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

A Predictive Model for Corticosteroid Response in Individual Patients with MS Relapses

<div><p>Objectives</p><p>To derive a simple predictive model to guide the use of corticosteroids in patients with relapsing remitting MS suffering an acute relapse.</p><p>Materials and Methods</p><p>We analysed individual patient randomised controlled trial data (n=98) using a binary logistic regression model based on age, gender, baseline disability scores [physician-observed: expanded disability status scale (EDSS) and patient reported: multiple sclerosis impact scale 29 (MSIS-29)], and the time intervals between symptom onset or referral and treatment.</p><p>Results</p><p>Based on two a priori selected cut-off points (improvement in EDSS ≥ 0.5 and ≥ 1.0), we found that variables which predicted better response to corticosteroids after 6 weeks were younger age and lower MSIS-29 physical score at the time of relapse (model fit 71.2% - 73.1%).</p><p>Conclusions</p><p>This pilot study suggests two clinical variables which may predict the majority of the response to corticosteroid treatment in patients undergoing an MS relapse. The study is limited in being able to clearly distinguish factors associated with treatment response or spontaneous recovery and needs to be replicated in a larger prospective study.</p></div

Calcitriol modulates the CD46 pathway in T cells

The complement regulator CD46 is a costimulatory molecule for human T cells that induces a regulatory Tr1 phenotype, characterized by large amounts of IL-10 secretion. Secretion of IL-10 upon CD46 costimulation is largely impaired in T cells from patients with multiple sclerosis (MS). Vitamin D can exert a direct effect on T cells, and may be beneficial in several pathologies, including MS. In this pilot study, we examined whether active vitamin D (1,25(OH)2D3 or calcitriol) could modulate the CD46 pathway and restore IL-10 production by CD46-costimulated CD4+ T cells from patients with MS. In healthy T cells, calcitriol profoundly affects the phenotype of CD46-costimulated CD4+ T cells, by increasing the expression of CD28, CD25, CTLA-4 and Foxp3 while it concomitantly decreased CD46 expression. Similar trends were observed in MS CD4+ T cells except for CD25 for which a striking opposite effect was observed: while CD25 was normally induced on MS T cells by CD46 costimulation, addition of calcitriol consistently inhibited its induction. Despite the aberrant effect on CD25 expression, calcitriol increased the IL-10:IFNc ratio, characteristic of the CD46-induced Tr1 phenotype, in both T cells from healthy donors and patients with MS. Hence, we show that calcitriol affects the CD46 pathway, and that it promotes anti-inflammatory responses mediated by CD46. Moreover, it might be beneficial for T cell responses in MS

Triggering of the dsRNA Sensors TLR3, MDA5, and RIG-I Induces CD55 Expression in Synovial Fibroblasts

Background: CD55 (decay-accelerating factor) is a complement-regulatory protein highly expressed on fibroblast-like synoviocytes (FLS). CD55 is also a ligand for CD97, an adhesion-type G protein-coupled receptor abundantly present on leukocytes. Little is known regarding the regulation of CD55 expression in FLS. Methods: FLS isolated from arthritis patients were stimulated with pro-inflammatory cytokines and Toll-like receptor (TLR) ligands. Transfection with polyinosinic-polycytidylic acid (poly(I:C)) and 5'-triphosphate RNA were used to activate the cytoplasmic double-stranded (ds)RNA sensors melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene-I (RIG-I). CD55 expression, cell viability, and binding of CD97-loaded beads were quantified by flow cytometry. Results: CD55 was expressed at equal levels on FLS isolated from patients with rheumatoid arthritis (RA), osteoarthritis, psoriatic arthritis and spondyloarthritis. CD55 expression in RA FLS was significantly induced by IL-1 beta and especially by the TLR3 ligand poly(I:C). Activation of MDA5 and RIG-I also enhanced CD55 expression. Notably, activation of MDA5 dose-dependently induced cell death, while triggering of TLR3 or RIG-I had a minor effect on viability. Upregulation of CD55 enhanced the binding capacity of FLS to CD97-loaded beads, which could be blocked by antibodies against CD55. Conclusions: Activation of dsRNA sensors enhances the expression of CD55 in cultured FLS, which increases the binding to CD97. Our findings suggest that dsRNA promotes the interaction between FLS and CD97-expressing leukocyte

The Dynamic Processing of CD46 Intracellular Domains Provides a Molecular Rheostat for T Cell Activation

Adequate termination of an immune response is as important as the induction of an appropriate response. CD46, a regulator of complement activity, promotes T cell activation and differentiation towards a regulatory Tr1 phenotype. This Tr1 differentiation pathway is defective in patients with MS, asthma and rheumatoid arthritis, underlying its importance in controlling T cell function and the need to understand its regulatory mechanisms. CD46 has two cytoplasmic tails, Cyt1 and Cyt2, derived from alternative splicing, which are co-expressed in all nucleated human cells. The regulation of their expression and precise functions in regulating human T cell activation has not been fully elucidated.Here, we first report the novel role of CD46 in terminating T cell activation. Second, we demonstrate that its functions as an activator and inhibitor of T cell responses are mediated through the temporal processing of its cytoplasmic tails. Cyt1 processing is required to turn T cell activation on, while processing of Cyt2 switches T cell activation off, as demonstrated by proliferation, CD25 expression and cytokine secretion. Both tails require processing by Presenilin/γSecretase (P/γS) to exert these functions. This was confirmed by expressing wild-type Cyt1 and Cyt2 tails and uncleavable mutant tails in primary T cells. The role of CD46 tails was also demonstrated with T cells expressing CD19 ectodomain-CD46 C-Terminal Fragment (CTF) fusions, which allowed specific triggering of each tail individually.We conclude that CD46 acts as a molecular rheostat to control human T cell activation through the regulation of processing of its cytoplasmic tails

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

Complement activation in myasthenia gravis (MG) may damage muscle endplate and complement regulatory proteins such as decay-accelerating factor (DAF) or CD55 may be protective. We hypothesize that the increased prevalence of severe extraocular muscle (EOM) dysfunction among African MG subjects reported earlier may result from altered DAF expression. To test this hypothesis, we screened the DAF gene sequences relevant to the classical complement pathway and found an association between myasthenics with EOM paresis and the DAF regulatory region c.-198C>G SNP (odds ratio=8.6; P=0.0003). This single nucleotide polymorphism (SNP) results in a twofold activation of a DAF 5′-flanking region luciferase reporter transfected into three different cell lines. Direct matching of the surrounding SNP sequence within the DAF regulatory region with the known transcription factor-binding sites suggests a loss of an Sp1-binding site. This was supported by the observation that the c.-198C>G SNP did not show the normal lipopolysaccharide-induced DAF transcriptional upregulation in lymphoblasts from four patients. Our findings suggest that at critical periods during autoimmune MG, this SNP may result in inadequate DAF upregulation with consequent complement-mediated EOM damage. Susceptible individuals may benefit from anti-complement therapy in addition to immunosuppression