serum …

Clinical isolated syndrome: A 3-year follow-up study in China

Objective To summarize the characteristics of Chinese clinically isolated syndrome (CIS) patients and their 3-year follow-up results. Investigate the relationship between CIS features and clinical outcomes. Methods Forty-nine CIS patients were recruited and 42 of them were able to be followed up for a mean of 38 months (range 26–48 months). We recorded baseline features including patient demographics, site of CIS, presence or absence of cerebrospinal fluid (CSF) oligoclonal bands (OCB) and MRI lesions in brain and spinal cord. The incidence of conversion to clinically definite MS (CDMS) or neuromyelitis optica (NMO) after CIS was calculated, and the relationship between baseline features and CDMS was explored. All data were statistically processed with SPSS for Windows Version 11.5. Results After a mean follow-up of 38 months, 10/42 patients had converted to CDMS (24%), and one patient had developed definite NMO. The other 31 patients remained in CIS status. A spinal cord syndrome was the initial CIS manifestation in 57% of patients. The conversion rates to MS were 22% (5/23) for patients presenting with a spinal cord syndrome and 27% (3/11) for multi-focal manifestations. The three-year CDMS conversion rates were 70% (7/10) for patients who fulfilled the MRI dissemination in space criteria (2005 revised McDonald) at onset of CIS, while only 9% (3/32) of patients who did not fulfill these criteria converted to CDMS. Females had significantly higher conversion rate than males. Conclusion A spinal cord syndrome was the most common initial presentation of our Chinese CIS group. After a mean follow-up of 38 months, the conversion rate to MS was approximately 25%. The 2005 revised McDonald MRI criteria for dissemination in space is a key prognostic factor for conversion to MS in CIS in Chinese patients.

RNFL thickness in MS-associated acute optic neuritis using SD-OCT: critical interpretation and limitations

Axonal loss is considered a key prognostic factor in diagnosing and monitoring the progress of multiple sclerosis (MS). The purpose of our research was to determine whether the measurement of retinal nerve fibre layer thickness (RNFLT) as measured with high-resolution spectral-domain optical coherence tomography (SD-OCT) differs between optic nerve injury following acute optic neuritis (ON) or following unregistered subclinical axonal damage in patients with MS. High-resolution SD-OCT measurements of RNFLT were initially carried out in the acute phase of ON and again after 3 months, in 25 patients with clinical definite MS and 25 sex- and age-matched healthy controls, all at the University Eye Hospital, Vienna. Conventional OCT-based RNFLT analysis correctly identified all three patients with initial RNFL swelling. However, only two of three acute ON eyes with a history of ON were registered with RNFLT decrease in seven peripapillary sectors (PPs). The remaining have only been revealed using RNFLT symmetry comparison. Two of 22 (9%) first-episode ON eyes were labelled as pathologic. The number and metric RNFL values of pathologically labelled PPs remained unchanged after 3 months. Our age- and sex-match-based measurement model, with patients with MS being plotted individually and towards the fellow eye, identified all acute ON eyes (with a history of prior ON) with RNFLT reduction in 11 PPs. A global RNFL loss was registered in 36.4% (eight of 22 eyes). However, in 72%, or 16 of 22 ON eyes presenting with first episode of acute ON, a segmental RNFL loss was initially registered in 39 PPs upon baseline examination. The number of PPs with identified axonal decrease increased to a total of 48 PPs within the observational period. Spectral-domain optical coherence tomography imaging of identical scanning locations, combined with an optimized scan centring around the optic disc, offers the technological potential of detecting prior, subtle, clinically unregistered optic nerve injury within MS individuals. Significant discrepancy in RNFLT to the potential ON eye may be achieved by comparing OCT metrics with the fellow eye and a sufficient number of age and sex-matched controls.

Serum elements and oxidative status in clinically isolated syndromes

Metals are suspected of being involved in the pathogenesis of various neurologic diseases. We previously found a complex imbalance in serum chemical elements and oxidative status in patients with clinically definite multiple sclerosis (CDMS). To understand whether this imbalance affects people with clinically isolated syndrome (CIS) and, if so, whether it predicts conversion to CDMS. We studied 22 chemical elements and the oxidative status in 49 patients with CIS, 49 patients with CDMS, and 49 healthy donors (HD). Univariate and multivariate approaches were used to identify profiles for each group. A logistic regression analysis was used to identify the predictive potential of baseline data (elements, oxidative status, and MRI findings) for conversion to CDMS over 36 months. Several elements and oxidative status values differed significantly among the 3 groups. Discriminant analysis revealed a major contribution of Ca, Fe, Sn, Zn, serum antioxidant capacity, and serum oxidative status, which resulted in distinct profiles (the prediction of group membership was 96% [cross-validated 92%] for HD, 92% [cross-validated 92%] for CDMS, and 90% [cross-validated 86%] for CIS). A weighted combination of element concentrations and oxidative status values, adjusting for all other predictors, would predict a reduction in the risk of conversion to CDMS within 3 years (odds ratio 0.37; 95% confidence interval 0.18-0.76; p = 0.007), thereby proving more effective than MRI at baseline. The peculiar imbalance in serum elements and oxidative status that characterizes patients with CIS and may predict conversion to CDMS warrants studies on larger sample sizes.

Exploring the Association between Retinal Nerve Fiber Layer Thickness and Initial Magnetic Resonance Imaging Findings in Patients with Acute Optic Neuritis

Background. Recent studies have shown that OCT-measured retinal nerve fiber layer (RNFL) values may represent a marker for axonal damage in the anterior visual pathway of optic neuritis (ON) and multiple sclerosis (MS) patients. The goal of this study was to determine the link between RNFL values and initial magnetic resonance imaging (MRI) evidence of central nervous system (CNS) inflammation in patients with acute ON. Methods. Fifty patients who experienced ON as a clinically isolated syndrome (CIS) were followed for a mean period of 34 months with OCT testing. RNFL values in affected (ON) eyes and clinically unaffected (non-ON) eyes were compared between patients with MRI evidence of white matter lesions and those with normal baseline MRI findings, over a two year period. Findings. Twenty-one patients (42%) developed clinically definite MS (CDMS) during the study. After two years, temporal RNFL values were thinner (P = .07) in ON patients with MRI lesions at baseline, but the results were not significant. Conclusions. There is no association between RNFL values and baseline MRI status in ON patients at risk for future CDMS over a two year period.