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No study has investigated red nucleus (RN) atrophy in multiple sclerosis (MS) despite cerebellum and its connections are elective sites of MS‐related pathology. In this study, we explore RN atrophy in early MS phases and its association with cerebellar damage (focal lesions and atrophy) and physical disability. Thirty‐seven relapse‐onset MS (RMS) patients having mean age of 35.6 ± 8.5 (18–56) years and mean disease duration of 1.1 ± 1.5 (0–5) years, and 36 age‐ and sex‐matched healthy controls (HC) were studied. Cerebellar and RN lesions and volumes were analyzed on 3 T‐MRI images. RMS did not differ from HC in cerebellar lobe volumes but significantly differed in both right (107.84 ± 13.95 mm3 vs. 99.37 ± 11.53 mm3, p = .019) and left (109.71 ± 14.94 mm3 vs. 100.47 ± 15.78 mm3, p = .020) RN volumes. Cerebellar white matter lesion volume (WMLV) inversely correlated with both right and left RN volumes (r = −.333, p = .004 and r = −.298, p = .010, respectively), while no correlation was detected between RN volumes and mean cortical thickness, cerebellar gray matter lesion volume, and supratentorial WMLV (right RN: r = −.147, p = .216; left RN: r = −.153, p = .196). Right, but not left, RN volume inversely correlated with midbrain WMLV (r = −.310, p = .008), while no correlation was observed between whole brainstem WMLV and either RN volumes (right RN: r = −.164, p = .164; left RN: r = −.64, p = .588). Finally, left RN volume correlated with vermis VIIb (r = .297, p = .011) and right interposed nucleus (r = .249, p = .034) volumes. We observed RN atrophy in early RMS, likely resulting from anterograde axonal degeneration starting in cerebellar and midbrain WML. RN atrophy seems a promising marker of neurodegeneration and/or cerebellar damage in RMS., The cerebellum and the brainstem are major sites of pathology in multiple sclerosis (MS) and their involvement, although frequently asymptomatic, is known to be associated with a more severe prognosis. We explored RN atrophy in early MS phases and its association with cerebellar damage and physical disability. We observed RN atrophy in early relapse‐onset (RMS), likely resulting from anterograde axonal degeneration starting in cerebellar and midbrain WML. RN atrophy seems a promising marker of neurodegeneration and/or cerebellar damage in RMS.

Background and ObjectivesMicroglia, the resident immune cell of the brain and retina, is widespread activated in the white and gray matter (GM) in multiple sclerosis (MS). The objective of this study is to evaluate the presence and number of hyperreflecting foci (HRF), considered clusters of activated and proliferating retinal microglia, and their association with clinical and radiologic disease parameters in relapsing-remitting MS (RRMS).MethodsAt baseline, 80 patients with RRMS underwent optical coherence tomography (OCT) and 3T-MRI (including 3-dimensional T1, fluid-attenuated inversion recovery, and double inversion recovery sequences), closed to their disease onset (6.3 ± 5.1 months). These patients were then clinically and radiologically followed up for a mean of 43 months, evaluating the no evidence of disease activity (NEDA) condition, further divided into clinical (cNEDA) and radiologic (rNEDA). Patients with a clinical history or MRI/OCT findings suggestive of optic neuritis (ON) were excluded from the study.ResultsCompared with healthy controls, the HRF number was significantly higher in the inner nuclear layer (INL) of patients with RRMS (19.55 ± 5.65 vs 13.84 ± 2.57, p < 0.001) and associated with INL volume (β: 1.21, p < 0.001). GM lesion volume significantly correlated with the INL HRF count (p = 0.008). Survival analysis revealed a significant association between INL HRF and both cNEDA (p = 0.017) and rNEDA (p = 0.002).DiscussionWe found a strong association between retinal microglial proliferation and cortical pathology in RRMS, a finding suggesting a possible underlying common immunopathologic mechanism. Furthermore, microglial activation at baseline was observed to predict subsequent inflammatory events, indicating that HRF might be a candidate prognostic biomarker worthy of further investigation.Classification of EvidenceThis study provides Class II evidence that in patients with early RRMS but without ON, the number of HRF on OCT of the retinal inner nuclear layer is associated with cNEDA and rNEDA.

Paediatric multiple sclerosis (pedMS) brain is known to be impacted by heightened inflammation and axonal degeneration.1 Structural changes in the normal-appearing white matter (NAWM) of pedMS have been disclosed by diffusion tensor imaging, further emphasising that MRI visible white matter (WM) lesions do not capture the full extent of tissue damage in MS.2 Understanding of the complexity of early brain pathology in pedMS can help to better characterise the relationship between inflammation and neurodegeneration in MS. Neurite orientation dispersion and density imaging (NODDI), a multicompartment model of diffusion MRI, is a clinically feasible method for better capturing brain microstructural complexity in vivo.3 Specifically, NODDI provides quantitative measures including the neurite density index (NDI), considered a measure of neurites (ie, axons and dendrites) volume and orientation dispersion index (ODI), reflecting neurite orientation variability. In this exploratory study, we applied NODDI to investigate the presence of early microstructural damage in pedMS compared with a matched group of healthy controls (HC), and its correlation with physical disability and WM lesion volume (LV) within tracts. A list of the acronyms used throughout the manuscript is provided in online supplemental table 1). ### Supplementary data [jnnp-2021-326355supp001.pdf] ### Subjects Nineteen relapsing-remitting pedMS patients (aged ≤17 years) were prospectively enrolled in a single MS Centre between January 2019 and April 2021. Eight patients were treatment naive; the remaining patients were in stable treatment with natalizumab. The median number of infusions at the time of MRI scan was 12 (IQR, 6–20). Twelve HC, balanced by age and sex, with no previous history of neurological dysfunction and a normal neurological examination, were also evaluated (see the online Supplemental Methods for pedMS inclusion criteria). All subjects underwent a detailed neurological evaluation, including Expanded Disability Status Scale (EDSS) score, within 1 week from the MRI acquisition. ### MRI The following sequences were acquired during a 3T …

Pediatric-onset multiple sclerosis (POMS) is characterized by high inflammatory activity, aggressive course and early development of physical and cognitive disability. A highly effective early treatment must be considered in POMS. To evaluate safety and efficacy of natalizumab (NTZ) in naive POMS. 20 naive POMS (13F, 7 M; mean age: 13.8 ± 2.7 years) were treated with NTZ for at least 24 months (mean number of infusions: 42 ± 20). No evidence of disease activity (NEDA)-3 plus status, i.e., no relapse, no disease progression (EDSS score), no radiological activity and no cognitive decline, was evaluated. After 2 years of NTZ treatment, a significant reduction in the mean EDSS score (p

Background Neurodegeneration is a major contributor of neurological disability in multiple sclerosis (MS). The possibility to fully characterize normal appearing white matter (NAWM) damage could provide the missing information needed to clarify the mechanisms beyond disability accumulation. Objective In the present study we aimed to characterize the presence and extent of NAWM damage and its correlation with clinical disability. Methods We applied Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) in a cohort of 27 early relapse-onset MS patients (disease duration5 years) compared to a population of 26 age- and sex-matched healthy controls (HCs). All patients underwent a neurological examination, including the Expanded Disability Status Scale (EDSS). Results MS patients showed lower fractional anisotropy (FA) and higher mean diffusivity (MD) values in the main WM bundles, such as the corticospinal tract, corpus callosum, superior and middle cerebellar peduncles, posterior thalamic radiation (which includes optic radiation), cingulum and external capsule. All brain areas with reduced FA/increased MD also displayed a reduction in neurite density index (NDI). However, comparing individual voxels of the WM skeleton between MS and HCs, a higher number of NDI significant voxels was disclosed compared to FA/MD (56.4% vs 11.2%/41.2%). No significant correlations were observed between DTI/NODDI metrics and EDSS. Conclusions Our findings suggest that NDI may allow for a better characterization and understanding of the microstructural changes in the NAWM since the early relapsing-remitting MS phases. Future longitudinal studies including a larger cohort of patients with different clinical phenotypes may clarify the association between NODDI metrics and disability progression.

Cerebellar dysfunctions have been associated to depressive disorders and cognitive impairment in neurodegenerative diseases. The objective is to analyze the associations between cerebellar atrophy, depression, and fatigue in the early phases of relapse-onset multiple sclerosis (RRMS). Sixty-one RRMS patients and 50 healthy controls (HC) were enrolled and clinically evaluated by means of expanded disability status scale (EDSS), Rao’s brief repeatable battery of neuropsychological tests (BRB-NT), Delis-Kaplan executive function system sorting test, beck depression inventory II (BDI-II), and fatigue severity scale (FSS). The relationships between MRI variables and clinical scores were assessed. Depressed RRMS (dRRMS) had significantly lower Vermis Crus I volume compared with not depressed RRMS (ndRRMS) (p = 0.009). Vermis Crus I volume was lower in dRRMS suffering from fatigue than in ndRRMS without fatigue (p = 0.01). The hierarchical regression models which included demographic and clinical data (age, sex, and disease duration, FSS or BDI-II) and cerebellar volumes disclosed that cerebellar lobule right V atrophy explained an increase of 4% of the variability in FSS (p = 0.25) and Vermis Crus I atrophy explained an increase of 6% of variability in BDI-II (p = 0.049). Since clinical onset, atrophy of specific cerebellar lobules associates with important clinical aspects of RRMS. Cerebellar pathology may be one of the determinants of fatigue and depression that contribute to worsen disability in RRMS.

No data are available on the occurrence of gray matter lesions (GML) in the cerebellum of pediatric multiple sclerosis (pedMS). We analyzed frequency, number and topography of GML, and their correlation with cerebellar-related disability in pedMS at clinical onset. Fifteen adolescents with pedMS (12F/3M; mean age 14.9 ± 2.2, range 11–17) were studied. Neurological and cognitive evaluations were done by means of EDSS, Trail Making Test—Part B (TMT-B) and Symbol Digit Modalities Test—oral version (SDMT). Cerebellar GML were investigated with double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) sequences obtained with a 3 T-MRI scan. All patients had white matter lesions (WML) and/or GML in the cerebellum. A significantly higher GML number was observed on PSIR compared to DIR (mean 2.3 ± 2.3 vs 1.1 ± 1.6; median 2.0 (IQR 1.0–2.0) vs 1.0 (IQR 0.0–1.5); p = 0.004). GML were observed in 14/15 (93.3%) patients and were more frequent in the posterior than in the anterior lobe (mean 1.8 ± 2.2 vs 0.47 ± 0.74; median 2.0 (IQR 0.5–2.0) vs 0.0 (IQR 0.0–1.0); p = 0.044). No correlation was found between lesion number or topography and EDSS (r = 0.12, p = 0.69), TMT-B and SDMT. At clinical onset, cerebellar GML are common in pedMS, are very often asymptomatic, do not correlate with physical and cognitive disability, and more frequently affect the posterior lobe.

We evaluated the occurrence of infusion-associated reactions, severe adverse events and no evidence of disease activity 3 status of a therapeutic course consisting of natalizumab followed by alemtuzumab in paediatric-onset multiple sclerosis. Five paediatric-onset multiple sclerosis (age range 16-17 years) were followed for a median of 3.9 years (interquartile range 3.1-5.0). At a natalizumab break (mean infusions 25.6 ± 1.3) patients were switched to alemtuzumab and completed the two therapy courses. Few mild/moderate infusion-associated reactions were observed during alemtuzumab infusion. No severe adverse events were detected. Natalizumab followed by alemtuzumab proved to be a well-tolerated therapeutic course in paediatric-onset multiple sclerosis. Moreover, paediatric-onset multiple sclerosis maintained the no evidence of disease activity 3 status throughout the follow-up.