Imaging the Visual Pathway in Neuromyelitis Optica

The focus of this paper is to summarize the current knowledge on visual pathway damage in neuromyelitis optica (NMO) assessed by magnetic resonance imaging (MRI) and optical coherence tomography (OCT)

Exercise in multiple sclerosis -- an integral component of disease management

Multiple sclerosis (MS) is the most common chronic inflammatory disorder of the central nervous system (CNS) in young adults. The disease causes a wide range of symptoms depending on the localization and characteristics of the CNS pathology. In addition to drug-based immunomodulatory treatment, both drug-based and non-drug approaches are established as complementary strategies to alleviate existing symptoms and to prevent secondary diseases. In particular, physical therapy like exercise and physiotherapy can be customized to the individual patient's needs and has the potential to improve the individual outcome. However, high quality systematic data on physical therapy in MS are rare. This article summarizes the current knowledge on the influence of physical activity and exercise on disease-related symptoms and physical restrictions in MS patients. Other treatment strategies such as drug treatments or cognitive training were deliberately excluded for the purposes of this article

Association of Retinal and Macular Damage with Brain Atrophy in Multiple Sclerosis

Neuroaxonal degeneration in the central nervous system contributes substantially to the long term disability in multiple sclerosis (MS) patients. However, in vivo determination and monitoring of neurodegeneration remain difficult. As the widely used MRI-based approaches, including the brain parenchymal fraction (BPF) have some limitations, complementary in vivo measures for neurodegeneration are necessary. Optical coherence tomography (OCT) is a potent tool for the detection of MS-related retinal neurodegeneration. However, crucial aspects including the association between OCT- and MRI-based atrophy measures or the impact of MS-related parameters on OCT parameters are still unclear. In this large prospective cross-sectional study on 104 relapsing remitting multiple sclerosis (RRMS) patients we evaluated the associations of retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV) with BPF and addressed the impact of disease-determining parameters on RNFLT, TMV or BPF. BPF, normalized for subject head size, was estimated with SIENAX. Relations were analyzed primarily by Generalized Estimating Equation (GEE) models considering within-patient inter-eye relations. We found that both RNFLT (p = 0.019, GEE) and TMV (p = 0.004, GEE) associate with BPF. RNFLT was furthermore linked to the disease duration (p<0.001, GEE) but neither to disease severity nor patients' age. Contrarily, BPF was rather associated with severity (p<0.001, GEE) than disease duration and was confounded by age (p<0.001, GEE). TMV was not associated with any of these parameters. Thus, we conclude that in RRMS patients with relatively short disease duration and rather mild disability RNFLT and TMV reflect brain atrophy and are thus promising parameters to evaluate neurodegeneration in MS. Furthermore, our data suggest that RNFLT and BPF reflect different aspects of MS. Whereas BPF best reflects disease severity, RNFLT might be the better parameter for monitoring axonal damage longitudinally. Longitudinal studies are necessary for validation of data and to further clarify the relevance of TMV

Metabolic Changes in the Visual Cortex Are Linked to Retinal Nerve Fiber Layer Thinning in Multiple Sclerosis

OBJECTIVE: To investigate the damage to the retinal nerve fiber layer as part of the anterior visual pathway as well as an impairment of the neuronal and axonal integrity in the visual cortex as part of the posterior visual pathway with complementary neuroimaging techniques, and to correlate our results to patients' clinical symptoms concerning the visual pathway. DESIGN, SUBJECTS AND METHODS: Survey of 86 patients with relapsing-remitting multiple sclerosis that were subjected to retinal nerve fiber layer thickness (RNFLT) measurement by optical coherence tomography, to a routine MRI scan including the calculation of the brain parenchymal fraction (BPF), and to magnetic resonance spectroscopy at 3 tesla, quantifying N-acetyl aspartate (NAA) concentrations in the visual cortex and normal-appearing white matter. RESULTS: RNFLT correlated significantly with BPF and visual cortex NAA, but not with normal-appearing white matter NAA. This was connected with the patients' history of a previous optic neuritis. In a combined model, both BPF and visual cortex NAA were independently associated with RNFLT. CONCLUSIONS: Our data suggest the existence of functional pathway-specific damage patterns exceeding global neurodegeneration. They suggest a strong interrelationship between damage to the anterior and the posterior visual pathway

Lipopolysaccharide Injection Induces Relapses of Experimental Autoimmune Encephalomyelitis in Nontransgenic Mice via Bystander Activation of Autoreactive CD4 +

Infections sometimes associate with exacerbations of autoimmune diseases through pathways that are poorly understood. Ag-specific mechanisms such as cross-reactivity between a microbial Ag and a self-Ag have received no direct support. In this study, we show that injection of LPS induces experimental autoimmune encephalomyelitis in TCR-transgenic mice and relapse of encephalomyelitis in normal mice. This form of treatment induces proliferation and cytokine production in a fraction of effector/memory Th lymphocytes in vitro via physical contact of Th cells with CD4(-) LPS-responsive cells. TCR-mediated signals are not necessary; rather what is required is ligation of costimulatory receptors on Th cells by costimulatory molecules on the CD4(-) cells. This form of bystander activation provides an Ag-independent link between infection and autoimmunity that might fit the clinical and epidemiological data on the connection between infection and autoimmunity better than the Ag-specific models

Description of study cohort with demographic and disease parameters.

<p>RRMS = relapsing remitting Multiple sclerosis; (N)ON = (non) optic neuritis; SD = standard deviation, BPF = brain parenchymal fraction, RNFLT = retinal nerve fiber layer thickness, TMV = total macular volume.</p

Association between BPF and OCT parameters in patients with RRMS.

<p>Patients (individual eyes) are labeled according to the history of optic neuritis (ON). Lines are derived from linear regression analyses with R² given in parentheses. Statistical significance level was calculated by Generalized Estimating Equation models controlling for the history of ON. A) Retinal nerve fiber layer thickness (RNFLT) vs. BPF (0.073, p = 0.019). B) Total macular volume (TMV) vs. BPF (0.113, p = 0.001).</p

Modulation of Dendritic Cell Immunobiology via Inhibition of 3-Hydroxy-3-Methylglutaryl-CoA (HMG-CoA) Reductase

<div><p>The maturation status of dendritic cells determines whether interacting T cells are activated or if they become tolerant. Previously we could induce T cell tolerance by applying a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (HMGCRI) atorvastatin, which also modulates MHC class II expression and has therapeutic potential in autoimmune disease. Here, we aimed at elucidating the impact of this therapeutic strategy on T cell differentiation as a consequence of alterations in dendritic cell function. We investigated the effect of HMGCRI during differentiation of peripheral human monocytes and murine bone marrow precursors to immature DC <i>in vitro</i> and assessed their phenotype. To examine the stimulatory and tolerogenic capacity of these modulated immature dendritic cells, we measured proliferation and suppressive function of CD4+ T cells after stimulation with the modulated immature dendritic cells. We found that an HMGCRI, atorvastatin, prevents dendrite formation during the generation of immature dendritic cells. The modulated immature dendritic cells had a diminished capacity to take up and present antigen as well as to induce an immune response. Of note, the consequence was an increased capacity to differentiate naïve T cells towards a suppressor phenotype that is less sensitive to proinflammatory stimuli and can effectively inhibit the proliferation of T effector cells <i>in vitro</i>. Thus, manipulation of antigen-presenting cells by HMGCRI contributes to an attenuated immune response as shown by promotion of T cells with suppressive capacities.</p></div

Generalized Estimating Equations for the association of RNFLT with BPF as primary endpoint.

<p>Results from GEEs with RNFLT and age as independent variables and controlling for history of optic neuritis and BPF as dependent variable. The standardized Beta was calculated as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0018132#s2" target="_blank">methods</a> section. RNFLT = retinal nerve fiber layer thickness, ON = history of optic neuritis, CI = confidence interval.</p