Radiologically Isolated Syndrome Research Articles

The confavreux lecture: The radiologically isolated syndrome diagnosis, prognosis and perspectives.

Radiologically isolated syndrome (RIS) is the earliest documented stage in the disease continuum of multiple sclerosis (MS). It is discovered incidentally in individuals who are asymptomatic but have typical lesions in the brain or spinal cord suggestive of autoimmune inflammatory demyelination. The revised 2023 RIS criteria aim to secure an accurate and timely diagnosis due to the presence of imaging mimics. These criteria require having at least one T2-weighted hyperintense lesion in one of the four suggestive MS locations along with two of the following three features: spinal cord lesion, cerebrospinal fluid (CSF)-restricted oligoclonal bands, or new T2 or gadolinium-enhancing lesion observed on a subsequent magnetic resonance imaging (MRI) study. Once the diagnosis is confirmed, established risk factors, including age, lesion location and CSF, significantly improve prognostic stratification, which is crucial for immunoactive interventions. Recent clinical trials have shown that oral disease-modifying treatments can delay or prevent the first clinical event in RIS patients. Consulting with an MS team for each RIS case is strongly recommended to enhance care and disease surveillance. The revised 2024 McDonald criteria will classify individuals with additional CSF and advanced MRI biomarkers as having preclinical MS, highlighting the importance of vigilance in this area.

Analysis of healthcare utilization before the diagnosis of radiologically isolated syndrome.

Previous studies have shown that people with multiple sclerosis (MS) had frequent healthcare visits up to 10 years before being diagnosed but with no information from magnetic resonance imaging (MRI) scans of the connection with the radiologically isolated syndrome (RIS). To analyze healthcare use 3 years before the RIS diagnosis. We examined healthcare usage before the first scan in RIS cases from 2010 to 2019. RIS subjects were identified from the French National MS observatory and compared to the general population (matched 10:1) and MS patients (matched 4:1). Among 482 RIS individuals, 223 (46.3%) were not linked to the healthcare resources database. The remaining RIS individuals (53.7%) had higher healthcare usage before their RIS diagnosis for issues related to neurology visits, headaches (odds ratio (OR): 3.34, confidence interval (CI): [2.00-5.57], p < 0.0001), and the use of anti-migraine drugs (OR: 2.61, CI: [1.37-4.99], p = 0.004) compared to MS. Only about half of RIS patients had MS-selected healthcare resources, which allowed for data linkage. Those who did seek care before their RIS diagnosis were most commonly known for other neurological comorbidities. These findings do not support the idea of a systemic prodrome before RIS diagnosis.

CXCL13 levels in cerebrospinal fluid in relapsing-remitting multiple sclerosis: The role of Borrelia in neuroinfections.

This study was compared the Borrelia antibodies and chemokine ligand 13 (CXCL13) levels in cerebrospinal fluid (CSF) samples from cases diagnosed with relapsing-remitting multiple sclerosis (RRMS), radiologically isolated syndrome (RIS), and pseudotumour cerebri (PTC). A total of 43 CSF samples were collected from patients diagnosed with RRMS, RIS and PTC. We prospectively investigated Borrelia IgG and IgM antibodies in the CSF samples of the cases by enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) method, and CXCL13 levels by ELISA. Data were statistically analysed using the the Spearman rank correlation test. Five antigens (protein 19, 20, 21, 58, and outer surface protein C (OspC)) were positive due to confirmation of the positive samples for Borrelia antibodies by the WB method. There were no significant differences in CSF CXCL13 levels between the three groups. The CXCL13 level was found to be statistically higher in the demyelinating group compared to the PTC group (p=0.001). The Borrelia antibodies were found positive in CSF samples of RRMS patients. The coexistence of high CXCL13 (may be a potential biomarker) suggests that LNB may also play a role in the etiopathogenesis of RRMS. In addition, the positive detection of OspC and p58 WB bands in most cases suggests that these protein bands can be used as in the differential diagnosis of neurodegenerative diseases and Lyme disease.

Evaluation of the content of microbial metabolites in cerebrospinal fluid of individuals with radiologically isolated syndrome

Over the past decade, a large amount of data has been obtained on the role of the gut microbiota in the development of diseases of the nervous system. In particular, the literature contains data on the composition of the gut microbiota in multiple sclerosis (MS). However, the body's microbiome is not limited to the gut microbiota. Of particular interest are the body fluids that are in direct contact with the nervous tissue, such as cerebrospinal fluid (CSF). In our previous studies, we have already analyzed the CSF in different variants of MS course and found the markers of different microbes, which confirms the hypothesis of the association of MS with polymicrobial infection. No less interesting is the transitional state – radiologically isolated syndrome (RIS), in which less attention was paid to analyzing the microbiome.Objective: to evaluate the content of microbial metabolites in the CSF of individuals with RIS and in the control group.Material and methods. The content of microbial markers in the CSF was determined using gas chromatography-mass spectrometry in 10 individuals with RIS and in 10 individuals in the control group.Results. We found a statistically significant increase in the content of microbiota markers in the CSF of individuals with RIS, namely a statistically significant increase in the content of markers of Epstein–Barr virus, Propionibacterium acnes bacteria, Pseudomonas, Moraxella and Acinetobacter.Conclusion. The results of this study are consistent with the hypothesis of a possible association between MS and polymicrobial infection, particularly infection with Epstein–Barr virus.

Early Disease-Modifying Treatments for Presymptomatic Multiple Sclerosis.

Radiologically isolated syndrome (RIS) is the earliest stage in the disease continuum of multiple sclerosis (MS). RIS is discovered incidentally in individuals who are asymptomatic but have typical lesions in the brain and/or spinal cord suggestive of demyelination. The2009 and revised 2023 RIS criteria weredeveloped for diagnosis.Presymptomatic individuals who fulfill the 2009 RIS criteria by having 3-4 of 4 dissemination in spaceMcDonald 2005 MS criteria are still diagnosed with RIS using therevised 2023 RIS criteria.Inpresymptomatic individuals who do not fulfill the 2009 RIS criteria, the revised 2023 RIS criteria target to secure an accurate and timely diagnosis: In addition to (a) having one lesion in two of four locations (periventricular, juxtacortical/cortical, infratentorial, spinal cord), (b) two of three features (spinal cord lesion, cerebrospinal fluid (CSF)-restricted oligoclonal bands, and new T2 or gadolinium-enhancing lesion) should be fulfilled. Among laboratory biomarkers,CSF kappa-free light chain can also increase diagnostic accuracy. Once the diagnosis is confirmed, the established risk factors, including demographics, imaging, and laboratory biomarkers, should be evaluated for symptomatic MS transition and prognosis. Younger age, male sex, increased neurofilament-light chain, CSF abnormality, and the presence of infratentorial, spinal cord, or gadolinium-enhancing lesions on imaging are the main risk factors for transition to symptomatic MS. Two randomized clinical trials showed significant efficacy of disease-modifying treatments in delaying or preventing the development of the first clinical event in RIS. However, because some individuals remain as RIS, it is crucial to identify the individuals with a higher number of risk factors to optimize disease outcomes by early intervention while minimizing adverse events. Discussing each RIS case with an expert MS team is recommended because there is still a lack of clinical guidelines to improve care, counseling, and surveillance.

Choroid plexus enlargement correlates with periventricular pathology but not with disease activity in radiologically isolated syndrome

Background: Choroid plexus (ChP) enlargement is an emerging radiological biomarker in multiple sclerosis (MS). Objectives: This study aims to assess ChP volume in a large cohort of patients with radiologically isolated syndrome (RIS) versus healthy controls (HC) and explore its relationship with other brain volumes, disease activity, and biological markers. Methods: RIS individuals were included retrospectively and compared with HC. ChPs were automatically segmented using an in-house automated algorithm and manually corrected. Results: A total of 124 patients fulfilled the 2023 RIS criteria, and 55 HCs were included. We confirmed that ChPs are enlarged in RIS versus HC (mean (±SD) normalized ChP volume: 17.24 (±4.95) and 11.61 (±3.58), respectively, p < 0.001). Larger ChPs were associated with more periventricular lesions (ρ = 0.26; r2 = 0.27; p = 0.005 for the correlation with lesion volume, and ρ = 0.2; r2 = 0.21; p = 0.002 for the correlation with lesion number) and lower thalamic volume (ρ = −0.38; r2 = 0.44; p < 0.001), but not with lesions in other brain regions. Conversely, ChP volume did not correlate with biological markers. No significant difference in ChP volume was observed between subjects who presented or did not have a clinical event or between those with or without imaging disease activity. Conclusions: This study provides evidence that ChP volume is higher in RIS and is associated with measures reflecting periventricular pathology but does not correlate with biological, radiological, or clinical markers of disease activity.

Assessing the visual afferent pathway with the multifocal visual evoked potentials in the radiologically isolated syndrome

The early identification of individuals with radiologically isolated syndrome (RIS) who are at an elevated risk of progressing to multiple sclerosis (MS) is essential for making informed treatment decisions. This study aimed to evaluate the predictive potential of multifocal Visual Evoked Potentials (mfVEP) measures in individuals with RIS with respect to their conversion to MS. A prospective observational cohort study was conducted, involving 21 individuals with RIS recruited from a MS center. Baseline assessments, including mfVEP, magnetic resonance imaging (MRI), and clinical examinations, were performed, and participants were longitudinally followed for up to 24 months. The primary outcome measures were the conversion to MS. Over a clinical follow-up period of 24 months, five individuals (5/21) with RIS progressed to MS. MfVEP amplitude responses (interocular and monocular probability analysis) demonstrated abnormal cluster visual field defects in 47.6% of RIS eyes at baseline, whereas multifocal VEP latency analysis showed significant delays in 38.4%. A reduction in interocular amplitude [OR = 0.036, (95% CI 0.003–0.503); P = 0.014], monocular amplitude [OR = 0.083, (95% CI 0.007–0.982); P = 0.048], and a prolonged interocular latency [OR = 0.095, (95% CI 0.009–0.972); P = 0.047] were associated with a higher relative risk of clinical conversion at the 2-year follow-up. Multifocal VEP may serve as a novel and independent risk factor for predicting the conversion to MS in individuals with Radiologically Isolated Syndrome.

Unveiling Parry-Romberg Syndrome With Native Demyelinating Etiology as the Underlying Cause

Parry-Romberg Syndrome (PRS) is an atypical condition characterized by hemiatrophy of the face. Despite its rarity, the precise pathophysiological processes underlying its etiology remain elusive. While previous reports have hinted at the potential involvement of autoimmune factors, our case report aims to explore a novel perspective. Specifically, we pose the question of whether multiple sclerosis (MS) could be a plausible causative factor for PRS. Additionally, we investigate the potential association between Radiologically Isolated Syndrome (RIS) and the development of Parry-Romberg Syndrome.

The prominence of Oligoclonal Bands for clinical conversion in Radiologically isolated syndrome: 10-year follow-up study in Isfahan, Iran

BackgroundSince data is limited on radiologically isolated syndrome (RIS) subjects in certain regions like the Middle East, we aimed to further explore the replicability and generalizability of previously suggested predictors among a cohort of Iranian RIS subjects and report the long-term clinically definite MS (CDMS) conversion rate in this cohort. MethodsWe conducted a prospective 10-year cohort on our RIS participants, during which we collected the MRI, paraclinical, and demographic data of the subjects, and identified those who converted to CDMS. ResultsOut of 35 participants, 10 (28.5 %) developed CDMS during an average of 5.58 ± 3.08 years (range: 4 months to 10.33 years). OCB positivity was the only definitive predictor for conversion to CDMS in this cohort (P-value = 0.006), but other previously reported risk factors such as spinal cord lesions or age lacked statistical significance (P-values > 0.05). We also reported the median survival time as 114 months, the proportion surviving after 14 months as 96.9 % ± 3.1 %, and the overall conversion rate as 0.05 cases per year. ConclusionOur results highlight OCB as an important predictive factor of clinical conversion in RIS. The prominence of OCB suggests a need for routine CSF analysis in RIS subjects and could guide clinicians in deciding which RIS subjects benefit from DMTs.

Dimethyl fumarate preserves brainstem and cervical spinal cord integrity in radiologically isolated syndrome.

The first randomized placebo-controlled therapeutic trial in radiologically isolated syndrome (RIS), ARISE, demonstrated that treatment with dimethyl fumarate (DMF) delayed the onset of a first clinical event related to CNS demyelination and was associated with a significant reduction in new and/or newly enlarging T2-weighted hyperintense lesions. The purpose of this study was to explore the effect of DMF on volumetric measures, including whole brain, thalamic, and subcortical gray matter volumes, brainstem and upper cervical spine three-dimensional (3D) volumes, and brainstem and upper cervical spine surface characteristics. Standardized 3T MRIs including 3D isotropicT1-weighted gradient echo images were acquired at baseline and end-of-study according to the ARISE study protocol. The acquired datawere analyzed using Structural Image Evaluation Using Normalization of Atrophy (SIENA), FreeSurfer v7.3, and an in-house pipeline for 3D conformational metrics. Multivariate mixed models for repeated measures were used to analyze rates of change in whole brain, thalamic, subcortical gray matter, as well as change in the 3D surface curvature of the dorsal pons and dorsal medulla and 3D volume change at the medulla-upper cervical spinal cord. The study population consisted of 64 RIS subjects (DMF:30, placebo:34). No significant difference was seen in whole brain, thalamic, or subcortical gray matter volumes in treated vs. untreated RIS patients. A significant difference was observed in dorsal pons curvature with the DMF group having a lower least squares mean change of -4.46 (standard estimate (SE): 3.77) when compared to placebo [6.94 (3.71)] (p = 0.036). In individuals that experienced a first clinical event,a greater reduction in medulla-upper cervical spinal cord volume (p = 0.044) and a decrease in surface curvature was observed at the dorsal medulla (p = 0.009) but not at the dorsal pons (p = 0.443). The benefit of disease-modifying therapy in RIS may extend to CNS structures impacted by neurodegeneration that is below the resolution of conventional volumetric measures.

The diagnostic workup of children with the radiologically isolated syndrome differs by age and by sex.

Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. We analyzed children (≤ 18y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). We included 103 children with RIS (67% girls, median age = 14.9y). Children ≥ 12y were more likely than children < 12y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12y (median 11d vs. 159d, p = 0.03). Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed.

The Time Trajectory of Choroid Plexus Enlargement in Multiple Sclerosis.

Choroid plexus (CP) can be seen as a watchtower of the central nervous system (CNS) that actively regulates CNS homeostasis. A growing body of literature suggests that CP alterations are involved in the pathogenesis of multiple sclerosis (MS) but the underlying mechanisms remain elusive. CPs are enlarged and inflamed in relapsing-remitting (RRMS) but also in clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) stages, far beyond MS diagnosis. Increases in the choroid plexus/total intracranial volume (CP/TIV) ratio have been robustly associated with increased lesion load, higher translocator protein (TSPO) uptake in normal-appearing white matter (NAWM) and thalami, as well as with higher annual relapse rate and disability progression in highly active RRMS individuals, but not in progressive MS. The CP/TIV ratio has only slightly been correlated with magnetic resonance imaging (MRI) findings (cortical or whole brain atrophy) and clinical outcomes (EDSS score) in progressive MS. Therefore, we suggest that plexus volumetric assessments should be mainly applied to the early disease stages of MS, whereas it should be taken into consideration with caution in progressive MS. In this review, we attempt to clarify the pathological significance of the temporal CP volume (CPV) changes in MS and highlight the pitfalls and limitations of CP volumetric analysis.

Shifting our attention earlier in the multiple sclerosis disease course.

Revisions of multiple sclerosis (MS) diagnostic criteria enable clinicians to diagnose patients earlier in the biologic disease course. Prompt initiation of therapy correlates with improved clinical outcomes. This has led to increased attention on the earliest stages of MS, including the MS prodrome and radiologically isolated syndrome (RIS). Here, we review current understanding and approach to patients with preclinical MS. MS disease biology often begins well before the onset of typical MS symptoms, and we are increasingly able to recognize preclinical and prodromal stages of MS. RIS represents the best characterized aspect of preclinical MS, and its diagnostic criteria were recently revised to better capture patients at highest risk of conversion to clinical MS. The first two randomized control trials evaluating disease modifying therapy use in RIS also found that treatment could delay or prevent onset of clinical disease. Despite progress in our understanding of the earliest stages of the MS disease course, additional research is needed to systematically identify patients with preclinical MS as well as capture those at risk for developing clinical disease. Recent data suggests that preventive immunomodulatory therapies may be beneficial for high-risk patients with RIS; though management remains controversial.

Emerging imaging markers in radiologically isolated syndrome: implications for earlier treatment initiation.

The presence of central nervous system lesions fulfilling the criteria of dissemination in space and time on MRI leads to the diagnosis of a radiologically isolated syndrome (RIS), which may be an early sign of multiple sclerosis (MS). However, some patients who do not fulfill the necessary criteria for RIS still evolve to MS, and some T2 hyperintensities that resemble demyelinating lesions may originate from mimics. In light of the recent recognition of the efficacy of disease-modifying therapy (DMT) in RIS, it is relevant to consider additional imaging features that are more specific of MS. We performed a narrative review on cortical lesions (CL), the central vein sign (CVS), and paramagnetic rim lesions (PRL) in patients with RIS. In previous RIS studies, the reported prevalence of CLs ranges between 20.0 and 40.0%, CVS + white matter lesions (WMLs) between 87.0 and 93.0% and PRLs between 26.7 and 63.0%. Overall, these imaging findings appear to be frequent in RIS cohorts, although not consistently taken into account in previous studies. The search for CLs, CVS + WML and PRLs in RIS patients could lead to earlier identification of patients who will evolve to MS and benefit from DMTs.

Retinal and Choroidal Vascularity Evaluation in Pediatric Radiologically Isolated Syndrome and Multiple Sclerosis

BackgroundTo assess vessel density (VD) and flow of retinal plexuses and peripapillary region related with the pediatric radiologically isolated syndrome (RIS) and multiple sclerosis (MS). MethodsWe analyzed 24 eyes of 12 participants with the diagnosis of RIS, 24 eyes of 12 participants with the diagnosis of MS, and 26 eyes of 13 age- and sex-matched healthy controls in this prospective, cross-sectional study. The superficial capillary plexus (SCP) and deep capillary plexus, foveal avascular zone, and the flow of choriocapillaris were investigated using optical coherence tomography angiography. ResultsParafoveal VD and all subregion parameters in SCP were significantly decreased in the MS group compared with the controls, whereas only nasal and inferior VD were significantly decreased in the pediatric RIS group compared with the controls. Ganglion cell layer (GCL) thickness of all subregions of the inner ring was significantly decreased in the pediatric MS group compared with the control group. No significant difference was observed between the pediatric RIS group and the control group regarding thickness. ConclusionsWe showed lower parafoveal VD in all subregions of SCP in pediatric MS, whereas only parafoveal nasal and inferior VD were decreased in pediatric RIS. GCL thickness of inner ring was significantly decreased in the pediatric MS, whereas GCL thickness did not change in pediatric RIS. Therefore, a decrease of parafoveal nasal and inferior VD without a decrease in thickness implies an early impairment of microvasculature in the RIS before impairment of thickness and that microvascular alterations begin from highly vascular superficial parafovea.

The diagnostic value of the central vein sign in radiologically isolated syndrome.

The radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS). Increasing evidence suggests that the central vein sign (CVS) enhances lesion specificity, allowing for greater MS diagnostic accuracy. This study evaluated the diagnostic performance of the CVS in RIS. Patients were prospectively recruited in a single tertiary center for MS care. Participants with RIS were included and compared to a control group of sex and age-matched subjects. All participants underwent 3 Tesla magnetic resonance imaging, including postcontrast susceptibility-based sequences, and the presence of CVS was analyzed. Sensitivity and specificity were assessed for different CVS lesion criteria, defined by proportions of lesions positive for CVS (CVS+) or by the absolute number of CVS+ lesions. 180 participants (45 RIS, 45 MS, 90 non-MS) were included, representing 5285 white matter lesions. Among them, 4608 were eligible for the CVS assessment (970 in RIS, 1378 in MS, and 2260 in non-MS). According to independent ROC comparisons, the proportion of CVS+ lesions performed similarly in diagnosing RIS from non-MS than MS from non-MS (p = 0.837). When a 6-lesion CVS+ threshold was applied, RIS lesions could be diagnosed with an accuracy of 87%. MS could be diagnosed with a sensitivity of 98% and a specificity of 83%. Adding OCBs or Kappa index to CVS biomarker increased the specificity to 100% for RIS diagnosis. This study shows evidence that CVS is an effective imaging biomarker in differentiating RIS from non-MS, with similar performances to those in MS.

The Canadian Prospective Cohort Study to understand progression in multiple sclerosis: baseline characteristics.

Disease progression is observed across the spectrum of people with multiple sclerosis (MS) and identification of effective treatment strategies to halt progression remains one of the greatest unmet clinical needs. The Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) was designed to evaluate a wide range of factors associated with the onset and rate of clinical disease progression in MS and to describe the interplay between these factors. A prospective cohort study. CanProCo is a national, prospective, observational cohort study that has recruited 944 individuals from 5 large academic MS centers in Canada. Participants include people with radiologically isolated syndrome (RIS), early relapsing-remitting and primary progressive MS (RRMS, PPMS), and healthy controls (HCs). Annually, participants complete self-reported questionnaires, undergo clinical evaluation and, if clinically indicated, magnetic resonance images (MRIs) of the brain and cervical spinal cord; in a subset of participants (n = 399), blood, and research MRIs of the brain and cervical spinal cord are collected. Linkages to health administrative databases are available at three sites. Overall, 944 participants were recruited (53 HCs, 63 RIS, 751 RRMS, 77 PPMS). RIS and MS participants had a mean age of 39.0 years and 70.5% female. The mean time since diagnosis was 2.7 years. There were differences observed in the Expanded Disability Status Scale score and components of the MS performance test (walking speed test, manual dexterity test, processing speed test, and low-contrast visual acuity) between RIS and MS subtypes. Questionnaires revealed more symptoms of depression and anxiety and impaired physical and mental quality of life in people with RIS/MS versus HCs and differences across RIS/MS subtypes. Physical and mental neurological disability is prevalent even in the earliest stages of MS. Transdisciplinary approaches such as those used in CanProCo are needed to better characterize clinical progression in MS. Additional CanProCo results, including MRI, biological, and pharmaco-economic data will be forthcoming. Going forward, CanProCo's data sharing and collaborative vision will facilitate numerous global collaborations, which will inform the development and implementation of effective interventions for people with MS around the world.

How Early Is Early Multiple Sclerosis?

The development and further optimization of the diagnostic criteria for multiple sclerosis (MS) emphasize the establishment of an early and accurate diagnosis. So far, numerous studies have revealed the significance of early treatment administration for MS and its association with slower disease progression and better late outcomes of the disease with regards to disability accumulation. However, according to current research results, both neuroinflammatory and neurodegenerative processes may exist prior to symptom initiation. Despite the fact that a significant proportion of individuals with radiologically isolated syndrome (RIS) progress to MS, currently, there is no available treatment approved for RIS. Therefore, our idea of "early treatment administration" might be already late in some cases. In order to detect the individuals who will progress to MS, we need accurate biomarkers. In this review, we present notable research results regarding the underlying pathology of MS, as well as several potentially useful laboratory and neuroimaging biomarkers for the identification of high-risk individuals with RIS for developing MS. This review aims to raise clinicians' awareness regarding "subclinical" MS, enrich their understanding of MS pathology, and familiarize them with several potential biomarkers that are currently under investigation and might be used in clinical practice in the future for the identification of individuals with RIS at high risk for conversion to definite MS.

Abnormal functional connectivity in radiologically isolated syndrome: A resting-state fMRI study

Background: Radiologically isolated syndrome (RIS) patients might have psychiatric and cognitive deficits, which suggests an involvement of major resting-state functional networks. Notwithstanding, very little is known about the neural networks involved in RIS. Objective: To examine functional connectivity differences between RIS and healthy controls using resting-state functional magnetic resonance imaging (fMRI). Methods: Resting-state fMRI data in 25 RIS patients and 28 healthy controls were analyzed using an independent component analysis; in addition, seed-based correlation analysis was used to obtain more information about specific differences in the functional connectivity of resting-state networks. Participants also underwent neuropsychological testing. Results: RIS patients did not differ from the healthy controls regarding age, sex, and years of education. However, in memory (verbal and visuospatial) and executive functions, RIS patients’ cognitive performance was significantly worse than the healthy controls. In addition, fluid intelligence was also affected. Twelve out of 25 (48%) RIS patients failed at least one cognitive test, and six (24.0%) had cognitive impairment. Compared to healthy controls, RIS patients showed higher functional connectivity between the default mode network and the right middle and superior frontal gyri and between the central executive network and the right thalamus (pFDR < 0.05; corrected). In addition, the seed-based correlation analysis revealed that RIS patients presented higher functional connectivity between the posterior cingulate cortex, an important hub in neural networks, and the right precuneus. Conclusion: RIS patients had abnormal brain connectivity in major resting-state neural networks and worse performance in neurocognitive tests. This entity should be considered not an “incidental finding” but an exclusively non-motor (neurocognitive) variant of multiple sclerosis.

Kappa Free Light Chain Index Predicts Disease Course in Clinically and Radiologically Isolated Syndromes.

To evaluate whether the kappa free light chain index (K-index) can predict the occurrence of new T2-weighted MRI lesions (T2L) and clinical events in clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS). All consecutive patients presenting for the diagnostic workup, including CSF analysis, of clinical and/or MRI suspicion of multiple sclerosis (MS) since May 1, 2018, were evaluated. All patients diagnosed with CIS and RIS with at least 1-year follow-up were included. Clinical events and new T2L were collected during follow-up. The K-index performances in predicting new T2L and a clinical event were evaluated using time-dependent ROC analyses. The time to clinical event or new T2L was estimated using survival analysis according to the binarized K-index using an independent cutoff of 8.9, and the ability of each variable to predict outcomes was compared using the Harrell c-index. One hundred and eighty two patients (146 CIS and 36 RIS, median age 39 [30; 48] y-o, 70% females) were included with a median follow-up of 21 [13, 33] months. One hundred five (58%) patients (85 CIS and 20 RIS) experienced new T2L, and 28 (15%; 21 CIS and 7 RIS) experienced a clinical event. The K-index could predict new T2L over time in CIS (area under the curve [AUC] ranging from 0.86 to 0.96) and in RIS (AUC ranging from 0.84 to 0.54) but also a clinical event in CIS (AUC ranging from 0.75 to 0.87). Compared with oligoclonal bands (OCBs), the K-index had a better sensitivity and a slight lower specificity in predicting new T2L and clinical events in both populations. In the predictive model, the K-index was the variable that best predict new T2L in both CIS and RIS but also clinical events in CIS (c-index ranging from 0.70 to 0.77), better than the other variables, including OCB. This study provides evidence that the K-index predicts new T2L in CIS and RIS but also clinical attack in patients with CIS. We suggest adding the K-index in the further MS diagnosis criteria revisions as a dissemination-in-time biomarker.