Vitamin D and Disease Severity in Multiple Sclerosis-Baseline Data From the Randomized Controlled Trial (EVIDIMS)

Objective: To investigate the associations between hypovitaminosis D and disease activity in a cohort of relapsing remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) patients. Methods: In 51 RRMS and 2 CIS patients on stable interferon-β-1b (IFN-β-1b) treatment recruited to the EVIDIMS study (Efficacy of Vitamin D Supplementation in Multiple Sclerosis (NCT01440062) baseline serum vitamin D levels were evaluated. Patients were dichotomized based on the definition of vitamin D deficiency which is reflected by a < 30 vs. ≥ 30 ng/ml level of 25-hydroxyvitamin D (25(OH)D). Possible associations between vitamin D deficiency and both clinical and MRI features of the disease were analyzed. Results: Median (25, 75% quartiles, Q) 25(OH)D level was 18 ng/ml (12, 24). Forty eight out of 53 (91%) patients had 25(OH)D levels < 30 ng/ml (p < 0.001). Patients with 25(OH)D ≥ 30 ng/ml had lower median (25, 75% Q) T2-weighted lesion counts [25 (24, 33)] compared to patients with 25(OH)D < 30 ng/ml [60 (36, 84), p = 0.03; adjusted for age, gender and disease duration: p < 0.001]. Expanded disability status scale (EDSS) score was negatively associated with serum 25(OH)D levels in a multiple linear regression, including age, sex, and disease duration (adjusted: p < 0.001). Interpretation: Most patients recruited in the EVIDIMS study were vitamin D deficient. Higher 25(OH)D levels were associated with reduced T2 weighted lesion count and lower EDSS scores

Imaging markers of disability in aquaporin-4 immunoglobulin G seropositive neuromyelitis optica: a graph theory study

Neuromyelitis optica spectrum disorders lack imaging biomarkers associated with disease course and supporting prognosis. This complex and heterogeneous set of disorders affects many regions of the central nervous system, including the spinal cord and visual pathway. Here, we use graph theory-based multimodal network analysis to investigate hypothesis-free mixed networks and associations between clinical disease with neuroimaging markers in 40 aquaporin-4-immunoglobulin G antibody seropositive patients (age = 48.16 ± 14.3 years, female:male = 36:4) and 31 healthy controls (age = 45.92 ± 13.3 years, female:male = 24:7). Magnetic resonance imaging measures included total brain and deep grey matter volumes, cortical thickness and spinal cord atrophy. Optical coherence tomography measures of the retina and clinical measures comprised of clinical attack types and expanded disability status scale were also utilized. For multimodal network analysis, all measures were introduced as nodes and tested for directed connectivity from clinical attack types and disease duration to systematic imaging and clinical disability measures. Analysis of variance, with group interactions, gave weights and significance for each nodal association (hyperedges). Connectivity matrices from 80% and 95% F-distribution networks were analyzed and revealed the number of combined attack types and disease duration as the most connected nodes, directly affecting changes in several regions of the central nervous system. Subsequent multivariable regression models, including interaction effects with clinical parameters, identified associations between decreased nucleus accumbens (β = −0.85, P = 0.021) and caudate nucleus (β = −0.61, P = 0.011) volumes with higher combined attack type count and longer disease duration, respectively. We also confirmed previously reported associations between spinal cord atrophy with increased number of clinical myelitis attacks. Age was the most important factor associated with normalized brain volume, pallidum volume, cortical thickness and the expanded disability status scale score. The identified imaging biomarker candidates warrant further investigation in larger-scale studies. Graph theory-based multimodal networks allow for connectivity and interaction analysis, where this method may be applied in other complex heterogeneous disease investigations with different outcome measures

Emotional experience in patients with clinically isolated syndrome and early multiple sclerosis

Background and purpose: Evidence suggests that there are changes in the processing of emotional information (EP) in people with multiple sclerosis (MS). It is unclear which functional domains of EP are affected, whether these changes are secondary to other MS-related neuropsychological or psychiatric symptoms and if EP changes are present in early MS. The aim of the study was to investigate EP in patients with early MS (clinically isolated syndrome and early relapsing/remitting MS) and healthy controls (HCs). Methods: A total of 29 patients without neuropsychological or psychiatric deficits and 29 matched HCs were presented with pictures from the International Affective Picture System with negative, positive or neutral content. Participants rated the induced emotion regarding valence and arousal using nine-level Likert scales. A speeded recognition test assessed memory for the emotional stimuli and for the emotional modulation of response time. A subgroup of participants was tested during a magnetic resonance imaging (MRI) session. Results: Patients in the MRI subgroup rated the experience induced by pictures with positive or negative emotional content significantly more weakly than HCs. Further, these patients were significantly less aroused when watching the pictures from the International Affective Picture System. There were no effects in the non-MRI subgroup or effects on emotional memory or response times. Conclusions: Emotional processing changes may be present in early MS in the form of flattened emotional experience on both the valence and arousal dimensions. These changes do not appear to be secondary to neuropsychological or psychiatric deficits. The fact that emotional flattening was only found in the MRI setting suggests that EP changes may be unmasked within stressful environments and points to the potential yet underestimated impact of the MRI setting on behavioral outcomes

Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders

Background: Pain is a frequent symptom in aquaporin-4-immunoglobulin-G-positive neuromyelitis optica spectrum disorders (AQP4-IgG-pos. NMOSD). Data on pain in myelin-oligodendrocyteglycoprotein- immunoglobulin-G autoimmunity with a clinical NMOSD phenotype (MOG-IgG-pos. NMOSD) are scarce. Objective: The objective of this paper is to investigate pain in MOG-IgG-pos. NMOSD, AQP4-IgG-pos. NMOSD and NMOSD without AQP4/MOG-IgG detection (AQP4/MOG-IgG-neg. NMOSD). Methods: Forty-nine MOG-IgG-pos. (n=14), AQP4-IgG-pos. (n=29) and AQP4/MOG-IgG-neg. (n=6) NMOSD patients were included in this cross-sectional baseline analysis from an ongoing observational study. We identified spinal cord lesions on magnetic resonance imaging, assessed pain by the painDETECT and McGill Pain questionnaires, quality of life by Short Form Health Survey, and depression by Beck Depression Inventory. Results: Twelve MOG-IgG-pos. NMOSD patients (86%), 24 AQP4-IgG-pos. NMOSD patients (83%), and all AQP4/MOG-IgG-neg. NMOSD patients (100%) suffered from pain. MOG-IgG-pos. NMOSD patients had mostly neuropathic pain and headache; AQP4-IgG-pos. and AQP4/MOG-IgG-neg. NMOSD patients had mostly neuropathic pain. A history of myelitis was less frequent in MOG-IgGpos. NMOSD than in AQP4-IgG-pos. NMOSD patients. Pain influenced quality of life in all patients. Thirty-six percent of patients with pain received pain medication; none of them were free of pain. Conclusions: Pain is a frequent symptom of patients with MOG-IgG-pos. NMOSD and is as important as in AQP4-IgG-pos. and AQP4/MOG-IgG-neg. NMOSD. Despite its impact on quality of life, pain is insufficiently alleviated by medication

Standardization of T1w/T2w Ratio Improves Detection of Tissue Damage in Multiple Sclerosis

Normal appearing white matter (NAWM) damage develops early in multiple sclerosis (MS) and continues in the absence of new lesions. The ratio of T1w and T2w (T1w/T2w ratio), a measure of white matter integrity, has previously shown reduced intensity values in MS NAWM. We evaluate the validity of a standardized T1w/T2w ratio (sT1w/T2w ratio) in MS and whether this method is sensitive in detecting MS-related differences in NAWM. T1w and T2w scans were acquired at 3 Tesla in 47 patients with relapsing-remitting MS and 47 matched controls (HC). T1w/T2w and sT1w/T2w ratios were then calculated. We compared between-group variability between T1w/T2w and sT1w/T2w ratio in HC and MS and assessed for group differences. We also evaluated the relationship between the T1w/T2w and sT1w/T2w ratios and clinically relevant variables. Compared to the classic T1w/T2w ratio, the between-subject variability in sT1w/T2w ratio showed a significant reduction in MS patients (0 <. 0.001) and HC < 0.001). However, only sT1w/T2w ratio values were reduced in patients compared to HC (p < 0.001). The sT1w/T2w ratio intensity values were significantly influenced by age, T2 lesion volume and group status (MS vs. HC) (adjusted R-2 = 0.30, p 0.001). We demonstrate the validity of the sT1w/T2w ratio in MS and that it is more sensitive to MS-related differences in NAWM compared to T1w/T2w ratio. The sT1w/T2w ratio shows promise as an easily-implemented measure of NAWM in MS using readily available scans and simple post-processing methods

Low-Density Granulocytes Are a Novel Immunopathological Feature in Both Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

Objective: To investigate whether low-density granulocytes (LDGs) are an immunophenotypic feature of patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD). Methods: Blood samples were collected from 20 patients with NMOSD and 17 patients with MS, as well as from 15 patients with Systemic Lupus Erythematosus (SLE) and 23 Healthy Donors (HD). We isolated peripheral blood mononuclear cells (PBMCs) with density gradient separation and stained the cells with antibodies against CD14, CD15, CD16, and CD45, and analyzed the cells by flow cytometry or imaging flow cytometry. We defined LDGs as CD14-CD15(high) and calculated their share in total PBMC leukocytes (CD45+) as well as the share of CD16(hi) LDGs. Clinical data on disease course, medication, and antibody status were obtained. Results: LDGs were significantly more common in MS and NMOSD than in HDs, comparable to SLE samples (median values HD 0.2%, MS 0.9%, NMOSD 2.1%, SLE 4.3%). 0/23 of the HDs, but 17/20 NMOSD and 11/17 MS samples as well as 13/15 SLE samples had at least 0.7 % LDGs. NMOSD patients without continuous immunosuppressive treatment had significantly more LDGs compared to their treated counterparts. LDG nuclear morphology ranged from segmented to rounded, suggesting a heterogeneity within the group. Conclusion: LDGs are a feature of the immunophenotype in some patients with MS and NMOSD

Uncovering convolutional neural network decisions for diagnosing multiple sclerosis on conventional MRI using layer-wise relevance propagation

Machine learning-based imaging diagnostics has recently reached or even superseded the level of clinical experts in several clinical domains. However, classification decisions of a trained machine learning system are typically non-transparent, a major hindrance for clinical integration, error tracking or knowledge discovery. In this study, we present a transparent deep learning framework relying on convolutional neural networks (CNNs) and layer-wise relevance propagation (LRP) for diagnosing multiple sclerosis (MS). MS is commonly diagnosed utilizing a combination of clinical presentation and conventional magnetic resonance imaging (MRI), specifically the occurrence and presentation of white matter lesions in T2-weighted images. We hypothesized that using LRP in a naive predictive model would enable us to uncover relevant image features that a trained CNN uses for decision-making. Since imaging markers in MS are well-established this would enable us to validate the respective CNN model. First, we pre-trained a CNN on MRI data from the Alzheimer's Disease Neuroimaging Initiative (n = 921), afterwards specializing the CNN to discriminate between MS patients and healthy controls (n = 147). Using LRP, we then produced a heatmap for each subject in the holdout set depicting the voxel-wise relevance for a particular classification decision. The resulting CNN model resulted in a balanced accuracy of 87.04% and an area under the curve of 96.08% in a receiver operating characteristic curve. The subsequent LRP visualization revealed that the CNN model focuses indeed on individual lesions, but also incorporates additional information such as lesion location, non-lesional white matter or gray matter areas such as the thalamus, which are established conventional and advanced MRI markers in MS. We conclude that LRP and the proposed framework have the capability to make diagnostic decisions of..

Association Between Fatigue and Motor Exertion in Patients With Multiple Sclerosis - a Prospective Study

Background: Fatigue in multiple sclerosis (MS) is conceived as a multidimensional construct. Objectives: This study aims to describe the changes of balance and gait parameters after 6 min of walking (6 MW) as potential quantitative markers for perceptions of state fatigue and trait fatigue in MS. Methods: A total of 19 patients with MS (17 with fatigue) and 24 healthy subjects underwent static posturography, gait analysis, and ratings of perceived exertion before and after 6 MW. Results: 6 MW was perceived as exhaustive, but both groups featured more dynamic comfortable speed walking after 6 MW. Shorter stride length at maximum speed and increased postural sway after 6 MW indicated fatigability of balance and gait in MS group only. While most changes were related to higher levels of perceived exertion after 6 MW (state fatigue), higher fatigue ratings (trait fatigue) were only associated with less increase in arm swing at comfortable speed. Further analysis revealed different associations of trait fatigue and performance fatigability with disability and motor functions. Performance fatigability was most closely related to the Expanded Disability Status Scale, while for trait fatigue, the strongest correlations were seen with balance function and handgrip strength. Conclusions: Fatigability of performance was closely related to perceptions of exertion after 6 MW (state fatigue) and disability in MS but distinct from fatigue ratings, conceived as trait fatigue. Our study identified postural sway, arm swing during gait, and hand grip strength as unexpected potential motor indicators of fatigue ratings in MS

Ketogenic diet and fasting diet as Nutritional Approaches in Multiple Sclerosis (NAMS): protocol of a randomized controlled study

BACKGROUND: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults that may lead to progressive disability. Since pharmacological treatments may have substantial side effects, there is a need for complementary treatment options such as specific dietary approaches. Ketone bodies that are produced during fasting diets (FDs) and ketogenic diets (KDs) are an alternative and presumably more efficient energy source for the brain. Studies on mice with experimental autoimmune encephalomyelitis showed beneficial effects of KDs and FDs on disease progression, disability, cognition and inflammatory markers. However, clinical evidence on these diets is scarce. In the clinical study protocol presented here, we investigate whether a KD and a FD are superior to a standard diet (SD) in terms of therapeutic effects and disease progression. METHODS: This study is a single-center, randomized, controlled, parallel-group study. One hundred and eleven patients with relapsing-remitting MS with current disease activity and stable immunomodulatory therapy or no disease-modifying therapy will be randomized to one of three 18-month dietary interventions: a KD with a restricted carbohydrate intake of 20-40 g/day; a FD with a 7-day fast every 6 months and 14-h daily intermittent fasting in between; and a fat-modified SD as recommended by the German Nutrition Society. The primary outcome measure is the number of new T2-weighted MRI lesions after 18 months. Secondary endpoints are safety, changes in relapse rate, disability progression, fatigue, depression, cognition, quality of life, changes of gut microbiome as well as markers of inflammation, oxidative stress and autophagy. Safety and feasibility will also be assessed. DISCUSSION: Preclinical data suggest that a KD and a FD may modulate immunity, reduce disease severity and promote remyelination in the mouse model of MS. However, clinical evidence is lacking. This study is the first clinical study investigating the effects of a KD and a FD on disease progression of MS

Disease modification in multiple sclerosis by flupirtine-results of a randomized placebo controlled phase II trial

Central nervous system inflammation and neurodegeneration are the pathophysiological hallmarks of multiple sclerosis (MS). While inflammation can readily be targeted by current disease modifying drugs, neurodegeneration is by far less accessible to treatment. Based on suggested additional neuroprotective capacities of the orally available non-opioid and centrally acting analgesic drug flupirtine maleate we hypothesized that treatment with flupirtine maleate might be beneficial in MS patients. The flupirtine as oral treatment in multiple sclerosis (FLORIMS) study was a multi-center, randomized and stratified, placebo-controlled double-blind phase II trial to investigate safety and efficacy in terms of clinical and radiographical activity of flupirtine maleate (300 mg per day) given orally for 12 months, add-on to interferon beta 1b subcutaneously in patients with relapsing remitting MS. Due to a substantial delay in recruitment, enrolment of patients was prematurely terminated after randomization of only 30 of the originally planned 80 patients. Of these, 24 regularly terminated study after 12 months of treatment. Data were analyzed as originally planned. Treatment with flupirtine maleate was overall well tolerated. We observed moderate and asymptomatic elevations of liver enzymes in several cases but no overt hepatotoxicity. Neither the intention to treat nor the per protocol analysis revealed any significant treatment effects of flupirtine maleate with respect to occurrence of MS relapses, disability progression, or development of new lesions on cranial MRI. However, substantial methodological limitations need to be considered when interpreting these results. In conclusion, the results of the FLORIMS study neither add further evidence to nor argue against the hypothesized neuroprotective or disease modifying effects of flupirtine maleate in MS