Evaluation of the ‘ring sign’ and the ‘core sign’ as a magnetic resonance imaging marker of disease activity and progression in clinically isolated syndrome and early multiple sclerosis

Background: Brain lesions with a hypointense ring or core were described in multiple sclerosis on susceptibility weighted imaging. Objective: The purpose of this study was to study the evolution and prognostic relevance of susceptibility weighted imaging hypointense lesions in clinically isolated syndrome and early multiple sclerosis. Methods: Sixty-six early multiple sclerosis and clinically isolated syndrome patients were followed over a median period of 2.9 years (range 1.6-4.6 years) and underwent 3T magnetic resonance imaging including 3D susceptibility weighted imaging and T2-weighted fluid-attenuated inversion recovery. We assessed the presence of susceptibility weighted imaging hypointense core or ring lesions, and Expanded Disability Status Scale at baseline and follow-up. Results: Of 611 lesions at baseline, 64 (10.5%) had a susceptibility weighted imaging hypointense core, and 28 (4.6%) had a susceptibility weighted imaging hypointense ring. Hypointense ring lesions were larger (p < 0.001) and more T1w hypointense (p = 0.002) than others. During follow-up, hypointense core lesions became susceptibility weighted imaging isointense (52 lesions, 81%); few developed into hypointense ring lesions (two lesions, 3%). Hypointense ring lesions did not shrink on T2-weighted fluid-attenuated inversion recovery images (p = 0.077, trend towards more enlargement compared to others), while hypointense core lesions more often shrunk in comparison to lesions without a hypointense core (p = 0.002). The number of susceptibility weighted imaging hypointense ring lesions at baseline correlated with Expanded Disability Status Scale progression at follow-up (p = 0.021, R = 0.289). Conclusion: In our cohort of patients with clinically isolated syndrome or early multiple sclerosis, susceptibility weighted imaging hypointense ring lesions were only rarely detectable, but did not shrink and were associated with future disability progression

Silent progression in disease activity-free relapsing multiple sclerosis.

ObjectiveRates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.MethodsDisability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.ResultsRelapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p &lt; 0.05).InterpretationLong-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666

Leptomeningitis in a person with radiologically isolated syndrome and latent tuberculosis. A case report with implications for clinical research

A 39-year-old man, followed with serial MRI of CNS for a radiologically isolate syndrome (RIS, a recently described condition considered a subclinical form of MS), was hospitalized for the occurrence of a leptomeningitis. Routine blood tests and contrast enhanced total body CT scan were unremarkable. Cerebrospinal fluid (CSF) examination showed increase of cells (22 mononuclear cells/mm3), albumin (294 mg/L), immunoglobilins G (161 mg/L) and Link Index (1.9), with 17 oligoclonal bands. Microbiological examinations of CSF (including those for Koch’s Bacillus) were negative. The Mantoux reaction and the QuantiFERON test were positive, featuring a latent tuberculosis (TB). The patient started prophylaxis with rifampicin and isoniazid for four months, until a new MRI showed the disappearance of the leptomeningeal enhancement, and the stability of white matter brain and spinal cord lesions. Two other MRI scans showed a new brain Gd-enhancing lesion nine month after anti-tubercular therapy and, after additional six months, new cerebral and spinal cord areas. This case provides the following suggestions about the effects of TB infection and related therapies on the underlying autoimmune status: the infection, while actively present, did not exacerbate the RIS condition; the worsening nine months after the prophylaxis discontinuation might have been the ‘natural’ evolution of RIS condition. Alternative speculative hypotheses include a remote effect of the infection, of isoniazid (that was reported in some cases to trigger MS), or the result of the clearance of the infection itself. Irrespective of the existence of any interaction between RIS and TB infection, It seems important to collect cases with MS-related diseases and concomitant infections, that may provide clues about disease pathogenesis and treatment

BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset

Abstract Background B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS. Methods Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh). Results Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes ( p \u2009<\u20090.01), lower values of BAFF Index (11.9\u2009\ub1\u20096.1 vs 17.5\u2009\ub1\u20095.2, p \u2009<\u20090.01), and higher CSF CXCL13 levels (27.7\u2009\ub1\u200933.5 vs 0.9\u2009\ub1\u20091.5, p \u2009<\u20090.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis ( r \u2009>\u20090.5 and p \u2009<\u20090.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB\u2212 ( p \u2009<\u20090.05) and HC ( p \u2009<\u20090.01), and correlated to CSF CXCL13 concentrations ( r 0.77, p \u2009<\u20090.001). The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41\u2009\ub1\u20090.1 vs 2.49\u2009\ub1\u20090.1\ua0mm, p \u2009<\u20090.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB\u2212. Conclusions The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by ..

Quantitative Susceptibility Mapping: Contrast Mechanisms and Clinical Applications.

Quantitative susceptibility mapping (QSM) is a recently developed MRI technique for quantifying the spatial distribution of magnetic susceptibility within biological tissues. It first uses the frequency shift in the MRI signal to map the magnetic field profile within the tissue. The resulting field map is then used to determine the spatial distribution of the underlying magnetic susceptibility by solving an inverse problem. The solution is achieved by deconvolving the field map with a dipole field, under the assumption that the magnetic field is a result of the superposition of the dipole fields generated by all voxels and that each voxel has its unique magnetic susceptibility. QSM provides improved contrast to noise ratio for certain tissues and structures compared to its magnitude counterpart. More importantly, magnetic susceptibility is a direct reflection of the molecular composition and cellular architecture of the tissue. Consequently, by quantifying magnetic susceptibility, QSM is becoming a quantitative imaging approach for characterizing normal and pathological tissue properties. This article reviews the mechanism generating susceptibility contrast within tissues and some associated applications

Clinically isolated syndromes and multiple sclerosis: prospective clinical and MRI follow up after 30 years and features at earlier time-points

This thesis is based on a 30-year follow-up study of a cohort of people who initially presented, in the 1980’s, with clinically isolated syndromes (CIS), suggestive of relapse-onset multiple sclerosis (MS). The main aims were: 1) to study the very long-term outcome of the cohort, with particular attention on those who have fared well over time, 2) review the idea and definition of ‘benign’ MS, a controversial entity, and 3) to identify any potential early clinical and radiological features, of 30-year outcome. MS is a very heterogenous condition and biomarkers of long-term prognostication remain limited. With the increasing range of disease modifying therapies available, it is important that treatment decisions should, as far as possible, involve a personalized risk-benefit analysis. At 30 years, I found that the clinical outcomes of the cohort were diverse. Approximately a third remained CIS, and two thirds developed MS. Within the MS group, who were largely untreated, ~40% remained ambulatory, ~35% had developed significant disability, and 20% had died related to their MS. Comparisons between the ambulatory MS group and CIS group, showed that the groups were not significantly different across several clinical measures. In this cohort, the strongest early predictors of 30-year outcomes identified were radiological features. The presence of MRI white matter lesions in specific locations in the brain, within one year of presentation, were able to predict 30-year clinical outcomes with accuracies in the 70-75% range. These results could potentially be applied in a clinical setting and help inform treatment decisions

Variations in multiple sclerosis practice within Europe - Is it time for a new treatment guideline?

In the past 5 years, the combination of developments in diagnostic strategy and approval of new disease-modifying therapies has provided an opportunity to achieve dramatic improvements in patient outcomes in multiple sclerosis (MS). However, across Europe there are several factors that may prevent patients from receiving the best therapy at the appropriate time, and there is variation among countries in terms of which of these factors are most relevant. Here, we review current MS clinical practices in a number of countries in the European Union to identify differences regarding initiation of treatment in patients with clinically isolated syndrome or relapsing-remitting MS, and differences in the timing of treatment switch or escalation. While recognizing that policy is not static in any country, we believe that patients' interests would be better served if a European treatment guideline was developed. Such a guideline could both inform and be informed by national policies, facilitating the dissemination of best clinical practice internationally.info:eu-repo/semantics/publishedVersio

Multiple sclerosis: oligoclonal IgG bands, prevalence, prognosis and effect of latitude

info:eu-repo/semantics/publishedVersio

Differential diagnosis of suspected multiple sclerosis: a consensus approach

BACKGROUND AND OBJECTIVES: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. METHODS: Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. RESULTS: We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. CONCLUSIONS: Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision

Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 201