Examining the validity of the multiple-sclerosis walking scale-12 with Rasch analysis: Results from an Italian study.

BACKGROUND: The Multiple Sclerosis Walking Scale (MSWS-12) has showed good psychometric properties in reports exploring its validity using Classical Test Theory methods. Findings from recent studies using Item Response Theory methods advance the idea that some aspects of the MSWS-12 does not fully comply with some requirements of sound measurement. RESEARCH QUESTION: The present study investigated whether the measurement properties of the Italian version of the MSWS-12 met the assumptions of the Rasch model. METHODS: Sample consisted of 199 patients with a diagnosis of MS (50% female; Mean age (SD) = 48.15 (12.33)). Analyses were performed using both unidimensional and multidimensional Rasch modeling techniques. RESULTS: Rating scale for items assessing need for support when walking, and ability to run, showed significant functioning problems. A revision of the rating scale improved the measurement properties of these items. Items assessing need for support showed signs of multidimensionality and differential item functioning when controlling for patients' disease course and EDSS score. Additionally, included items did not appear to cover the full range of impairment as observed in the sample. SIGNIFICANCE: Emerging findings are consistent with those from previous studies in highlighting the need for a revision of the current content of the MSWS-12, and the inclusion of new items assessing impairment at the lower end of the disability continuum.

Italian validation of the 12-item multiple sclerosis walking scale.

Objective. Gait impairment is commonly in people with multiple sclerosis (MS). The 12-item MS walking scale (MSWS-12) assesses patients' measurement of walking quality. The aim of this study was to cross-culturally adapt and validate the MSWS-12 for the Italian population with MS. Methods. Six MS out-patient clinics across Italy enrolled subjects between June 2013 and December 2013. Construct validity of MSWS-12 was determined by examining correlations with the Italian version of the EDSS, the timed 25-foot walk (T25FW), and the Fatigue Severity Scale (FSS). Results. 321 MS subjects were enrolled. Mean age was 47.55 years and mean disease duration was 13.8 years. Mean EDSS score was 4.46. 185 subjects had a relapsing-remitting course, 92 were secondary progressive, 43 were primary progressive, and 1 had a clinically isolated syndrome. The mean total score of the MSWS-12 was 49.6 (SD: 31) with values ranging between 0 and 100. Correlations between the MSWS-12 with age, disease duration, and disease course were found but not with gender. Values of the MSWS-12/IT were significantly related to EDSS (0.71), to the T25FW (0.65), and to the FSS (0.51). Conclusion. MSWS-12/IT has been adapted and validated, it is a reliable and reproducible scale for Italian patients with MS.

Growth hormone and disease severity in early stage of multiple sclerosis.

Evidence suggests that neurohormones such as GH and IGF-I are involved in the neuroreparative processes in multiple sclerosis (MS). GH and IGF-I blood levels in naïve MS patients with different disease courses were investigated in this study. Serum GH and IGF-I in untreated MS patients (n = 64), healthy controls (HC, n = 62), and patients affected by other neurological diseases (OND, n = 46) were evaluated with a solid-phase-enzyme-labeled-chemiluminescent-immunometric assay. No differences were detected in GH across MS, OND, and HC (MS = 0.87 ± 1.32 ng/mL; OND = 1.66 ± 3.7; and HC = 1.69 ± 3.35; P = 0.858) when considering gender, disease duration, and disease course. However, GH was lower (P = 0.007) in patients with more severe disease (expanded disability scale score, EDSS ≥ 4.0) compared with milder forms (EDSS < 4). IGF-I l did not differ across the 3 groups (P = 0.160), as far as concern disease course, disability, and gender were. Lower IGF-I levels were detected in subjects older than 50 years compared to younger ones for all 3 groups. Lower GH was detected in patients with more severe MS, and age was confirmed as the main factor driving IGF-I levels in all subjects. These findings, relying on the natural course of the disease, could help in shedding lights on the mechanisms involved in autoreparative failure associated with poorer prognosis in MS.

Oxidative imbalance in different neurodegenerative diseases with memory impairment.

BACKGROUND: Byproducts of oxidative metabolic reactions could play a role in the pathogenesis of several neurodegenerative diseases (ND) including Alzheimer's disease (AD). We designed a study aimed at investigating a large set of oxidative and antioxidant markers in a sample of patients affected by different forms of dementia or memory impairment. METHODS: Serum levels of coenzyme Q(10), malondialdehyde (MDA), the total, oxidized and reduced forms of glutathione (GStot, GSSG and GSH, respectively), reactive oxygen species, anti-oxidized low-density lipoprotein antibodies and antioxidant power (PAO) were investigated in patients affected by AD, mild cognitive impairment, dementia with Lewy bodies and Parkinson's disease with dementia. The patient sample (n = 66) was compared with healthy subjects (HC; n = 62), and a comparison across pathological subgroups was also performed. A multivariate logistic regression model was implemented in order to calculate an algorithm model for predicting the risk of developing a neurodegenerative disorder. RESULTS: The comparison between the memory deficit (MD) group and HC showed a significant difference for MDA (MD: 6.3 ± 2.8 µg/l; HC: 9.1 ± 4.9 µg/l; p = 1.7 × 10(-6)), GStot (MD: 260.4 ± 62.6 mg/l; HC: 306.5 ± 60.7 mg/l; p = 2.2 × 10(-5)), GSH (MD: 208.9 ± 68.4 mg/l; HC: 295.3 ± 101.3 mg/l; p = 2.2 × 10(-7)) and PAO (MD: 1,066.5 ± 247.7 µmol; HC: 954.9 ± 200.4 µmol; p = 0.8 × 10(-3)). By contrast, no differences in the levels of the studied markers were detected across the different forms of ND. An older age, higher levels of PAO, lower levels of GSH and MDA and the use of cardiovascular or antidepressant drugs were the most important factors associated with the carrier ship of neurodegenerative disorder. CONCLUSION: To our knowledge, this is the first study reporting similar oxidative imbalance in different forms of memory impairment, regardless of the specific etiology. Low GSH levels could be considered as a favorable factor in ND; at the same time it could be suggested that higher levels of PAO represent a counteracting mechanism against an increased oxidative stress. The association between vascular risk factors, depressive status and cognitive impairment is in line with findings in the literature.

HLA-DRB1 polymorphisms distribution in chronic dysimmune polyneuropathy.

The frequency of HLA-DRB1*15 polymorphism, which is strongly associated to multiple sclerosis, was investigated in 84 adult patients with chronic dysimmune polyneuropathy and 272 healthy controls. No significant differences were detected between cases and controls and, among patients, according to gender, peripheral nerve antigen antibody seropositivity, and electrophysiological features. A trend towards an increase of HLA-DRB1*11 in anti-MAG neuropathy was detected.

A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis.

A sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality of life. Clinical and biochemical evaluations were serially performed. Protein concentration of beta-endorphins (BE) and mRNA levels and allelic variants of the mu-opiod receptor gene (OPRM1) were analyzed. Five dropouts and two major adverse events occurred. The remaining adverse events did not interfere with daily living. Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.

Procedure for the quantitative evaluation of motor disturbances in cerebellar ataxic patients.

Cerebellar ataxia is a complex motor disturbance that involves the planning and execution of movements and reduces movement accuracy and co-ordination. The quantification of ataxic signs is commonly realised through visual examination of motor tasks performed by the patient and assignment of scores to specific items composing the international co-operative ataxia rating scale (ICARS). The present work studied an experimental procedure to characterise specific aspects of motor disturbances in ataxia objectively. Four tests belonging to the ICARS were considered: walking, knee-tibia test, finger-to-nose and finger-to-finger test. Through a kinematic analysis performed during the above tests, specific indices were defined to quantify velocity, linearity, asymmetry, tremor, instability and smoothness of movement or posture. The procedure was applied to five patients with cerebellar ataxia and to ten healthy adult subjects. Results demonstrated that the patients moved significantly more slowly than the healthy subjects (0.67 against 0.97m s(-1) and 0.81 against 1.02 m s(-1), respectively, for straight walk and finger-to-nose tests) and showed poorer linearity and smoothness behaviour. Velocity, linearity, tremor, smoothness and instability indices showed moderate to good correlation with the corresponding ICARS score. Some of these indices can separately evaluate aspects that are combined in single ICARS subscores. It is concluded that the combination of clinical assessments and instrumental evaluations allows a better insight into ataxic patients' motor disturbances and is a useful tool for the definition and follow-up of rehabilitation programmes.

Stiff person syndrome does not always occur with maternal passive transfer of GAD65 antibodies.

The authors report the presence of high titer antibodies to glutamic acid decarboxylase (anti-GAD65) until age 24 months in two asymptomatic newborns of a woman with stiff-person syndrome (SPS). No signs of SPS were detectable in the two children at ages 6 and 8 years. This observation indicates that other cofactors are involved in the pathogenesis of SPS.

Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency.

Two brothers had late-onset progressive ataxia, cerebellar atrophy, and hypergonadotropic hypogonadism associated with coenzyme Q10 (CoQ10) deficiency in skeletal muscle. Both patients improved on high-dose CoQ10 supplementation, stressing the importance of CoQ10 deficiency in the differential diagnosis of cerebellar ataxia, even when onset is late.

Beta endorphin concentrations in PBMC of patients with different clinical phenotypes of multiple sclerosis.

The possible link between the opioid peptide beta endorphin and the heterogeneity of the clinical course of multiple sclerosis (MS) was investigated. Peripheral blood mononuclear cells (PBMC) concentrations of beta endorphin were measured in 50 patients in different phases of MS. Thirty nine patients also underwent post-contrast magnetic resonance imaging of the brain. Among MS forms, the highest beta endorphin concentrations were found in PBMC from patients with relapsing remitting MS and the lowest in patients with the progressive forms. Average beta endorphin concentrations were lower, although not significantly, in patients with than in those without magnetic resonance imaging enhanced lesions. These data suggest that beta endorphin may have a role in the downregulation of the inflammatory process.

Cytokines and immunity in multiple sclerosis: the dual signal hypothesis.

Multiple sclerosis (MS) is considered an immune-mediated disease of the central nervous system (CNS) sustained by a chronic inflammatory process leading to patchy demyelination and axonal loss. However, the inflammatory triggering event as well as the target of the pathogenic process in MS are still partially unknown. We report evidence that a 'local' inflammatory process occurring in the CNS (considered as a reaction of blood vessels in vascularized living tissue to a local injury leading to the accumulation of fluid and blood cells) along with a concomitant, but possibly unrelated, peripheral inflammatory event may trigger a CNS-specific autoimmune reaction cascade sustaining the MS pathogenesis. In the CNS, inflammatory mediators (mainly cytokines) act either as regulatory (i.e. activation of glial cells, shaping the autoimmune response) or effector molecules (i.e. myelinotoxicity, oligodendrotoxicity). In the periphery, inflammatory cytokines induce, in a bystander fashion, activation of monocytes and T cells. Among this latter cell population there are myelin-specific T cells belonging to the normal 'autoimmune' repertoire that home to the CNS where they may trigger the continuous recruitment of effector cells (macrophages) from the periphery. The concept that two concomitant, but possibly unrelated, inflammatory events, occurring in the CNS and in the periphery, represent the crucial elements sustaining MS, might reveal a more comprehensive view (dual signal hypothesis) of the entire etiopathogenic process underlying this disease.

Beta-endorphin concentrations in peripheral blood mononuclear cells of patients with multiple sclerosis: effects of treatment with interferon beta.

CONTEXT: It has been reported that the opioid peptide beta-endorphin (BE) has immunosuppressive effects. Interferon beta (IFN-beta) is a well-established therapy for multiple sclerosis (MS), but immunological mechanisms underlying its beneficial effects in MS are partially undefined. OBJECTIVES: To determine BE levels in peripheral blood mononuclear cells (PBMCs) of patients with relapsing-remitting MS during different phases of disease activity and the possible modulating effects of IFN-beta treatment on PBMC BE synthesis in patients with MS. DESIGN: We measured BE levels in blood samples collected from 6 patients with MS who had not experienced clinical changes during the previous 3 months (patients with stable MS) and from 7 patients with MS during a clinical relapse. We also surveyed BE levels in PBMC samples from 8 patients with MS before treatment and for 6 months after the beginning of IFN-beta administration. The control group was 13 healthy subjects. RESULTS: Low PBMC BE levels were detected in patients with stable MS and in those entering IFN-beta treatment compared with control subjects. Increased BE concentrations were observed in MS patients experiencing a clinical relapse compared with patients with stable MS. During IFN-beta treatment, the levels of BE in PBMC samples from patients with MS increased significantly (after 1 month, P =.02; after 3 months, P =.007; and after 6 months, P =.16). CONCLUSIONS: A reduction of BE levels was present in patients with clinically inactive MS. Treatment with IFN-beta seems to induce an increase of this opioid in PBMCs of MS patients. The increase of BE concentration during a clinical relapse may represent a possible control mechanism aimed at counterbalancing the inflammatory phase of the disease. Arch Neurol. 2000;57:1178-1181

Immunological markers in multiple sclerosis.

Multiple sclerosis (MS) is characterized by the presence in the central nervous system (CNS) of perivascular inflammatory infiltrates containing, among others, autoreactive T cells and activated macrophages. These observations indicate that MS is a T cell-mediated CNS-confined chronic inflammatory demyelinating disease in which the ultimate effector cell is the activated macrophage. The inflammatory process, leading to patchy demyelination and axonal loss, is mainly sustained by pro-inflammatory cytokines that, along with chemokines, adhesion molecules and metalloproteases, modulate at different levels the pathogenic process underlying MS. Due to their central role in MS pathogenesis, "inflammatory" molecules might represent suitable peripheral markers of disease (disease-trait) and/or disease activity (state-trait). However, reliable disease-trait or state-trait immunological markers for MS have not yet been identified. The intrinsic characteristics of these molecules (i.e. autocrine/paracrine activity, short half-life, redundancy) may in part explain their inconsistency as disease markers. Additionally, the unreliability of methodologies and the lack of careful patient stratification can also, at least in part, account for the unsatisfactory results so far obtained.

Occurrence of thyroid autoimmunity in relapsing remitting multiple sclerosis patients undergoing interferon-beta treatment.

We analyzed the titer of antithyroid autoantibodies (Abs) and thyroid function in 17 multiple sclerosis (MS) patients undergoing interferon-beta (IFN-beta) treatment and in 40 MS control patients. Basal evaluation revealed normal thyroid function in all patients. Abs were detected in 5 IFN-beta-treated patients (29%) and in 4 MS control patients (10%). Our results indicate that IFN-beta treatment may lead to thyroid autoimmunity. We therefore recommend periodic evaluations of antithyroid Abs and thyroid functionality in IFN-beta-treated MS patients.