Enlarged perivascular spaces are associated with brain microangiopathy and aging in multiple sclerosis.

BACKGROUND: Growing evidence links brain-MRI enlarged perivascular spaces (EPVS) and multiple sclerosis (MS), but their role remains unclear. OBJECTIVE: This study aimed to investigate the cross-sectional associations of EPVS with several neuroinflammatory and neurodegenerative features in a large multicentric-MS cohort. METHODS: In total, 207 patients underwent 3T axial-T2-weighted brain-MRI for EPVS assessment (EPVS dichotomized into high/low according to ⩾ 2/< 2 rating categories). MRI biomarkers included brain-predicted age and brain-predicted age difference (brain-PAD), central vein sign (CVS)-positive lesion percentage (CVS%), paramagnetic rim and cortical lesions, T2-lesion load, and brain volumetry. The variable relative importance for EPVS-category prediction was explored using a classification random forest approach. RESULTS: High EPVS patients were older (49 vs 44 years, p = 0.003), had ⩾ 1 vascular risk factors (VRFs; p = 0.005), lower CVS% (67% vs 78%, p < 0.001), reduced brain volumes (whole brain: 0.63 vs 0.73, p = 0.01; gray matter: 0.36 vs 0.40; p = 0.002), and older brain-predicted age (58 vs 50 years, p < 0.001). No differences were found for neuroinflammatory markers. After adjusting for age and VFRs (multivariate analyses), the high EPVS category correlated with lower CVS% (odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.96-0.99; p = 0.02), lower whole brain (OR = 0.01, 95% CI = 0.0003-0.5; p = 0.02), gray matter (OR = 0.0004, 95% CI = 0.0000004-0.4; p = 0.03) volumes, and higher brain-PAD (OR = 1.05, 95% CI = 1.01-1.09; p = 0.02). Random forest identified brain-PAD as the most important predictor of high EPVS. CONCLUSION: EPVS in MS likely reflect microangiopathic disease rather than neuroinflammation, potentially contributing to accelerated neurodegeneration.

Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging.

Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy control subjects and normal-appearing multiple sclerosis tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P < 0.0001) and peri-plaque white matter (P < 0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P < 0.0001 and P < 0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P < 0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P < 0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P < 0.01, beta = -10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort (P < 0.01, beta = -3.60 and P < 0.01, beta = 0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting patients because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.

Paramagnetic Rim Lesions are Specific to Multiple Sclerosis: An International Multicenter 3T MRI Study.

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research-based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non-inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non-MS cases), yielded high specificity (93%) in differentiating MS from non-MS. Future prospective multicenter studies should validate their role as a diagnostic biomarker. ANN NEUROL 2020;88:1034-1042.

The central vein sign in multiple sclerosis patients with vascular comorbidities.

BACKGROUND: The central vein sign (CVS) is an imaging biomarker able to differentiate multiple sclerosis (MS) from other conditions causing similar appearance lesions on magnetic resonance imaging (MRI), including cerebral small vessel disease (CSVD). However, the impact of vascular risk factors (VRFs) for CSVD on the percentage of CVS positive (CVS+) lesions in MS has never been evaluated. OBJECTIVE: To investigate the association between different VRFs and the percentage of CVS+ lesions in MS. METHODS: In 50 MS patients, 3T brain MRIs (including high-resolution 3-dimensional T2*-weighted images) were analyzed for the presence of the CVS and MRI markers of CSVD. A backward stepwise regression model was used to predict the combined predictive effect of VRF (i.e. age, hypertension, diabetes, obesity, ever-smoking, and hypercholesterolemia) and MRI markers of CSVD on the CVS. RESULTS: The median frequency of CVS+ lesions was 71% (range: 35%-100%). In univariate analysis, age (p < 0.0001), hypertension (p < 0.001), diabetes (p < 0.01), obesity (p < 0.01), smoking (p < 0.05), and the presence of enlarged-perivascular-spaces on MRI (p < 0.005) were all associated with a lower percentage of CVS+ lesions. The stepwise regression model showed that age and arterial hypertension were both associated with the percentage of CVS+ lesions in MS (adjusted R2 = 0.46; p < 0.0001 and p = 0.01, respectively). CONCLUSION: The proportion of CVS+ lesions significantly decreases in older and hypertensive MS patients. Although this study was conducted in patients with an already established MS diagnosis, the diagnostic yield of the previously proposed 35% CVS proportion-based diagnostic threshold appears to be not affected. Overall these results suggest that the presence of VRF for CSVD should be taken into account during the CVS assessment.

CVSnet: A machine learning approach for automated central vein sign assessment in multiple sclerosis.

The central vein sign (CVS) is an efficient imaging biomarker for multiple sclerosis (MS) diagnosis, but its application in clinical routine is limited by inter-rater variability and the expenditure of time associated with manual assessment. We describe a deep learning-based prototype for automated assessment of the CVS in white matter MS lesions using data from three different imaging centers. We retrospectively analyzed data from 3 T magnetic resonance images acquired on four scanners from two different vendors, including adults with MS (n = 42), MS mimics (n = 33, encompassing 12 distinct neurological diseases mimicking MS) and uncertain diagnosis (n = 5). Brain white matter lesions were manually segmented on FLAIR* images. Perivenular assessment was performed according to consensus guidelines and used as ground truth, yielding 539 CVS-positive (CVS+ ) and 448 CVS-negative (CVS- ) lesions. A 3D convolutional neural network ("CVSnet") was designed and trained on 47 datasets, keeping 33 for testing. FLAIR* lesion patches of CVS+ /CVS- lesions were used for training and validation (n = 375/298) and for testing (n = 164/150). Performance was evaluated lesion-wise and subject-wise and compared with a state-of-the-art vesselness filtering approach through McNemar's test. The proposed CVSnet approached human performance, with lesion-wise median balanced accuracy of 81%, and subject-wise balanced accuracy of 89% on the validation set, and 91% on the test set. The process of CVS assessment, in previously manually segmented lesions, was ~ 600-fold faster using the proposed CVSnet compared with human visual assessment (test set: 4 seconds vs. 40 minutes). On the validation and test sets, the lesion-wise performance outperformed the vesselness filter method (P < 0.001). The proposed deep learning prototype shows promising performance in differentiating MS from its mimics. Our approach was evaluated using data from different hospitals, enabling larger multicenter trials to evaluate the benefit of introducing the CVS marker into MS diagnostic criteria.

The "central vein sign" in patients with diagnostic "red flags" for multiple sclerosis: A prospective multicenter 3T study.

BACKGROUND: The central vein sign (CVS) has been shown to help in the differential diagnosis of multiple sclerosis (MS), but most prior studies are retrospective. OBJECTIVES: To prospectively assess the diagnostic predictive value of the CVS in diagnostically difficult cases. METHODS: In this prospective multicenter study, 51 patients with suspected MS who had clinical, imaging, or laboratory "red flags" (i.e. features atypical for MS) underwent 3T fluid-attenuated inversion recovery (FLAIR*) magnetic resonance imaging (MRI) for CVS assessment. After the diagnostic work-up, expert clinicians blinded to the results of the CVS assessment came to a clinical diagnosis. The value of the CVS to prospectively predict an MS diagnosis was assessed. RESULTS: Of the 39 patients who received a clinical diagnosis by the end of the study, 27 had MS and 12 received a non-MS diagnosis that included systemic lupus erythematosus, sarcoidosis, migraine, Sjögren disease, SPG4-spastic-paraparesis, neuromyelitis optica, and Susac syndrome. The percentage of perivenular lesions was higher in MS (median = 86%) compared to non-MS (median = 21%; p < 0.0001) patients. A 40% perivenular lesion cutoff was associated with 97% accuracy and a 96% positive/100% negative predictive value. CONCLUSION: The CVS detected on 3T FLAIR* images can accurately predict an MS diagnosis in patients suspected to have MS, but with atypical clinical, laboratory, and imaging features.

Human Leukocyte Antigen Genotype as a Marker of Multiple Sclerosis Prognosis.

OBJECTIVE: In a previous pilot monocentric study, we investigated the relation between human leukocyte antigen (HLA) genotype and multiple sclerosis (MS) disease progression over 2 years. HLA-A*02 allele was correlated with better outcomes, whereas HLA-B*07 and HLA-B*44 were correlated with worse outcomes. The objective of this extension study was to further investigate the possible association of HLA genotype with disease status and progression in MS as measured by sensitive and complex clinical and imaging parameters. METHODS: Hundred and forty-six MS patients underwent HLA typing. Over a 4-year period of follow-up, we performed three clinical and magnetic resonance imaging (MRI) assessments per patient, which respectively included Expanded Disability Status Scale, Multiple Sclerosis Severity Scale, Timed-25-Foot-Walk, 9-Hole Peg Test, Symbol Digit Modalities Test, Brief Visual Memory Test, California Verbal Learning Test-II, and whole-brain atrophy, fluid-attenuated inversion recovery (FLAIR) lesion volume change and number of new FLAIR lesions using icobrain. We then compared the clinical and MRI outcomes between predefined HLA patient groups. RESULTS: Results of this larger study with a longer follow-up are in line with what we have previously shown. HLA-A*02 allele is associated with potentially better MS outcomes, whereas HLA-B*07, HLA-B*44, HLA-B*08, and HLA-DQB1*06 with a potential negative effect. Results for HLA-DRB1*15 are inconclusive. CONCLUSION: In the era of MS treatment abundance, HLA genotype might serve as an early biomarker for MS outcomes to inform individualized treatment decisions.

Central vein sign differentiates Multiple Sclerosis from central nervous system inflammatory vasculopathies.

OBJECTIVES: In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the "central vein sign") improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS). METHODS: In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing-remitting MS, 3-dimensional T2*-weighted and T2-fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed. RESULTS: MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behçet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjögren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%. INTERPRETATION: The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283-294.

Novel marmoset (Callithrix jacchus) model of human Herpesvirus 6A and 6B infections: immunologic, virologic and radiologic characterization.

Human Herpesvirus 6 (HHV-6) is a ubiquitous virus with an estimated seroprevalence of 95% in the adult population. HHV-6 is associated with several neurologic disorders, including multiple sclerosis, an inflammatory demyelinating disease affecting the CNS. Animal models of HHV-6 infection would help clarify its role in human disease but have been slow to develop because rodents lack CD46, the receptor for cellular entry. Therefore, we investigated the effects of HHV-6 infections in a non-human primate, the common marmoset Callithrix jacchus. We inoculated a total of 12 marmosets with HHV-6A and HHV-6B intravenously and HHV-6A intranasally. Animals were monitored for 25 weeks post-inoculation clinically, immunologically and by MRI. Marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms and generated virus-specific antibody responses, while those inoculated intravenously with HHV-6B were asymptomatic and generated comparatively lower antibody responses. Viral DNA was detected at a low frequency in paraffin-embedded CNS tissue of a subset of marmosets inoculated with HHV-6A and HHV-6B intravenously. When different routes of HHV-6A inoculation were compared, intravenous inoculation resulted in virus-specific antibody responses and infrequent detection of viral DNA in the periphery, while intranasal inoculation resulted in negligible virus-specific antibody responses and frequent detection of viral DNA in the periphery. Moreover, marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms, while marmosets inoculated with HHV-6A intranasally were asymptomatic. We demonstrate that a marmoset model of HHV-6 infection can serve to further define the contribution of this ubiquitous virus to human neurologic disorders.

The formation of inflammatory demyelinated lesions in cerebral white matter.

OBJECTIVE: Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. METHODS: By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood-brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. RESULTS: On average, BBB permeability increased 3.5-fold (p < 0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood-derived macrophages or demyelination. These foci had no visible MRI correlates, although permeability within the foci, but not outside, increased in the weeks before the animals died (p < 0.0001). INTERPRETATION: This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood-derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions.

Seven-tesla phase imaging of acute multiple sclerosis lesions: a new window into the inflammatory process.

OBJECTIVE: In multiple sclerosis (MS), accurate, in vivo characterization of dynamic inflammatory pathological changes occurring in newly forming lesions could have major implications for understanding disease pathogenesis and mechanisms of tissue destruction. Here, we investigated the potential of ultrahigh-field magnetic resonance imaging (MRI; 7T), particularly phase imaging combined with dynamic contrast enhancement, to provide new insights in acute MS lesions. METHODS: Sixteen active MS patients were studied at 7T. Noncontrast, high-resolution T2* magnitude and phase scans, T1 scans before/after gadolinium contrast injection, and dynamic contrast-enhanced (DCE) T1 scans were acquired. T2*/phase features and DCE pattern were determined for acute and chronic lesions. When possible, 1-year follow-up 7T MRI was performed. RESULTS: Of 49 contrast-enhancing lesions, 44 could be analyzed. Centrifugal DCE lesions appeared isointense or hypointense on phase images, whereas centripetal DCE lesions showed thin, hypointense phase rims that clearly colocalized with the initial site of contrast enhancement. This pattern generally disappeared once enhancement resolved. Conversely, in 43 chronic lesions also selected for the presence of hypointense phase rims, the findings were stable over time, and the rims were typically thicker and darker. These considerations suggest different underlying pathological processes in the 2 lesion types. INTERPRETATION: Ultrahigh-field MRI and, especially, phase contrast, are highly sensitive to tissue changes in acute MS lesions, which differ from the patterns seen in chronic lesions. In acute lesions, the hypointense phase rim reflects the expanding inflammatory edge and may directly correspond to inflammatory byproducts and sequelae of blood-brain barrier opening.

Perivenular brain lesions in a primate multiple sclerosis model at 7-tesla magnetic resonance imaging.

BACKGROUND Magnetic resonance imaging (MRI) can provide in vivo assessment of tissue damage, allowing evaluation of multiple sclerosis (MS) lesion evolution over time--a perspective not obtainable with postmortem histopathology. Relapsing-remitting experimental autoimmune encephalomyelitis (EAE) is an experimental model of MS that can be induced in the common marmoset, a small new world primate, and that causes perivenular white matter (WM) lesions similar to those observed in MS. METHODS Brain lesion development and evolution were studied in vivo and postmortem in four marmosets with EAE through serial T2- and T2*-weighted scans at 7-tesla. Supratentorial WM lesions were identified and characterized. RESULTS Of 97 lesions observed, 86 (88%) were clearly perivenular, and 62 (72%) developed around veins that were visible even prior to EAE induction. The perivenular configuration was confirmed by postmortem histopathology. Most affected veins, and their related perivascular Virchow-Robin spaces, passed into the subarachnoid space rather than the ventricles. CONCLUSION As in human MS, the intimate association between small veins and EAE lesions in the marmoset can be studied with serial in vivo MRI. This further strengthens the usefulness of this model for understanding the process of perivenular lesion development and accompanying tissue destruction in MS.

Comparative overview of multi-shell diffusion MRI models to characterize the microstructure of multiple sclerosis lesions and periplaques.

In multiple sclerosis (MS), accurate in vivo characterization of the heterogeneous lesional and extra-lesional tissue pathology remains challenging. Marshalling several advanced imaging techniques - quantitative relaxation time (T1) mapping, a model-free average diffusion signal approach and four multi-shell diffusion models - this study investigates the performance of multi-shell diffusion models and characterizes the microstructural damage within (i) different MS lesion types - active, chronic active, and chronic inactive - (ii) their respective periplaque white matter (WM), and (iii) the surrounding normal-appearing white matter (NAWM). In 83 MS participants (56 relapsing-remitting, 27 progressive) and 23 age and sex-matched healthy controls (HC), we analysed a total of 317 paramagnetic rim lesions (PRL+), 232 non-paramagnetic rim lesions (PRL-), 38 contrast-enhancing lesions (CEL). Consistent with previous findings and histology, our analysis revealed the ability of advanced multi-shell diffusion models to characterize the unique microstructural patterns of CEL, and to elucidate their possible evolution into a resolving (chronic inactive) vs smoldering (chronic active) inflammatory stage. In addition, we showed that the microstructural damage extends well beyond the MRI-visible lesion edge, gradually fading out while moving outward from the lesion edge into the immediate WM periplaque and the NAWM, the latter still characterized by diffuse microstructural damage in MS vs HC. This study also emphasizes the critical role of selecting appropriate diffusion models to elucidate the complex pathological architecture of MS lesions and their periplaque. More specifically, multi-compartment diffusion models based on biophysically interpretable metrics such as neurite orientation dispersion and density (NODDI; mean auc=0.8002) emerge as the preferred choice for MS applications, while simpler models based on a representation of the diffusion signal, like diffusion tensor imaging (DTI; mean auc=0.6942), consistently underperformed, also when compared to T1 mapping (mean auc=0.73375).

Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions for the Diagnostic and Prognostic Workup of Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice because MS presentation can be atypical and mimicked by other diseases. We evaluated the diagnostic performance, alone or in combination, of the central vein sign (CVS), paramagnetic rim lesion (PRL), and cortical lesion (CL), as well as their association with clinical outcomes. METHODS: In this multicenter observational study, we first conducted a cross-sectional analysis of the CVS (proportion of CVS-positive lesions or simplified determination of CVS in 3/6 lesions-Select3*/Select6*), PRL, and CL in MS and non-MS cases on 3T-MRI brain images, including 3D T2-FLAIR, T2*-echo-planar imaging magnitude and phase, double inversion recovery, and magnetization prepared rapid gradient echo image sequences. Then, we longitudinally analyzed the progression independent of relapse and MRI activity (PIRA) in MS cases over the 2 years after study entry. Receiver operating characteristic curves were used to test diagnostic performance and regression models to predict diagnosis and clinical outcomes. RESULTS: The presence of ≥41% CVS-positive lesions/≥1 CL/≥1 PRL (optimal cutoffs) had 96%/90%/93% specificity, 97%/84%/60% sensitivity, and 0.99/0.90/0.77 area under the curve (AUC), respectively, to distinguish MS (n = 185) from non-MS (n = 100) cases. The Select3*/Select6* algorithms showed 93%/95% specificity, 97%/89% sensitivity, and 0.95/0.92 AUC. The combination of CVS, CL, and PRL improved the diagnostic performance, especially when Select3*/Select6* were used (93%/94% specificity, 98%/96% sensitivity, 0.99/0.98 AUC; p = 0.002/p < 0.001). In MS cases (n = 185), both CL and PRL were associated with higher MS disability and severity. Longitudinal analysis (n = 61) showed that MS cases with >4 PRL at baseline were more likely to experience PIRA at 2-year follow-up (odds ratio 17.0, 95% confidence interval: 2.1-138.5; p = 0.008), whereas no association was observed between other baseline MRI measures and PIRA, including the number of CL. DISCUSSION: The combination of CVS, CL, and PRL can improve MS differential diagnosis. CL and PRL also correlated with clinical measures of poor prognosis, with PRL being a predictor of disability accrual independent of clinical/MRI activity.

Diagnostic Performance of Cortical Lesions and the Central Vein Sign in Multiple Sclerosis.

Importance: Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice. Objective: To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI). Design, Setting, and Participants: This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2). Exposures: MS/CIS vs non-MS conditions. Main Outcomes and Measures: Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model. Results: The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P < .001), and was increased when combining the 2 imaging markers (AUC, 0.92 [95% CI, 0.90-0.94]; P = .04); in the random forest model, both CVS and CLs outperformed the presence of infratentorial, periventricular, and juxtacortical WMLs in supporting MS differential diagnosis. Conclusions and Relevance: The findings in this study suggest that CVS and CLs may be valuable tools to increase the accuracy of MS diagnosis.

Present and future of the diagnostic work-up of multiple sclerosis: the imaging perspective.

In recent years, the use of magnetic resonance imaging (MRI) for the diagnostic work-up of multiple sclerosis (MS) has evolved considerably. The 2017 McDonald criteria show high sensitivity and accuracy in predicting a second clinical attack in patients with a typical clinically isolated syndrome and allow an earlier diagnosis of MS. They have been validated, are evidence-based, simplify the clinical use of MRI criteria and improve MS patients' management. However, to limit the risk of misdiagnosis, they should be applied by expert clinicians only after the careful exclusion of alternative diagnoses. Recently, new MRI markers have been proposed to improve diagnostic specificity for MS and reduce the risk of misdiagnosis. The central vein sign and chronic active lesions (i.e., paramagnetic rim lesions) may increase the specificity of MS diagnostic criteria, but further effort is necessary to validate and standardize their assessment before implementing them in the clinical setting. The feasibility of subpial demyelination assessment and the clinical relevance of leptomeningeal enhancement evaluation in the diagnostic work-up of MS appear more limited. Artificial intelligence tools may capture MRI attributes that are beyond the human perception, and, in the future, artificial intelligence may complement human assessment to further ameliorate the diagnostic work-up and patients' classification. However, guidelines that ensure reliability, interpretability, and validity of findings obtained from artificial intelligence approaches are still needed to implement them in the clinical scenario. This review provides a summary of the most recent updates regarding the application of MRI for the diagnosis of MS.

B cell depletion therapy does not resolve chronic active multiple sclerosis lesions.

BACKGROUND: Chronic active lesions (CAL) in multiple sclerosis (MS) have been observed even in patients taking high-efficacy disease-modifying therapy, including B-cell depletion. Given that CAL are a major determinant of clinical progression, including progression independent of relapse activity (PIRA), understanding the predicted activity and real-world effects of targeting specific lymphocyte populations is critical for designing next-generation treatments to mitigate chronic inflammation in MS. METHODS: We analyzed published lymphocyte single-cell transcriptomes from MS lesions and bioinformatically predicted the effects of depleting lymphocyte subpopulations (including CD20 B-cells) from CAL via gene-regulatory-network machine-learning analysis. Motivated by the results, we performed in vivo MRI assessment of PRL changes in 72 adults with MS, 46 treated with anti-CD20 antibodies and 26 untreated, over ∼2 years. FINDINGS: Although only 4.3% of lymphocytes in CAL were CD20 B-cells, their depletion is predicted to affect microglial genes involved in iron/heme metabolism, hypoxia, and antigen presentation. In vivo, tracking 202 PRL (150 treated) and 175 non-PRL (124 treated), none of the treated paramagnetic rims disappeared at follow-up, nor was there a treatment effect on PRL for lesion volume, magnetic susceptibility, or T1 time. PIRA occurred in 20% of treated patients, more frequently in those with ≥4 PRL (p = 0.027). INTERPRETATION: Despite predicted effects on microglia-mediated inflammatory networks in CAL and iron metabolism, anti-CD20 therapies do not fully resolve PRL after 2-year MRI follow up. Limited tissue turnover of B-cells, inefficient passage of anti-CD20 antibodies across the blood-brain-barrier, and a paucity of B-cells in CAL could explain our findings. FUNDING: Intramural Research Program of NINDS, NIH; NINDS grants R01NS082347 and R01NS082347; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Cariplo Foundation (grant #1677), FRRB Early Career Award (grant #1750327); Fund for Scientific Research (FNRS).

Spontaneous rupture of urinary bladder: a case report and review.

Spontaneous rupture of the bladder is a rare event. The clinical presentation shows the signs and symptoms of peritonitis, but the diagnosis is made at the operating table. This event is burdened with a high mortality rate. We present a case report of a 73-year-old man who came to our observation. He was a chronic carrier of urinary catheter, at least 7 times removed traumatically by himself. At the time of admission he showed drastic reduction in urine output, absence of hydronephrosis, normal functioning of the catheter, a tense and widely meteoric abdomen, the presence of air-fluid levels, normal kidneys, absence of free fluid in the abdomen. The CT showed a fluid collection of about 7 cm diameter between the bladder and rectum. The explorative laparotomy found a small fissuration of the posterior wall of the bladder. For his severe conditions, the patient died a few hours after surgery, in intensive care unit. Although it is a rare event, since 1980, 177 cases of spontaneous rupture of the bladder are reported in the literature. Their causes may be essentially divided into two groups: for increase of intravesical pressure; or for weakening of the bladder wall. In most cases, the spontaneous rupture of the bladder takes place in presence of a urothelial neoplasm or after radiation therapy of the pelvic organs. The etiology of spontaneous rupture of the bladder in our case does not relate to a bladder tumor or radiotherapy. It may have been caused by repeated episodes of acute retention of urine with extreme bladder distension up to 3 liters. It is not easy to think of a bladder perforation in patients presenting signs of peritonitis without a history of bladder cancer or pelvic radiotherapy. A CT with intravesical contrast medium could help the diagnostic orientation.

BMAT: An open-source BIDS managing and analysis tool.

Magnetic Resonance Imaging (MRI) is an established technique to study in vivo neurological disorders such as Multiple Sclerosis (MS). To avoid errors on MRI data organization and automated processing, a standard called Brain Imaging Data Structure (BIDS) has been recently proposed. The BIDS standard eases data sharing and processing within or between centers by providing guidelines for their description and organization. However, the transformation from the complex unstructured non-open file data formats coming directly from the MRI scanner to a correct BIDS structure can be cumbersome and time consuming. This hinders a wider adoption of the BIDS format across different study centers. To solve this problem and ease the day-to-day use of BIDS for the neuroimaging scientific community, we present the BIDS Managing and Analysis Tool (BMAT). The BMAT software is a complete and easy-to-use local open-source neuroimaging analysis tool with a graphical user interface (GUI) that uses the BIDS format to organize and process brain MRI data for MS imaging research studies. BMAT provides the possibility to translate data from MRI scanners to the BIDS structure, create and manage BIDS datasets as well as develop and run automated processing pipelines, and is faster than its competitor. BMAT software propose the possibility to download useful analysis apps, especially applied to MS research with lesion segmentation and processing of imaging contrasts for novel disease biomarkers such as the central vein sign and the paramagnetic rim lesions.

Cortical lesions, central vein sign, and paramagnetic rim lesions in multiple sclerosis: Emerging machine learning techniques and future avenues.

The current diagnostic criteria for multiple sclerosis (MS) lack specificity, and this may lead to misdiagnosis, which remains an issue in present-day clinical practice. In addition, conventional biomarkers only moderately correlate with MS disease progression. Recently, some MS lesional imaging biomarkers such as cortical lesions (CL), the central vein sign (CVS), and paramagnetic rim lesions (PRL), visible in specialized magnetic resonance imaging (MRI) sequences, have shown higher specificity in differential diagnosis. Moreover, studies have shown that CL and PRL are potential prognostic biomarkers, the former correlating with cognitive impairments and the latter with early disability progression. As machine learning-based methods have achieved extraordinary performance in the assessment of conventional imaging biomarkers, such as white matter lesion segmentation, several automated or semi-automated methods have been proposed as well for CL, PRL, and CVS. In the present review, we first introduce these MS biomarkers and their imaging methods. Subsequently, we describe the corresponding machine learning-based methods that were proposed to tackle these clinical questions, putting them into context with respect to the challenges they are facing, including non-standardized MRI protocols, limited datasets, and moderate inter-rater variability. We conclude by presenting the current limitations that prevent their broader deployment and suggesting future research directions.