non-MS Diseases Research Articles

Intrathecal B cell-related markers for an optimized biological investigation of multiple sclerosis patients

In multiple sclerosis (MS) disease, the importance of the intrathecal B cell response classically revealed as IgG oligoclonal bands (OCB) in cerebrospinal fluid (CSF) was reaffirmed again in the recently revised diagnostic criteria. We aimed to optimize Laboratory investigation by testing the performance of new B cell-related molecules in CSF (Ig free light chains (FLCκ and λ) and CXCL13 (B-Cell Attracting chemokine1)) for MS diagnosis. 320 paired (CSF-serum) samples were collected from 160 patients with MS (n = 82) and non-MS diseases (n = 78). All patients benefited from IgG index determination, OCB detection, CSF CXCL13 and FLC (κ and λ) measurement in CSF and serum for metrics calculation (κ/λ ratio, FLC-related indexes, and κFLC-intrathecal fraction (IF)). CXCL13 and FLC metrics in CSF were higher in patients with MS and positive OCB. As expected, κFLC metrics—in particular, κFLC index and κFLC IF—had the highest accuracy for MS diagnosis. κ index showed the best performance (sensitivity 83% and specificity 91.7%) at a cut-off of 14.9. Most of the FLC-related parameters were positively correlated with IgG index and the level of CXCL13. In conclusion, the quantitative, standardizable, and technically simple CSF FLCκ metrics seem to be reliable for MS diagnosis, but could not replace OCB detection. CXCL13 appears to be an effective parameter reflecting the intrathecal B cell response. An optimized way for CSF testing combining the conventional and the new B cell-related parameters is proposed in this study.

Atypical Optic Neuritis: The Potential Red Flags.

Many potential causes of optic nerve inflammation exist, including typical and atypical causes, which require different management strategies. The objective of this study is to identify red flags that help differentiate typical from atypical optic neuritis (ON). This prospective study included 66 patients (100 eyes) with immune-mediated ON from January 2016 to June 2019, carefully excluding the nonimmune causes. The clinico-radiological features, investigations, therapy, and outcome were analyzed. We evaluated 33 cases each of typical and atypical ON. The typical group included 29 idiopathic ON and four associated with multiple sclerosis. Atypical ON included 19 neuromyelitis optica (NMO), seven MOG-associated ON (MOG-ON), and others due to Sjogren's syndrome, granulomatous polyangiitis, sarcoidosis, and IgG4 disease. Atypical ON occurred significantly and more frequently with extremes of ages (<10 or >70 years), bilateral simultaneous or severe vision loss with early disc pallor, multiple attacks, symptoms/neuro-imaging indicating non-MS disease e.g., long segment ON/myelitis, large confluent lesions, the involvement of optic tract, chiasma, area postrema or diencephalon, and (pachy) meningitis. Systemic involvement and poor outcomes despite steroids and second-line immunosuppression were observed more often in the atypical ON. The red flags indicating atypical ON are onset at extremes of age, multiple attacks, bilateral simultaneous or severe to very severe vision loss, early disc pallor, neurological symptoms, or imaging abnormalities suggesting non-MS disease, systemic involvement, and poor steroid responsiveness. The awareness might help the clinician promptly identify and escalate therapy to ensure a better outcome.

Serum MOG-IgG in children meeting multiple sclerosis diagnostic criteria

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is now recognized as distinct from multiple sclerosis (MS). Objective: To evaluate the importance of considering myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin-G (IgG) serology when applying MS diagnostic criteria in children. Methods: Within a prospective cohort of children meeting MS criteria (median follow-up = 6 years, interquartile range (IQR) = 4–9), we measured MOG-IgG in serial archived serum obtained from presentation, and compared imaging and clinical features between seropositive and seronegative participants. Results: Of 65 children meeting MS criteria (median age = 14.0 years, IQR = 10.9–15.1), 12 (18%) had MOG-IgG at disease onset. Seropositive participants were younger, had brain magnetic resonance imaging (MRI) features atypical for MS, rarely had cerebrospinal fluid (CSF) oligoclonal bands (2/8, 25%), and accumulated fewer T2 lesions over time. On serial samples, 5/12 (42%) were persistently seropositive, 5/12 (42%) became seronegative, and 2/12 (17%) had fluctuating results. All 12 children experienced a disease course different from typical MS. Conclusion: While children with MOG-IgG can have clinical, CSF, and MRI features conforming to MS criteria, the presence of MOG-IgG is associated with atypical features and predicts a non-MS disease course. Given MOG-IgG seropositivity can wane over time, testing at first attack is of considerable importance for the diagnosis of MOGAD.

Differential Binding of Autoantibodies to MOG Isoforms in Inflammatory Demyelinating Diseases.

ObjectiveTo analyze serum immunoglobulin G (IgG) antibodies to major isoforms of myelin oligodendrocyte glycoprotein (MOG-alpha 1-3 and beta 1-3) in patients with inflammatory demyelinating diseases.MethodsRetrospective case-control study using 378 serum samples from patients with multiple sclerosis (MS), patients with non-MS demyelinating disease, and healthy controls with MOG alpha-1-IgG positive (n = 202) or negative serostatus (n = 176). Samples were analyzed for their reactivity to human, mouse, and rat MOG isoforms with and without mutations in the extracellular MOG Ig domain (MOG-ecIgD), soluble MOG-ecIgD, and myelin from multiple species using live cell-based, tissue immunofluorescence assays and ELISA.ResultsThe strongest IgG reactivities were directed against the longest MOG isoforms alpha-1 (the currently used standard test for MOG-IgG) and beta-1, whereas the other isoforms were less frequently recognized. Using principal component analysis, we identified 3 different binding patterns associated with non-MS disease: (1) isolated reactivity to MOG-alpha-1/beta-1 (n = 73), (2) binding to MOG-alpha-1/beta-1 and at least one other alpha, but no beta isoform (n = 64), and (3) reactivity to all 6 MOG isoforms (n = 65). The remaining samples were negative (n = 176) for MOG-IgG. These MOG isoform binding patterns were associated with a non-MS demyelinating disease, but there were no differences in clinical phenotypes or disease course. The 3 MOG isoform patterns had distinct immunologic characteristics such as differential binding to soluble MOG-ecIgD, sensitivity to MOG mutations, and binding to human MOG in ELISA.ConclusionsThe novel finding of differential MOG isoform binding patterns could inform future studies on the refinement of MOG-IgG assays and the pathophysiologic role of MOG-IgG.

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorders: Toward a New Spectrum of Inflammatory Demyelinating CNS Disorders?

Inflammatory demyelinating CNS syndromes include, besides their most common entity multiple sclerosis (MS), several different diseases of either monophasic or recurrent character—including neuromyelitis optica spectrum disorders (NMOSDs) and acute disseminated encephalomyelitis (ADEM). Early diagnostic differentiation is crucial for devising individual treatment strategies. However, due to overlapping clinical and paraclinical features diagnosis at the first demyelinating event is not always possible. A multiplicity of potential biological markers that could discriminate the different diseases was studied. As the use of autoantibodies in patient management of other autoimmune diseases, is well-established and evidence for the critical involvement of B cells/antibodies in disease pathogenesis in inflammatory demyelinating CNS syndromes increases, antibodies seem to be valuable diagnostic tools. Since the detection of antibodies against aquaporin-4 (AQP-4), the understanding of immunopathogenesis and diagnostic management of NMOSDs has dramatically changed. However, for most inflammatory demyelinating CNS syndromes, a potential antigen target is still not known. A further extensively studied possible target structure is myelin oligodendrocyte glycoprotein (MOG), found at the outermost surface of myelin sheaths and oligodendrocyte membranes. With detection methods using cell-based assays with full-length, conformationally correct MOG, antibodies have been described in early studies with a subgroup of patients with ADEM. Recently, a humoral immune reaction against MOG has been found not only in monophasic diseases, but also in recurrent non-MS diseases, particularly in pediatric patients. This review presents the findings regarding MOG antibodies as potential biological markers in discriminating between these different demyelinating CNS diseases, and discusses recent developments, clinical implementations, and data on immunopathogenesis of MOG antibody-associated disorders.

Validation of CSF free light chain in diagnosis and prognosis of multiple sclerosis and clinically isolated syndrome: prospective cohort study in Buenos Aires.

The objective was to evaluate the precision of kappa and lambda free light chains (KFLC and LFLC) in CSF for the diagnosis of multiple sclerosis (MS) and prognosis of clinically isolated syndrome (CIS). CSF and serum samples from CIS, MS and other neurological non-MS disease were collected between 2015 and 2017. FLC concentrations were measured using immunoassay Freelite™. Results were correlated with the patients' diagnoses and ROC curve analysis was used to determine accuracy. In CIS patients, analysis of FLC were compared in CIS converters vs. non-converter during follow-up. In the MS group (n = 41), the optimal cut-off for KFLC determined was 7mg/L, with a diagnostic sensitivity and specificity of 95% and 97%, respectively. The optimal cut-off for LFLC was 0.7mg/L, with a diagnostic sensitivity and specificity of 71% and 81%, respectively. 36 CIS patients were included; mean follow-up time was 28 ± 9months, and 22 (61.1%) patients converted to MS. The median concentration of CSF K and LFLCs at CIS diagnosis was slightly higher in CIS-converters compared to non-converters, but this did not reach statistical significance (KFLC: median 7 ± 5.3mg/L vs. 5 ± 2.3mg/L, p = 0.11; LFLC 0.7 ± 0.33mg/L vs. 0.5 ± 0.23mg/L p = 0.16). A strong correlation was observed between the concentration of K and L FLCs at diagnosis and the change in PBVC during follow-up (r = 0.72 and r = 0.65, respectively). KFLCs have a high sensitivity and specificity for the diagnosis of MS. FLC concentrations at CIS diagnosis were not significantly higher in CIS-converters.

Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.

To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS). Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study. Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p < 0.0001) and OCB (p = 0.007). An MOG-ab cutoff titer ≥1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%. Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course.

Functional plasticity of the visual system in multiple sclerosis.

OPINION article Front. Neurol., 08 April 2015Sec. Multiple Sclerosis and Neuroimmunology Volume 6 - 2015 | https://doi.org/10.3389/fneur.2015.00079

Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children.

Objective:To determine whether myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) were predictive of a demyelination phenotype in children presenting with acquired demyelinating syndrome (ADS).Method:Sixty-five children with a first episode of ADS (12 acute disseminated encephalomyelitis, 24 optic neuritis, 18 transverse myelitis, 11 other clinically isolated syndrome) were identified from 2 national demyelination programs in the United Kingdom and France. Acute serum samples were tested for MOG-Abs by cell-based assay. Antibodies were used to predict diagnosis of multiple sclerosis (MS) at 1 year.Results:Twenty-three of 65 (35%) children had MOG-Abs. Antibody-positive and antibody-negative patients were not clinically different at presentation, but identification of MOG-Abs predicted a non-MS course at 1-year follow-up: only 2/23 (9%) MOG-Ab–positive patients were diagnosed with MS compared to 16/42 (38%) MOG-Ab–negative patients (p = 0.019, Fisher exact test). Antibody positivity at outset was a useful predictor for a non-MS disease course, with a positive predictive value of 91% (95% confidence interval [CI] 72–99), negative predictive value of 38% (95% CI 24–54), positive likelihood ratio of 4.02 (CI 1.0–15.4), and odds ratio of 6.5 (CI 1.3–31.3).Conclusions:MOG-Abs are found at presentation in 35% of patients with childhood ADS, across a range of demyelinating disorders. Antibody positivity can be useful in predicting a non-MS disease course at onset.

TWEAK is expressed at the cell surface of monocytes during multiple sclerosis

The TNF superfamily ligand, TNF-like weak inducer of apoptosis (TWEAK), regulates cellular responses ranging from proliferation to cell death in a manner highly dependent on the cell type and the microenvironmental context. We have shown previously that treatment of experimental autoimmune encephalomyelitis mice after the priming phase with neutralizing anti-TWEAK antibodies results in a reduction in the severity of the disease and leukocyte infiltration. To further characterize TWEAK/fibroblast growth factor-inducible 14-kDa protein (Fn14) involvement during multiple sclerosis (MS), we evaluated in MS patients and controls: TWEAK and Fn14 expression on PBMC and soluble TWEAK concentration in serum and cerebrospinal fluid (CSF). Thirty-six consecutive patients were enrolled, including 11 patients with relapsing-remitting MS, 11 with a clinical isolated syndrome suggestive of MS (CISSMS), and 14 controls with non-MS diseases. Intracellular TWEAK could be observed in lymphocytes and/or monocytes in all groups of patients. None of the 36 patients displayed TWEAK expression at the cell surface of lymphocytes. In contrast, 12 out of the 36 patients were positive for membrane TWEAK expression on their monocytes. Among these patients, eight were from the CISSMS group. Fn14 was not detected in PBMC. The soluble form of TWEAK is detectable in serum and CSF of patients, and TWEAK concentrations were not statistically different between the disease groups. We demonstrated for the first time that TWEAK is expressed at the cell surface of monocytes during MS, especially in the CISSMS group. Our results support the proposal that TWEAK could be a target for antibody therapy in MS.

Effect of low saturated fat diet in early and late cases of multiple sclerosis

144 multiple sclerosis patients took a low-fat diet for 34 years. For each of three categories of neurological disability (minimum, moderate, severe) patients who adhered to the prescribed diet (less than or equal to 20 g fat/day) showed significantly less deterioration and much lower death rates than did those who consumed more fat than prescribed (greater than 20 g fat/day). The greatest benefit was seen in those with minimum disability at the start of the trial; in this group, when those who died from non-MS diseases were excluded from the analysis, 95% survived and remained physically active.

Cerebrospinal fluid virus antibodies: A diagnostic indicator for multiple sclerosis?

Specific antibody activities (antibody per weight unit IgG) of serum and CSF against a broad variety of viruses were compared in multiple sclerosis and certain inflammatory diseases of the central nervous system, e.g. neurosyphilis, as well as herpes simplex and zoster encephalitis. No “unspecific” antiviral activities within the CSF compartment were found in the non-MS diseases. The most frequent antibodies locally produced were directed against measles, rubella and zoster antigens. A diagnostic test with these three viruses would give positive results in about 80% of patients with MS. This finding is not as frequent as the oligoclonal pattern of the CSF γ-globulins but would have a considerably greater diagnostic significance.