Stages Of Relapsing-remitting Multiple Sclerosis Research Articles

Trans-synaptic degeneration in the optic pathway: Exploring the role of lateral geniculate nucleus in early stages of relapsing-remitting multiple sclerosis.

Optic pathway is considered an ideal model to study the interaction between inflammation and neurodegeneration in multiple sclerosis (MS). Optical Coherence Tomography (OCT) and 3.0 T magnetic resonance imaging (MRI) were acquired in 92 relapsing remitting (RR) MS at clinical onset. Peripapillary RNFL (pRNFL) and macular layers were measured. White matter (WM) and gray matter (GM) lesion volumes (LV), lateral geniculate nucleus (LGN) volume, optic radiations (OR) WM LV, thickness of pericalcarine cortex were evaluated. OCT and MRI control groups (healthy controls [HC]-OCT and HC-MRI) were included. A significant thinning of temporal pRNFL and papillo-macular bundle (PMB) was observed (p<0.001) in 16 (17%) patients presented with monocular optic neuritis (MSON+), compared to 76 MSON- and 30 HC (-15μm). In MSON-, PMB was reduced (-3μm) compared to HC OCT (p<0.05). INL total volume was increased both in MSON+ (p<0.001) and MSON- (p=0.033). Inner retinal layers volumes (macular RNFL, GCL and IPL) were significantly decreased in MSON+ compared to HC (p<0.001) and MSON- (p<0.001). Reduced GCL volume in the parafoveal ring was observed in MSON- compared to HCOCT (p < 0.05). LGN volume was significantly reduced only in MSON+ patients compared to HC-MRI (p<0.001) and MSON- (p<0.007). GCL, IPL and GCIP volumes associated with ipsilateral LGN volume in MSON+ and MSON-. Finally, LGN volume associated with visual cortex thickness with no significant difference between MSON+ and MSON-. Anterograde trans-synaptic degeneration is early detectable in RRMS presenting with optic neuritis but does not involve LGN.

Detecting disability using self-reported and clinical assessments in early-stage relapsing-remitting multiple sclerosis: Looking for a complementary approach.

Disability accrual is mainly driven by progression independent of relapse activity, which is present even in early stages of relapsing-remitting multiple sclerosis (RRMS) and sometimes overlooked. This multicenter, non-interventional study evaluated whether patient-reported outcomes measures (PROMs) could capture disability in 189 early-stage RRMS patients (mean age: 36.1 ± 9.4 years, 71.4% female, mean disease duration: 1.4 ± 0.8 years, median EDSS: 1.0). The 9-Hole Peg Test (9-HPT), NeuroQoL Upper Extremity (NeuroQoL-UE), Timed 25-Foot Walk (T25-FW), Multiple Sclerosis Walking Scale (MSWS-12), Symbol Digit Modalities Test (SDMT), and Perceived Deficits Questionnaire (PDQ-5) were used to assess hand function, gait, and cognition, respectively. These functions were at least mildly affected in this early-stage population, finding significant correlations between PROMs and clinical assessments. PROMs could enable early-stage RRMS patients to communicate their perceived disability in different domains, assisting clinicians in disease monitoring and decision making.

Pattern of thalamic nuclei atrophy in early relapse-onset multiple sclerosis

BackgroundThalamic atrophy is prominent in multiple sclerosis; however, it is unclear which thalamic nuclei are most vulnerable, especially early in disease. IntroductionTo investigate which thalamic nuclei differ between patients in early stages of relapsing-remitting multiple sclerosis (RRMS) versus healthy controls and examine the relationship between thalamic nuclei volume and T2 lesion volume. MethodsWe derived 15 thalamic subfields from high-resolution 3T magnetic resonance images in 182 patients with early RRMS (diagnosed ≤5.0 years, median 2.0 years). Independent t-tests assessed differences between patients and 35 controls across thalamic subfield volumes. Pearson correlations assessed the relationships between thalamic volumes and T2 lesion volumes. ResultsPatients had lower anterior and posterior nuclei volume than controls, whereas medial and ventral nuclei volumes were preserved. Higher T2 lesion volumes were disproportionately related to lower posterior subfield volumes. ConclusionsWe found specific thalamic subfields were more vulnerable to early disease-related changes. We discuss potential mechanisms of differential thalamic subfield atrophy in early MS, including cortical demyelination, CSF toxicity, leptomeningeal inflammation, and iron deposition.

Nanoimmunosensor based on atomic force spectroscopy to detect anti-myelin basic protein related to early-stage multiple sclerosis

Multiple Sclerosis (MS) is a chronic inflammatory disorder in the central nervous system for which biomarkers for diagnosis still remain unknown. One potential biomarker is the myelin basic protein. Here, a nanoimmunosensor based on atomic force spectroscopy (AFS) successfully detected autoantibodies against the MBP85-99 peptide from myelin basic protein. The nanoimmunosensor consisted of an atomic force microscope tip functionalization with MBP85-99 peptide, which was made to interact with a mica surface coated either with a layer of anti-MBP85-99 (positive control) or samples of cerebrospinal fluid (CSF) from five multiple sclerosis (MS) patients at different stages of the disease and five non-MS subjects. The adhesion forces obtained from AFS pointed to a high concentration of anti-MBP85-99 for the two patients at early stages of relapsing-remitting multiple sclerosis (RRMS), which were indistinguishable from the positive control. In contrast, considerably lower adhesion forces were measured for all the other eight subjects, including three MS patients with longer history of the disease and under treatment, without episodes of acute MS activity. We have also shown that the average adhesion force between MBP85-99 and anti-MBP85-99 is compatible with the value estimated using steered molecular dynamics. Though further tests will be required with a larger cohort of patients, the present results indicate that the nanoimmunosensor may be a simple tool to detect early-stage MS patients and be useful to understand the molecular mechanisms behind MS.

MSPrecise: a new diagnostic test for relapsing-remitting multiple sclerosis by cerebrospinal fluid B cell sequencing (HUM3P.267)

Abstract Patients with relapsing-remitting multiple sclerosis (RRMS), or who will convert to RRMS, have cerebrospinal fluid (CSF) B cells that accumulate specific replacement mutations in their rearranged VH4 gene segments as identified by single-cell Sanger sequencing. To harness this observation in a clinical setting, we have developed a diagnostic test to extract and score this genetic information from bulk CSF lymphocytes by next-generation DNA sequencing (NGS). Our current aim is to determine the accuracy of this test on a cohort of patients with varying times of RRMS onset and disease modifying therapies, as well as on a diverse cohort of patients with other neurological diseases (OND) that generally mimic the presentation of MS. Our initial testing on 39 patients has shown an accuracy of 84% in distinguishing RRMS from OND patients. As we continue to expand the size of the cohorts being tested, we will also focus on identifying differences between sub-cohorts of patients at different stages of RRMS or with particular OND diagnoses. With a growing need for a faster and more accurate diagnosis of RRMS, MSPrecise may be a useful addition to the existing diagnostic toolkit that clinicians use to achieve this goal.

Segmented corpus callosum diffusivity correlates with the Expanded Disability Status Scale score in the early stages of relapsing-remitting multiple sclerosis

OBJECTIVE:The aim of this study was to characterize the microscopic damage to the corpus callosum in relapsing-remitting multiple sclerosis (RRMS) with diffusion tensor imaging and to investigate the correlation of this damage with disability. The diffusion tensor imaging parameters of fractional anisotropy and mean diffusivity provide information about the integrity of cell membranes, offering two more specific indices, namely the axial and radial diffusivities, which are useful for discriminating axon loss from demyelination.METHOD:Brain magnetic resonance imaging exams of 30 relapsing-remitting multiple sclerosis patients and 30 age- and sex-matched healthy controls were acquired in a 3T scanner. The axial diffusivities, radial diffusivities, fractional anisotropy, and mean diffusivity of five segments of the corpus callosum, correlated to the Expanded Disability Status Scale score, were obtained.RESULTS:All corpus callosum segments showed increased radial diffusivities and mean diffusivity, as well as decreased fractional anisotropy, in the relapsing-remitting multiple sclerosis group. The axial diffusivity was increased in the posterior midbody and splenium. The Expanded Disability Status Scale scores correlated more strongly with axial diffusivities and mean diffusivity, with an isolated correlation with radial diffusivities in the posterior midbody of the corpus callosum. There was no significant correlation with lesion loads.CONCLUSION:Neurological dysfunction in relapsing-remitting multiple sclerosis can be influenced by commissural disconnection, and the diffusion indices of diffusion tensor imaging are potential biomarkers of disability that can be assessed during follow-up.

Oligoclonal bands in the cerebrospinal fluid and increased brain atrophy in early stages of relapsing-remitting multiple sclerosis

To determine if the presence of oligoclonal bands (OB) at early stages of multiple sclerosis was associated with higher brain atrophy, when compared with patients without OB. Relapsing-remitting multiple sclerosis (RRMS) patients with less than two years of disease onset and OB detection in cerebrospinal fluid (CSF) were included. SIENAX was used for total brain volume (TBV), gray matter volume (GMV), and white matter volume (WMV). Forty patients were included, 29 had positive IgG-OB. No differences were found between positive and negative patients in gender, expanded disability status scale (EDSS), treatment received, and T2/T1 lesion load. TBV in positive IgG-OB patients was 1.5 mm³ x 10(6) compared with 1.64 mm³ x 10(6) in the negative ones (p=0.02). GMV was 0.51 mm³ x 10(6) in positive IgG-OB compared with 0.62 mm³ x 10(6) in negative ones (p=0.002). No differences in WMV (p=0.09) were seen. IgG-OB in the CSF was related to neurodegeneration magnetic resonance (MR) markers in early RRMS.

White and Gray Matter Changes in Early Multiple Sclerosis (P03.049)

Objective: To evaluate damage in white and gray matter during early stages of relapsing-remitting multiple sclerosis (MS-RR). Background MS is an autoimmune, inflammatory CNS disease. Early in the disease, patients report significant problems in both physical and cognitive tasks. There is a paucity of literature on the extent of damage that occurs in patients even during the early stages of MS. This study further explores areas of the brain that are most affected in the early stages of RRMS. Design/Methods: Subjects included 9 controls (ages 26-48) and 20 MS patients (ages 22-45). MS patients had onset of symptoms Results: Compared to controls, MS patients showed significant FA white matter tract abnormalities in the corpus callosum, frontal, parietal, fornix, and thalamic tracts (P Conclusions: MS patients showed significant abnormalities both in the normal appearing white and gray matter structures. This study underscores the extent of damage both in the white and gray mater even in this early stage of MS and argues for early treatment of these patients. Disclosure: Dr. Williamson has received personal compensation for activities with Accorda Therapeutics as a participant on an advisory board. Dr. Shi has nothing to disclose. Dr. Javed has received personal compensation for activities with Teva Neuroscience, Bayer Pharmaceuticals, Serono, Inc., Novartis, Questcor and Biogen Idec as a consultant and/or speaker.

Corpus Callosum Microstructural Changes Correlate with Cognitive Dysfunction in Early Stages of Relapsing-Remitting Multiple Sclerosis: Axial and Radial Diffusivities Approach

The corpus callosum is the largest fiber bundle in the central nervous system and it takes part in several cognitive pathways. It can be affected by multiple sclerosis (MS) early in the disease. DTI is capable of infering the microstructural organization of the white matter. The vectorial analysis of the DTI offers the more specific indices of axial diffusivity (AD) and radial diffusivity (RD), which have shown to be useful to discriminate myelin damage from axon loss, respectively. This study presents DTI results (mean diffusivity (MD), fractional anisotropy (FA), RD, and AD) of 23 relapsing-remitting MS patients and its correlation with cognitive performance. There were 47.8% of cognitive impaired patients (MS CI). We found signs of demyelination, reflected by increased RD, and incipient axon loss, reflected by AD increase, which was slightly higher in the MS CI. The cognitive changes correlated with the DTI parameters, suggesting that loss of complexity in CC connections can impair neural conduction. Thus, cognitive impairment can be related to callosal disconnection, and DTI can be a promising tool to evaluate those changes.

FP30-WE-01 Chemokine profile in different stages of relapsing-remitting multiple sclerosis

FP30-WE-01 Chemokine profile in different stages of relapsing-remitting multiple sclerosis

Steroid Therapy Altered Serum Levels of CCL2 and CCL5 Chemokines in Multiple Sclerosis Patients during Relapse

Chemokines are involved in the pathogenesis of multiple sclerosis. The aim of this study was to determine the impact of steroid therapy on the levels of CCL2 and CCL5 chemokines. The study encompassed 30 patients with clinically definite relapsing-remitting multiple sclerosis who were treated with methylprednisolone due to the relapse of the disease. The control groups consisted of 20 patients during the stable stage of relapsing-remitting multiple sclerosis and of 15 patients with noninflammatory diseases of the nervous system. Both chemokines were markedly expresssed in serum by enzyme-linked immunosorbent assay. During relapse, the levels of both chemokines differed significantly from the levels measured in both control groups. After the methylprednisolone treatment, the chemokine levels changed significantly: the levels of CCL2 increased, whilst the levels of CCL5 decreased. These alterations did not correlate with the clinical state of the patients or with the therapeutic effect of the treatment and indicated that the inflammatory reaction accompanying the relapse was receding.

Correlations between IL-4, IL-12 levels and CCL2, CCL5 levels in serum and cerebrospinal fluid of multiple sclerosis patients.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Both cytokines and chemokines have been implicated in the pathogenesis of MS. The aim of the study was to assess whether cytokine levels are correlated with chemokine levels during a different stage of relapsing-remitting MS (RR-MS). The study included 53 patients with RR-MS (20 subjects in stable stage and 18 patients with relapse). By ELISA method, the levels of the interleukin-4 (IL-4), interleukin-12 (IL-12), CCL2 and CCL-5 chemokines were measured both in serum and cerebrospinal fluid (CSF) of all patients. The serum IL-4 and IL-12 levels and CSF CCL5 level of patients with stable RR-MS were significantly different from the control level and the IL-12 levels were correlated with CCL5 levels in serum. During the relapse, a significant change in chemokine levels both in serum and CSF and IL-12 in CSF were noted, however no correlations were found between cytokines and chemokines.

Evidence of Wallerian degeneration in normal appearing white matter in the early stages of relapsing-remitting multiple sclerosis: a HMRS study.

Wallerian degeneration in normal appearing white matter in early relapsing-remitting multiple sclerosis (RRMS), and its correlation with the number of relapses and disease duration. Background Recent pathological studies have demonstrated Wallerian degeneration in normal appearing white matter (NAWM) in multiple sclerosis (MS), in established RRMS, and in chronic MS. However, the presence of Wallerian degeneration early in the disease and its correlation with relapse and with disease duration has not been studied. We performed proton magnetic resonance spectroscopic imaging in 21 MS patients, and 4 healthy controls, age and gender matched, aged under 45 years, with a maximum of 4 years since first bout, and an EDSS score of less than 3.0. N-acetyl-aspartate (NAA) (an index of axonal integrity) was measured in the NAWM from the pons and the cerebellar peduncles. We observed that the NAA levels were abnormally low in the NAWM in the early RRMS patients (p = 0.04, Student's t-test). The decrease in the NAA concentration correlated with disease duration in the two areas studied (p = 0.03 for pons and p = 0.04 for cerebellar peduncle); and with the number of previous relapses (Pearson's correlation = -0.582, p < 0.002). Wallerian degeneration measured by the NAA concentration at pons and cerebellar peduncles is present early in the disease and correlates with the number of relapses and disease duration.

A longitudinal study of callosal atrophy and interhemispheric dysfunction in relapsing-remitting multiple sclerosis.

To determine if callosal atrophy and interhemispheric dysfunction can be detected in the early stages of relapsing-remitting multiple sclerosis (MS) and to evaluate their progression in relation to the disability and evolution of lesions seen on magnetic resonance imaging during a 5-year period. We compared 30 patients who had clinically definite early-onset replasing-remitting MS and mild disability with control subjects. Regional and segmental callosal size and extent of white matter abnormalities on magnetic resonance imaging, as well as performance on tasks exploring interhemispheric transfer of motor, auditory, and sensory information were assessed. Patients with MS were evaluated at baseline and after 5 years. Physical disability was determined at both times using the Expanded Disability Status Scale score. Patients with MS were seen with significant callosal atrophy and functional impairment of interhemispheric transfer at baseline that worsened during the 5-year study. A significant correlation was found between the magnitude of disability and the severity of morphological and functional callosal involvement at baseline. This association persisted at year 5. Baseline clinical characteristics such as age and prestudy relapse rate were unrelated to callosal size or interhemispheric performance. However, the number of baseline T2-weighted lesions was correlated with callosal involvement and this relation persisted at year 5. Patients who had relapsing-remitting MS in the early stages of the disease and mild disability had significant callosal involvement that progressed over time. The relationship between disability, T2-weighted lesions load, and degree of morphological and functional callosal impairment confirm the potential value of using callosal dysfunction as a surrogate marker of disease progression in MS.