Clinically Isolated Syndrome Patients Research Articles

Interactions of serum cholesterol with anti-herpesvirus responses affect disease progression in clinically isolated syndromes

ObjectivesTo investigate whether anti-herpesvirus antibodies are associated with serum cholesterol profiles in clinically isolated syndromes (CIS). MethodsPre-treatment serum samples from 118 high-risk CIS patients were analyzed for IgG antibodies against cytomegalovirus (anti-CMV), Epstein Barr virus (EBV) viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1). A lipid profile consisting of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) was obtained. Clinical and MRI assessments were obtained at baseline, 6, 12, and 24months after start of interferon-beta treatment. ResultsThe study included 118 CIS patients (77 females, 41 males, 65.3% female; mean age: 28.1±SD 8.1years). Anti-EBV EBNA-1 antibody levels were associated with LDL-C (p=0.009) and TC (p=0.008) levels. Anti-CMV positivity status was associated with reduced time to relapse (p=0.006) and the greater number of relapses (p=0.009) in patients with high HDL-C. Anti-EBV VCA antibody levels were associated with greater number of new T2 lesions (p=0.002) and with increased brain atrophy (p<0.001) in patients with high LDL-C. ConclusionsOur results indicate that higher levels of anti-EBV EBNA-1 antibodies are associated with higher LDL-C and TC levels. Anti-CMV positive individuals have greater disease progression in the presence of higher HDL-C levels. Individuals with higher levels of anti-EBV VCA antibodies have greater progression on MRI measures in the presence of higher LDL-C.

Application of the 2010 revised criteria for the diagnosis of multiple sclerosis to patients with clinically isolated syndromes

Recently, the McDonald criteria for the diagnosis of multiple sclerosis (MS) have been revised, with the aims to diagnose earlier and to simplify the use of brain MRI. To validate the 2010 revised criteria they were applied to a cohort of patients with clinically isolated syndromes (CIS). In all, 178 CIS patients were followed from onset. Test characteristics were calculated after 1, 3 and 5 years and compared between the 2005 and 2010 revised criteria. The time to diagnosis of the 2005 and 2010 criteria was compared using survival analysis and the log-rank test. Clinical evidence for dissemination in space and time was the gold standard for clinically definite MS (CDMS). During follow-up, 76 patients converted to CDMS (mean time to conversion 23.9 months). At 1 year, the specificity and accuracy of the 2005 criteria were a little higher than those of the 2010 criteria (98.0% and 98.4% vs. 86.3% and 88.5%). However, at 5 years, differences completely disappeared (specificity 85.7% and accuracy 93.3% for both criteria). MS diagnosis could be made significantly faster with the 2010 criteria (P = 0.007). Using the 2010 criteria, in 19% of patients the diagnosis could already be made at baseline. By applying the 2010 revised criteria a diagnosis of MS can be made earlier, whilst prediction of disease progression is maintained. This validation brings along great advantages, for treatment possibilities as well as patient counselling.

Vitamin D levels and risk of multiple sclerosis in patients with clinically isolated syndromes

Background: Growing evidence suggests that vitamin D deficiency may be one of the most important environmental factors for the development of multiple sclerosis (MS). Objectives: The objectives of this paper are to evaluate serum 25-hydroxyvitamin D (25(OH)D) levels in patients with clinically isolated syndromes (CIS) and to examine whether they are related to MS risk. Methods: This is a retrospective study of 100 CIS patients hospitalized from 2000 to 2009 at San Raffaele Hospital, Milan, Italy. We evaluated baseline 25(OH)D level as well as clinical, brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data. Results: A total of 52% of CIS patients had vitamin D deficiency (25(OH)D < 50 nmol/l). During follow-up (median: 7.17 years), 55 patients developed clinically definite MS (CDMS). Patients with very low (< 10th percentile) and low (< 25th percentile) 25(OH)D levels were particularly at risk of CDMS (HRs (95% CIs): 2.12 (0.91–4.96) and 1.61 (0.85–3.03), respectively), while no further reduction in the HRs of disease was observed at high levels of 25(OH)D. This association was even stronger after adjustment for additional risk factors for CDMS development (HRs (95% CIs) for 25(OH)D levels < 10th and 25th percentiles: 3.34 (1.32–8.45) and 2.04 (0.96–4.36), respectively). Conclusion: Low serum vitamin D is associated with increased MS risk in patients with CIS.

Identification of coronin-1a as a novel antibody target for clinically isolated syndrome and multiple sclerosis

Recently, we identified the mimotope UH-CIS6 as a novel candidate antibody target for clinically isolated syndrome (CIS) and relapsing-remitting (RR) multiple sclerosis (MS). The purpose of this study was to further validate UH-CIS6 as an antibody target for CIS and MS and to identify the in vivo antibody target of UH-CIS6. First, a UH-CIS6 peptide ELISA was optimized. Next, we investigated the antibody response toward UH-CIS6 in cerebrospinal fluid (CSF) from patients with CIS (n=20), MS (n=43) and other neurological diseases (n=42). Immunoprecipitation of anti-UH-CIS6 antibodies on a normal human brain lysate was performed to identify the in vivo antibody target of UH-CIS6. The cellular expression of an in vivo candidate target was investigated by immunohistochemistry using MS brain tissue sections. Antibody reactivity toward UH-CIS6 was detected in a significantly increased proportion of CSF samples from CIS and RR-MS patients as compared with neurological controls (p=0.046). We identified and confirmed coronin-1a as the in vivo antibody target for UH-CIS6. Furthermore, coronin-1a was expressed by T cells and macrophages in an active MS lesion. Together, these results demonstrate that coronin-1a is a novel antibody target for CIS and MS.

Autoantigen induced clonal expansion in immortalized B cells from the peripheral blood of multiple sclerosis patients

We studied Ig heavy chain (VDJ) sequences and antigen reactivity of 412 immortalized B cell lines from the peripheral blood of 10 multiple sclerosis (MS) patients, 4 clinically isolated syndrome (CIS) patients and 6 healthy controls (HCs). 78/238 (32.8%) MS and CIS B cell lines were part of 9 clonally expanded B cell populations, of which 5 were present in multiple patients. Increased VH1 gene family usage was evidenced for MS B cells, with 29.2% expressing VH1–69. Affinity maturation in MS and CIS was indicated by increased Ig VDJ mutations. Autoantibody producing B cells reactive to intracellular antigens were significantly higher in MS (25%) and CIS (28%) patients than in HCs (5%), including 3/9 expanded B cell clones. Specificity for phosphatidylcholine was observed for 1/9 B cell clones. These findings indicate clonally expanded autoreactive B cells with affinity maturation in the peripheral blood in MS and CIS.

Interleukin-12p40 in the spinal fluid as a biomarker for clinically isolated syndrome

Background: The cerebrospinal (CSF) constitutes a specific immune micro-environment to the central nervous system, thus it may contain specific biomarkers involved in the pathogenesis of multiple sclerosis (MS). Objectives: We aimed to study a large array of inflammatory CSF biomarkers in patients with suspected MS to recognize potential early diagnostic markers. Methods: CSF samples were obtained from 115 patients who presented with neurological symptomatology suggestive of MS as follows: clinically isolated syndrome (CIS) = 49, relapsing–remitting multiple sclerosis (RRMS) = 29, and other neurologic disorders (OND) = 37. Protein expression profiles of 30 inflammatory biomarkers were measured by multiplex Luminex bead assay and further analyzed by group comparison statistics, correlation studies and receiver-operating characteristic (ROC) analysis. Results: Interleukin-12 subunit p40 (IL12p40) demonstrated a significant differential expression pattern between the groups (CIS vs OND: p = 1.17*10−7; RRMS vs OND: p = 4.98*10−5), with higher levels in CIS and RRMS patients. ROC analysis demonstrated excellent diagnostic performance of IL12p40 for discrimination between CIS and OND patients (area under the curve = 0.87 (95% CI 0.78–0.93), p = 0.0001). No associations were found with disease activity or severity measures. Conclusions: An increased IL12p40 level characterizes the CSF of MS patients and appears to be helpful in identifying CIS and OND patients early in the process of clinical diagnostic assessment.

Cerebrospinal fluid and plasma oxidative stress biomarkers in different clinical phenotypes of neuroinflammatory acute attacks. Conceptual accession: from fundamental to clinic.

Oxidative stress is revealed as the main contributor in the pathophysiology of neuroinflammation. Analyzing plasma and cerebrospinal fluid (CSF) of patients with different clinical phenotypes of neuroinflammation, defined as clinically isolated syndrome (CIS), and those defined as relapsing remitting multiples sclerosis (RRMS), we tested peripheral and CNS oxidative stress intensity in these neuroinflammatory acute attacks. All obtained values changes were assessed regarding clinical and radiological features of CNS inflammation. The obtained results revealed an increase in malondialdehyde levels in plasma and CSF in CIS and RRMS patients compared to control values (p < 0.05). The obtained values were most prevailed in both study group, CIS and RRMS, in patients with severe clinical presentation (p < 0.05). Measured activities of catalase and total superoxide dismutase were higher in CIS and RRMS patients in plasma compared to control values (p < 0.05), parallel with an increased catalase activity and decrease in superoxide dismutase activity in CSF regarding values obtained in control group (p < 0.05). The positive correlations regarding clinical score were obtained for all tested biomarkers (p < 0.01). Although the positive correlations were observed in MDA levels in plasma and CSF, for both study patients, and their radiological findings (p < 0.01), and a negative correlation in plasma SOD activity and CIS patients' radiological findings (p < 0.01), no other similar correlations were obtained. These findings might be useful in providing the earliest antioxidative treatment in neuroinflammation aimed to preserve total and CNS antioxidative capacity parallel with delaying irreversible, later neurological disabilities.

Serum and cerebrospinal fluid heavy neurofilaments and antibodies against them in early multiple sclerosis

Heavy neurofilaments (NFH) released from neurons during axonal injury induce a humoral immune response. We measured CSF and serum levels of NFH proteins and anti-NFH IgG antibodies in 19 patients with clinically isolated syndrome (CIS) converting to multiple sclerosis, in 20 stable CIS patients, 23 patients with multiple sclerosis (MS) and 32 control subjects using ELISA. CSF and intrathecal levels and CSF/serum ratios of anti-NFH antibodies were increased in the CIS patients early developing MS while NFH protein concentrations were similar among the groups. Changes associated with NFH are more pronounced for antibodies than for protein itself and may aid in prediction of CIS patients.

Verbal fluency deficits in clinically isolated syndrome suggestive of multiple sclerosis

BackgroundLittle is known about relationships between Cognitive Impairment (CI) and verbal fluency measures in patients with a Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis. The aim of this study was to assess the extent of verbal fluency deficits and their predictive value for the presence of a CI in a population of CIS patients. MethodsCI was detected by the Rao's Brief Repeatable Battery (BRB) and the Stroop Test (ST) in 100 CIS patients. The BRB includes the Word List Generation (WLG) test for semantic verbal fluency. The FAS test was used to investigate phonemic verbal fluency. CI was defined as the failure in at least 3 tests on BRB (without WLG to exclude criterion contamination bias) and ST. ResultsEleven patients failed in at least 3 of the BRB tests and were classified as cognitively impaired. The comparison of Receiver Operating Characteristic curves showed that the Area Under the Curve (AUC) of the WLG was not significantly different from the AUC of the FAS (0.787 vs 0.755; p=N.S.). A cut-off <17 words for the WLG achieved 64% of sensitivity and a 79% of specificity, and a cut-off <28 words achieved 82% of sensitivity and a 66% of specificity in discriminating patients with CI. ConclusionsVerbal fluency deficits occur early in the disease course and may predict the presence of CI in CIS patients.

Reports of Patients and Relatives from the CogniCIS Study about Cognition in Clinically Isolated Syndrome: What Are Our Patients Telling Us?

Objective: To assess the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) in patients with clinically isolated syndrome (CIS). Methods: 130 European CIS patients and 60 relatives completed the MSNQ. Results: The mean (SD) MSNQ score for CIS patients was 15.5 (10.8) and for their informants 11.3 (9.6). Neither the CIS patient nor relative MSNQ report scores correlated with any of the cognitive test scores in the Brief Repeatable Battery of Neuropsychological Tests, but they were significantly related to psychosocial scales including depression. Conclusions: In CIS, patient and relative MSNQ scores are influenced by psychosocial variables rather than actual objective cognitive status. Formal cognitive test assessment is recommended for CIS patients.

Thalamic Atrophy Is Associated with Development of Clinically Definite Multiple Sclerosis

To investigate the association between the development of thalamic and cortical atrophy and the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome (CIS). This prospective study was approved by the institutional review board. Informed consent was given by 216 CIS patients, and patients were treated with 30 µg of intramuscular interferon β1a once a week. They were assessed with a magnetic resonance (MR) imaging examination at baseline, 6 months, 1 year, and 2 years. Patients were evaluated within 4 months of an initial demyelinating event, had two or more brain lesions on MR images, and had two or more oligoclonal bands in cerebrospinal fluid. MR imaging measures of progression included cumulative number and volume of contrast agent-enhanced (CE) new and enlarged T2 lesions, and changes in whole-brain, tissue-specific global, and regional gray matter volumes. Regression and mixed-effect model analyses were used. Over 2 years, 92 of 216 patients (42.6%) converted to CDMS; 122 (56.5%) CIS patients fulfilled McDonald 2005 criteria and 153 (70.8%) fulfilled McDonald 2010 criteria for MR imaging dissemination in time and space. The mean time to first relapse was 3.1 months, and mean annual relapse rate was 0.46. In mixed-effect model analysis, the lateral ventricle volume (P = .005), accumulation of CE (P = .007), new total T2 (P = .009) and new enlarging T2 lesions (P = .01) increase, and thalamic (P = .009) and whole-brain (P = .019) volume decrease were associated with development of CDMS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes (P = .009) were MR imaging variables associated with the development of CDMS. Measurement of thalamic atrophy and increase in ventricular size in CIS is associated with CDMS development and should be used in addition to the assessment of new T2 and CE lesions.

Association of serum bilirubin and uric acid levels changes during neuroinflammation in patients with initial and relapsed demyelination attacks

In order to examine the endogenous antioxidants values in the earliest phase of demyelination, we have determined bilirubin and uric acid (UA) serum values in the patients with clinically isolated syndrome (CIS) and relapsing remitting multiple sclerosis (RRMS), regarding their clinical disability, measured by Extended Disability Status Scale (EDSS), Magnetic Resonance Imaging (MRI), disease duration, gender and other parameters. The bilirubin and UA levels were lower in CIS and RRMS patients than in control group, whether male or female (p < 0.05). The bilirubin and UA levels were decreased in RRMS compared to CIS patients (p < 0.05). Regarding EDSS, MRI and disease duration, obtained values of bilirubin and UA were higher in both study groups in patients with lower EDSS, lower MRI lesion number and shorter disease duration (p < 0.05). The greatest significance in decreased bilirubin and UA levels was observed in female compared to male patients, in both study groups (p < 0.05). The results suggest negative linear correlation between bilirubin and UA levels and disease duration, EDSS and MRI in CIS (p < 0.01), with the same correlation between bilirubin and UA levels and disease duration in RRMS patients (p < 0.01). There was also significant correlation between bilirubin level and MRI findings and UA levels and EDSS in RRMS patients (p < 0.01). The obtained results point to the importance of endogenous antioxidants in the outbreak and course of neuroinflammation. This could be favorable for the new pathogenetically conditioned neuroinflammatory therapy concepts which do not initially rely only on immunomodulatory, but also on the antioxidative effects.

Expansion of CD27high plasmablasts in transverse myelitis patients that utilize VH4 and JH6 genes and undergo extensive somatic hypermutation

Patients with the autoimmune disease multiple sclerosis (MS) typically present with the clinically isolated syndromes (CIS) transverse myelitis (TM) or optic neuritis (ON). B-cell disturbances have been well documented in patients with MS and CIS patients with ON, but not in CIS patients with TM, despite the fact that these patients have the worst clinical outcome of all CIS types. The goal of this study was to characterize the B-cell populations and immunoglobulin genetics in TM patients. We found a unique expansion of CD27(high) plasmablasts in both the cerebrospinal fluid and periphery of TM patients that is not present in ON patients. Additionally, plasmablasts from TM patients show evidence for positive selection with increased somatic hypermutation accumulation in VH4(+) B cells and receptor editing that is not observed in ON patients. These characteristics unique to TM patients may impact disease severity and progression.

A cost-effectiveness analysis of subcutaneous interferon beta-1a 44mcg 3-times a week vs no treatment for patients with clinically isolated syndrome in Sweden

Objective:To assess the cost-effectiveness of subcutaneous interferon (sc IFN) beta-1a 44 mcg 3-times weekly (tiw) vs no treatment at reducing the risk of conversion to multiple sclerosis (MS) in patients with clinically isolated syndrome (CIS) in Sweden.Methods:A Markov model was constructed to simulate the clinical course of patients with CIS treated with sc IFN beta-1a 44 mcg tiw or no treatment over a 40-year time horizon. Costs were estimated from a societal perspective in 2012 Swedish kronor (SEK). Treatment efficacy data were derived from the REFLEX trial; resource use and quality-of-life (QoL) data were obtained from the literature. Costs and outcomes were discounted at 3%. Sensitivity analyses explored whether results were robust to changes in input values and use of Poser criteria.Results:Using McDonald criteria sc IFN beta-1a was cost-saving and more effective (i.e., dominant) vs no treatment. Gains in progression free life years (PFLYs) and quality-adjusted life-years (QALYs) were 1.63 and 0.53, respectively. Projected cost savings were 270,263 SEK. For Poser criteria cost savings of 823,459 SEK were estimated, with PFLY and QALY gains of 4.12 and 1.38, respectively. Subcutaneous IFN beta-1a remained dominant from a payer perspective. Results were insensitive to key input variation. Probabilistic sensitivity analysis estimated a 99.9% likelihood of cost-effectiveness at a willingness-to-pay threshold of 500,000 SEK/QALY.Conclusion:Subcutaneous IFN beta-1a is a cost-effective option for the treatment of patients at high risk of MS conversion. It is associated with lower costs, greater QALY gains, and more time free of MS.Limitations:The risk of conversion from CIS to MS was extrapolated from 2-year trial data. Treatment benefit was assumed to persist over the model duration, although long-term data to support this are unavailable. Cost and QoL data from MS patients were assumed applicable to CIS patients.

Neuroprotection with glatiramer acetate: evidence from the PreCISe trial

The phase III, multicenter, randomized, placebo-controlled PreCISe trial assessed glatiramer acetate (GA) effects in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS). To assess the neuroprotective effect of GA in a subset of patients in the PreCISe trial, we used proton magnetic resonance spectroscopy (MRS) to measure N-acetylaspartate (NAA), a marker of neuronal integrity, in a large central volume of brain. Thirty-four CIS patients randomized to GA 20 mg/day (n = 19) SC or placebo (n = 15) were included. Patients who relapsed (developed clinically definite MS [CDMS]) were removed from the substudy. NAA/creatine (NAA/Cr) ratios were compared between GA-treated and placebo-treated patients. Twenty patients with CIS had not converted to CDMS and were still in the double-blind phase of the trial at 12 months of follow-up. Paired changes in NAA/Cr differed significantly in patients treated with GA (+0.14, n = 11) compared with patients receiving placebo (−0.33, n = 9, p = 0.03) at 12 months, consistent with a neuroprotective effect of GA in vivo. Patients with CIS who received GA showed improvement in brain neuroaxonal integrity, as indicated by increased NAA/Cr, relative to comparable patients treated with placebo, who showed a decline in NAA/Cr consistent with findings from natural history studies.

A comparative study of CSF neurofilament light and heavy chain protein in MS

Background: There is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH)). Methods: We evaluated the analytical and clinical performance of the UmanDiagnostics NF-light® enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) of a group of 148 patients with clinically isolated syndrome (CIS) or multiple sclerosis (MS), and 72 controls. We compared our results with referring levels of our previously-developed CSF NfHSMI35 assay. Results: Exposure to room temperature (up to 8 days) or repetitive thawing (up to 4 thaws) did not influence measurement of NfL concentrations. Values of NfL were higher in all disease stages of CIS/MS, in comparison to controls (p ≤ 0.001). NfL levels correlated with the Expanded Disability Status Scale (EDSS) score in patients with relapsing disease (rs = 0.31; p = 0.002), spinal cord relapses and with CSF markers of acute inflammation. The ability of NfL to distinguish patients from controls was greater than that of NfHSMI35 in both CIS patients (p = 0.001) and all MS stages grouped together (p = 0.035). Conclusions: NfL proved to be a stable protein, an important prerequisite for a reliable biomarker, and the NF-light® ELISA performed better in discriminating patients from controls, compared with the ECL-NfHSMI35 immunoassay. We confirmed and expanded upon previous findings regarding neurofilaments as quantitative markers of neurodegeneration. Our results further support the role of neurofilaments as a potential surrogate measure for neuroprotective treatment in MS studies.

The patients with clinically isolated syndrome and relapsing remitting multiple sclerosis show different levels of advanced protein oxidation products and total thiol content in plasma and CSF

Advanced oxidation protein products (AOPP) and total thiol (SH) groups levels in plasma and CSF were studied in a cohort of 50 clinically isolated syndrome (CIS) and 57 relapsing remittent multiple sclerosis (RRMS) patients related to 20 control group (CG) patients’ values. The obtained results were compared regarding patients demographic, biochemical, clinical (EDSS) and MRI features (total T2 weighted lesions number and Gd enhancement lesion volume).Plasma and CSF AOPP levels in CIS and RRMS patients were higher than those in CG, while SH groups showed lower values compared to CG (p<0.05). Both parameters were higher in CIS than in RRMS patients (p<0.05). Related to EDSS median range, all patients were divided into those with slight or mild and those with severe clinical presentation. AOPP and SH group changes were more pronounced in both, CIS and RRMS patients with higher, compared to those with lower EDSS (p<0.05). AOPP, SH group levels and EDSS positive correlations were observed in both study groups (p<0.01). Both parameters showed the same approach regarding the median range of total T2 weighted lesions and Gd enhancement lesion volume mean values (p<0.05), but no correlation was found between AOPP and SH levels and these patients radiological characteristics (p>0.01).The data support the fact that oxidative stress is always involved in CIS and RRMS pathophysiology, but not always as a disease determinant dependent on its intensity, which might be important for new therapeutic strategies based on antioxidant approach in those patients.

Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude

BackgroundOligoclonal bands (OCBs) unique to the cerebrospinal fluid are used in the diagnosis of multiple sclerosis (MS). The precise prevalence of OCBs in MS and clinically isolated syndrome (CIS) is...

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.

Load-dependent dysfunction of the putamen during attentional processing in patients with clinically isolated syndrome suggestive of multiple sclerosis

Background: Load-related functional magnetic resonance imaging (fMRI) abnormalities of brain activity during performance of attention tasks have been described in definite multiple sclerosis (MS). No data are available in clinically isolated syndrome (CIS) suggestive of MS. Objectives: The objective of this research is to evaluate in CIS patients the fMRI pattern of brain activation during an attention task and to explore the effect of increasing task load demand on neurofunctional modifications. Methods: Twenty-seven untreated CIS patients and 32 age- and sex-matched healthy controls (HCs) underwent fMRI while performing the Variable Attentional Control (VAC) task, a cognitive paradigm requiring increasing levels of attentional control processing. Random-effects models were used for statistical analyses of fMRI data. Results: CIS patients had reduced accuracy and greater reaction time at the VAC task compared with HCs (p=0.007). On blood oxygenation level-dependent (BOLD)-fMRI, CIS patients had greater activity in the right parietal cortex (p=0.0004) compared with HCs. Furthermore, CIS patients had greater activity at the lower (p=0.05) and reduced activity at the greater (p=0.04) level of attentional control demand in the left putamen, compared with HCs. Conclusions: This study demonstrates the failure of attentional control processing in CIS. The load-related fMRI dysfunction of the putamen supports the role of basal ganglia in the failure of attention observed at the earliest stage of MS.