Background: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID). Methods: We enrolled patients who underwent a diagnostic spinal tap throughout two years. KFLC levels were determined using a Freelite assay (Binding Site) and the turbidimetric Optilite analyzer. Results: Of 540 included patients, 223 had a CNSID, and 84 had MS. The kappa index was more sensitive (0.89 versus 0.85) and less specific (0.84 versus 0.89), with the same AUC (0.87) as OCB for MS diagnosis (optimal cut-off: 6.2). Adding patients with a single CSF IgG band to the OCB-positive group slightly increased the AUC (0.88). Likewise, the kappa index (cut-off: 3.9) was more sensitive (0.67 versus 0.50) and less specific (0.81 versus 0.97), with the same AUC (0.74) as OCB, for a CNSID diagnosis. Conclusion: The kappa index and CSF OCB have comparable diagnostic accuracies for a MS or CNSID diagnosis and supply the clinician with useful, complementary information.

Objective To describe onset clinical features predicting time to first relapse and time to long-term visual, motor and cognitive disabilities in paediatric-onset aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSDs). Methods In this retrospective UK multicentre cohort study, we recorded clinical data of paediatric-onset AQP4-IgG NMOSD. Univariate and exploratory multivariable Cox proportional hazard models were used to identify long-term predictors of permanent visual disability, Expanded Disability Status Scale (EDSS) score of 4 and cognitive impairment. Results We included 49 paediatric-onset AQP4-IgG patients (38.8% white, 34.7% black, 20.4% Asians and 6.1% mixed), mean onset age of 12±4.1 years, and 87.7% were female. Multifocal onset presentation occurred in 26.5% of patients, and optic nerve (47%), area postrema/brainstem (48.9%) and encephalon (28.6%) were the most involved areas. Overall, 52.3% of children had their first relapse within 1 year from disease onset. Children with onset age <12 years were more likely to have an earlier first relapse (p=0.030), despite showing no difference in time to immunosuppression compared with those aged 12–18 years at onset. At the cohort median disease duration of 79 months, 34.3% had developed permanent visual disability, 20.7% EDSS score 4 and 25.8% cognitive impairment. Visual disability was associated with white race (p=0.032) and optic neuritis presentations (p=0.002). Cognitive impairment was predicted by cerebral syndrome presentations (p=0.048), particularly if resistant to steroids (p=0.034). Conclusions Age at onset, race, onset symptoms and resistance to acute therapy at onset attack predict first relapse and long-term disabilities. The recognition of these predictors may help to power future paediatric clinical trials and to direct early therapeutic decisions in AQP4-IgG NMOSD.

BACKGROUND AND PURPOSE: Quantitative susceptibility mapping has been used to characterize iron and myelin content in the deep gray matter of patients with multiple sclerosis. Our aim was to characterize the susceptibility mapping of cortical lesions in patients with MS and compare it with neuropathologic observations. MATERIALS AND METHODS: The pattern of microglial activation was studied in postmortem brain tissues from 16 patients with secondary-progressive MS and 5 age-matched controls. Thirty-six patients with MS underwent 3T MR imaging, including 3D double inversion recovery and 3D-echo-planar SWI. RESULTS: Neuropathologic analysis revealed the presence of an intense band of microglia activation close to the pial membrane in subpial cortical lesions or to the WM border of leukocortical cortical lesions. The quantitative susceptibility mapping analysis revealed 131 cortical lesions classified as hyperintense; 33, as isointense; and 84, as hypointense. Quantitative susceptibility mapping hyperintensity edge found in the proximity of the pial surface or at the white matter/gray matter interface in some of the quantitative susceptibility mapping–hyperintense cortical lesions accurately mirrors the microglia activation observed in the neuropathology analysis. CONCLUSIONS: Cortical lesion susceptibility maps are highly heterogeneous, even at individual levels. Quantitative susceptibility mapping hyperintensity edge found in proximity to the pial surface might be due to the subpial gradient of microglial activation.

Background and ObjectivesCognitive impairment (CI) in multiple sclerosis (MS) is frequent and determined by a complex interplay between inflammatory and neurodegenerative processes. We aimed to investigate whether CSF parvalbumin (PVALB), measured at the ...

Background: Multiple sclerosis (MS) pathology is characterized by acute and chronic inflammation, demyelination, axonal injury, and neurodegeneration. After decades of research into MS-related degeneration, recent efforts have shifted toward recovery and the prevention of further damage. A key area of focus is the remyelination process, where researchers are studying the effects of pharmacotherapy on myelin repair mechanisms. Multiple compounds are being tested for their potential to foster remyelination in different clinical settings through the application of less or more complex techniques to assess their efficacy. Objective: To review current methods and biomarkers to track myelin regeneration and recovery over time in people with MS (PwMS), with potential implications for promyelinating drug testing. Methods: Narrative review, based on a selection of PubMed articles discussing techniques to measure in vivo myelin repair and functional recovery in PwMS. Results: Non-invasive tools, such as structural Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET), are being implemented to track myelin repair, while other techniques like evoked potentials, functional MRI, and digital markers allow the assessment of functional recovery. These methods, alone or in combination, have been employed to obtain precise biomarkers of remyelination and recovery in various clinical trials on MS. Conclusions: Combining different techniques to identify myelin restoration in MS could yield novel biomarkers, enhancing the accuracy of clinical trial outcomes for remyelinating therapies in PwMS.

The objective of this study was to determine, at the time of diagnosis, a CSF and MRI profile of intrathecal compartmentalized inflammation predictive of progression independent of relapse activity (PIRA) in early relapsing-remitting multiple sclerosis (RRMS). This five-year prospective study included 80 treatment-naïve patients with RRMS enrolled at time of diagnosis. All patients underwent a lumbar puncture, regular neurologic evaluations including an Expanded Disability Status Scale (EDSS) assessment every 6 months, and an annual 3T brain MRI. PIRA was defined as having a confirmed disability progression independent of relapse activity. CSF levels of 68 inflammatory molecules were evaluated in combination with white matter and cortical lesion number (CLn) and volume, and regional gray matter thickness and volume. During the follow-up, 23 patients with RRMS (28.8%) experienced PIRA. At diagnosis, participants with PIRA were older (44.0 ± 10.7 vs 37.4 ± 12.4, p = 0.017) and with more disability (median EDSS score [interquartile range] of 3 [range 2-4] for PIRA vs 1.5 [range 1-2] for no PIRA group, p < 0.001). Random forest selected LIGHT, CXCL13, sTNFR1, sTNFR2, CCL7, MIF, sIL6Rbeta, IL35, CCL2, and IFNβ as the CSF markers best associated with PIRA. sTNFR1 (hazard ratio [HR] 10.11 [2.61-39.10], p = 0.001), sTNFR2 (HR 5.05 [1.63-15.64], p = 0.005), and LIGHT (HR 1.79 [1.11-2.88], p = 0.018) were predictors of PIRA at regression analysis. Baseline thalamus volume (HR 0.98 [0.97-0.99], p = 0.005), middle frontal gyrus thickness (HR 0.05 [0.01-0.72], p = 0.028), and CLn (HR 1.15 [1.05-1.25], p = 0.003) were MRI predictors of PIRA. A specific intrathecal inflammatory profile associated with TNF superfamily markers, CLn, and atrophy of several cortical and deep gray matter regions, assessed at time of diagnosis, is predictive of PIRA in early MS.