UNASSIGNED: Choroid plexus (ChP) enlargement is an emerging radiological biomarker in multiple sclerosis (MS).
UNASSIGNED: 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.
UNASSIGNED: RIS individuals were included retrospectively and compared with HC. ChPs were automatically segmented using an in-house automated algorithm and manually corrected.
UNASSIGNED: 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.
UNASSIGNED: 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.

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.

The radiologically isolated syndrome is defined by the presence of incidentally identified T2-weighted hyperintense lesions, highly suggestive of central nervous system demyelination, following an MRI study that is performed for reasons other than for the investigation of symptoms related to multiple sclerosis (MS). These individuals also have no evidence of prior neurological symptoms associated with inflammatory demyelination and no alternative explanation for the observed MRI findings. Recently, the introduction of novel imaging techniques such as the \"central vein sign\" has improved lesion specificity for MS. In addition, the observation of T2-fluid attenuated inversion recovery (FLAIR) mismatch characteristics associated with gliomas and in those with MS with a higher disease burden appear to provide morphological data that relate to disease severity. The value of T2-FLAIR mismatch characteristics in discrete multi-focal lesions has not yet been well defined. Here, we present the value of a fat-suppressed T2-FLAIR sequence in the identification and characterization of T2-weighted hyperintensities resulting from inflammatory demyelination.

BACKGROUND: Since 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.
METHODS: We 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.
RESULTS: Out 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.
CONCLUSIONS: Our 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.

BACKGROUND: Radiologically isolated syndrome (RIS) is a condition characterized by asymptomatic, incidentally detected demyelinating plaques in the CNS in a patient without typical clinical findings of multiple sclerosis (MS). This study aimed to compare the mental status and cognitive functions of child and adolescent RIS cases with healthy controls and to investigate the relationship between psychometric test results and the demyelinating lesion characteristics.
METHODS: The mental status and cognitive functions of 12 RIS cases and 12 healthy controls were compared. Semi-structured interviews, behavioral evaluations, depression and anxiety scales, neuropsychological test battery, and an intelligence test were applied for the evaluation of mental state and cognitive functions. These results were compared with the number and localization of demyelinating lesions.
RESULTS: Sustained attention, visual-motor coordination, short-term memory skills, and ability to use visual-spatial information were found worse in the RIS group. There was no correlation between mental state and cognitive functions, and the number and localization of demyelinating lesions.
CONCLUSIONS: Our study showed that pediatric RIS cases may have worse cognitive performance than healthy controls, but no correlation was found between the number and location of demyelinating lesions and psychiatric findings. Although it is controversial whether psychiatric disorders and cognitive disabilities have predictive value in terms of MS conversion in pediatric RIS cases, these subjects were not included in the scope of this study.

OBJECTIVE: 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.
METHODS: Standardized 3T MRIs including 3D isotropic T1-weighted gradient echo images were acquired at baseline and end-of-study according to the ARISE study protocol. The acquired data were 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.
RESULTS: 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).
CONCLUSIONS: 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 radiologically isolated syndrome (RIS) currently represents the earliest detectable preclinical phase of multiple sclerosis (MS). Remarkable advancements have been recently made, including the identification of risk factors for disease evolution, revisions to the existing 2009 RIS criteria, and our understanding of the impact of early disease-modifying therapy use in the prevention/delay of symptomatic MS from two randomized clinical trials. Here, we discuss RIS in the context of the spectrum of MS, implications in the clinical management of individuals, and provide insights into future opportunities and challenges given the anticipated inclusion of asymptomatic MS in the formal definition of MS.

BACKGROUND: Although certain subsets patients with multiple sclerosis (MS), an immune-mediated disorder, are at higher risk of worse acute COVID-19 outcomes compared to the general population, it is not clear whether SARS-CoV-2 infection impacts long-term outcomes compared with MS patients without COVID-19 infection.
OBJECTIVE: This study investigated MS disease activity and mortality 3.5 years post SARS-CoV-2 infection and compared with MS patients without COVID-19.
METHODS: This retrospective study evaluated 1,633 patients with MS in the Montefiore Health System in the Bronx from January 2016 to July 2023. This health system serves a large minority population and was an epicenter for the early pandemic and subsequent surges of infection. Positive SARS-CoV-2 infection was determined by a positive polymerase-chain-reaction test. Primary outcomes were all-cause mortality, and optic neuritis post SARS-CoV-2 infection. Secondary outcomes included change in disease-modifying therapy (DMT), treatment with high-dose methylprednisolone, cerebellar deficits, relapse, and all-cause hospitalization post-infection.
RESULTS: MS patients with COVID-19 had similar demographics but higher prevalence of pre-existing major comorbidities (hypertension, type-2 diabetes, chronic obstructive pulmonary disease, congestive heart failure, chronic kidney disease, and coronary artery disease), optic neuritis, and history of high dose steroid treatment for relapses compared to MS patients without COVID-19. MS patients with COVID-19 had greater risk of mortality (adjusted HR=4.34[1.67, 11.30], p < 0.005), greater risk of post infection optic neuritis (adjusted HR=2.97[1.58, 5.58], p < 0.005), higher incidence of methylprednisolone treatment for post infection acute relapse (12.65% vs. 2.54 %, p < 0.001), and more hospitalization (78.92% vs. 66.81 %, p < 0.01), compared to MS patients without COVID-19.
CONCLUSIONS: MS patients who survived COVID-19 infection experienced worse long-term outcomes, as measured by treatment for relapse, hospitalization and mortality. Identifying risk factors for worse long-term outcomes may draw clinical attention to the need for careful follow-up of at-risk individuals post-SARS-CoV-2 infection.

BACKGROUND: 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.
OBJECTIVE: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests.
METHODS: We analyzed children (≤ 18 y) 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).
RESULTS: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y 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 ≥ 12 y (median 11d vs. 159d, p = 0.03).
CONCLUSIONS: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed.

The widespread use of magnetic resonance imaging (MRI) has led to increased detection of individuals exhibiting asymptomatic brain and spinal cord lesions suggestive of multiple sclerosis (MS), defined as \"radiologically isolated syndrome\" (RIS). Specific criteria have been proposed and updated over time to identify individuals with RIS. Moreover, a younger age, the presence of infratentorial, spinal cord or gadolinium-enhancing lesions, as well as of cerebrospinal fluid-specific oligoclonal bands have been recognized as relevant risk factors for the occurrence of a first clinical event. Recent randomized controlled trials conducted in individuals with RIS have shown that dimethyl fumarate and teriflunomide significantly reduce the occurrence of clinical events in this population. These findings support the notion that early treatment initiation may positively influence the prognosis of these patients. However, several aspects should be taken into account before treating individuals with RIS in the real-world clinical setting, including an accurate identification of individuals with RIS to avoid misdiagnosis, a precise stratification of their risk of experiencing a first clinical event and further data supporting favorable balance between benefits and risks, even in the long term. This commentary provides an overview of the latest updates in RIS diagnosis, prognosis, and emerging treatment evidence.