Relapsing-remitting and secondary-progressive multiple sclerosis patients differ in decoding others' emotions by their eyes.

BACKGROUND AND PURPOSE: Difficulties in emotion processing and social cognition identified in multiple sclerosis (MS) patients have a potential impact on their adaptation to the social environment. We aimed to explore the neural correlates of emotion recognition in MS and possible differences between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) patients by the Reading the Mind in the Eyes test (RMEt). METHODS: A total of 43 MS patients (27 RRMS, 16 SPMS) and 25 matched healthy controls (HC) underwent clinical assessments, RMEt, and a high-resolution T1-weighted 3-T magnetic resonance imaging (MRI) scan. The number of correct answers on the RMEt was compared between groups. T1-weighted volumes were processed according to an optimized voxel-based morphometry (VBM) protocol to obtain gray matter (GM) maps. Voxelwise analyses were run to assess potential associations between RMEt performance and regional GM volumes. RESULTS: Taken altogether, MS patients reported significantly lower performance on the RMEt compared to HC. When dividing the patients into those with RRMS and those with SPMS, only the latter group was found to perform significantly worse than HC on the RMEt. VBM analysis revealed significant association between RMEt scores and GM volumes in several cortical (temporoparieto-occipital cortex) and subcortical (hippocampus, parahippocampus, and basal ganglia) brain regions, and in the cerebellum in SPMS patients only. CONCLUSIONS: Results suggest that, in addition to other clinical differences between RRMS and SPMS, the ability to recognize others' emotional states may be affected in SPMS more significantly than RRMS patients. This is supported by both behavioral and MRI data.

Dynamic changes of MMP-9 plasma levels correlate with JCV reactivation and immune activation in natalizumab-treated multiple sclerosis patients.

The aim of the study was to investigate the changes of matrix metalloproteinase (MMP)-2 and MMP-9 plasma levels during natalizumab treatment and their correlation with JC virus (JCV) reactivation and T-lymphocyte phenotypic modifications in peripheral blood samples from 34 relapsing-remitting multiple sclerosis (RRMS) patients. MMP-9 levels were assessed by zymography in plasma samples. JCV-DNA was detected through quantitative real time PCR in plasma samples. T-lymphocyte phenotype was assessed with flow cytometry. MMP-9 plasma levels resulted increased from 12 to 24 natalizumab infusions. Stratifying plasma samples according to JCV-DNA detection, MMP-9 plasma levels were significantly increased in JCV-DNA positive than JCV-DNA negative samples. MMP-9 plasma levels resulted positively correlated with JCV viral load. CD4 immune senescence, CD8 immune activation and CD8 effector percentages were positively correlated to MMP-9 plasma levels, whereas a negative correlation between CD8 naïve percentages and MMP-9 plasma levels was found. Our data indicate an increase of MMP-9 plasma levels between 12 and 24 natalizumab infusions and a correlation with JCV-DNA detection in plasma, T-lymphocyte immune activation and senescence. These findings could contribute to understand PML pathogenesis under natalizumab treatment, suggesting a potential role of MMP-9 as a predictive marker of PML in RRMS patients.

H-magnetic resonance spectroscopy: diagnostic tool in recurrent headache in systemic lupus erythematosus. A case report.

We describe serial MR-spectroscopy studies in a patient with systemic lupus erythematosus and headache. We used MR-spectroscopy to monitor disease activity during periods with and without headache. MR-spectroscopy investigates metabolic alterations and was used to explore the pathophysiological mechanism involved in the complications of systemic lupus erythematosus. Our patient underwent serial conventional MRI and MR-spectroscopy at times of controlled and uncontrolled headache, with or without visual aura. MR-spectroscopy showed an increase in the choline/creatine ratio in thalamus and posterior white matter only during periods of uncontrolled headache with visual aura. Conventional MRI scans were normal at all times. MR-spectroscopy should be used in the diagnosis and follow-up of headache in patients with systemic lupus erythematosus.

Disruption of neurite morphology parallels MS progression.

OBJECTIVES: To apply advanced diffusion MRI methods to the study of normal-appearing brain tissue in MS and examine their correlation with measures of clinical disability. METHODS: A multi-compartment model of diffusion MRI called neurite orientation dispersion and density imaging (NODDI) was used to study 20 patients with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS), and 20 healthy controls. Maps of NODDI were analyzed voxel-wise to assess the presence of abnormalities within the normal-appearing brain tissue and the association with disease severity. Standard diffusion tensor imaging (DTI) parameters were also computed for comparing the 2 techniques. RESULTS: Patients with MS showed reduced neurite density index (NDI) and increased orientation dispersion index (ODI) compared with controls in several brain areas (p < 0.05), with patients with SPMS having more widespread abnormalities. DTI indices were also sensitive to some changes. In addition, patients with SPMS showed reduced ODI in the thalamus and caudate nucleus. These abnormalities were associated with scores of disease severity (p < 0.05). The association with the MS functional composite score was higher in patients with SPMS compared with patients with RRMS. CONCLUSIONS: NODDI and DTI findings are largely overlapping. Nevertheless, NODDI helps interpret previous findings of increased anisotropy in the thalamus of patients with MS and are consistent with the degeneration of selective axon populations.

Safety and Efficacy of Dimethyl Fumarate in Multiple Sclerosis: An Italian, Multicenter, Real-World Study.

BACKGROUND: Two phase III trials have demonstrated the clinical and radiological efficacy of delayed-release dimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis (RRMS). However, data on its safety and effectiveness in real-world practice are still limited. OBJECTIVES: The aim of our study was to explore the safety and tolerability profile of DMF in RRMS. We also tried to identify individual variables associated with better clinical and radiological outcomes. METHODS: We collected the clinical and magnetic resonance imaging (MRI) data of patients with RRMS who started DMF between 2012 and 2017 in seven MS clinics in central Italy. We first evaluated DMF discontinuation rates and the incidence of adverse events and side effects. We then assessed the annualized relapse rate (ARR), the number of patients with clinical relapses or disability worsening and the presence of radiological activity. Third, we investigated which baseline variables were associated with clinical and radiological outcomes. RESULTS: We collected data for 1089 patients with a mean on-treatment follow-up of 17 ± 8 months; 331 (30.4%) of these patients were treatment naïve. In total, 210 (19.5%) patients discontinued DMF mainly because of poor tolerability (n = 103) and disease activity (n = 63), and 166 (16.5%) patients presented with lymphopenia. The ARR reduced from 0.55 to 0.13. Mean change in Expanded Disability Status Scale (EDSS) score was 0.08 ± 0.44 per year. The occurrence of clinical and/or radiological activity during follow-up was associated with younger age [hazard ratio (HR) 0.97; p < 0.001], higher EDSS score (HR 1.18; p < 0.001), greater number of Gd-enhancing lesions at baseline scan (HR 1.14; p = 0.003) and prior exposure to MS treatments (HR 1.43; p = 0.02). CONCLUSION: This post-marketing data confirms the short-term safety, tolerability and effectiveness of DMF, supporting its use as an early treatment in MS.

Abortion induces reactivation of inflammation in relapsing-remitting multiple sclerosis.

OBJECTIVE: To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion. METHODS: An independent, multicentre retrospective study was conducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covariance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit. RESULTS: From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63±0.74) was significantly increased (p=0.037) compared with the preconception year (0.50±0.71) as well as the postabortion mean number of new Gd+ lesions (0.77±1.40 vs 0.39±1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treatment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, discontinuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion. CONCLUSIONS: Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly.

Fingolimod vs dimethyl fumarate in multiple sclerosis: A real-world propensity score-matched study.

OBJECTIVE: To directly compare fingolimod (FNG) and dimethyl fumarate (DMF) on no evident disease activity (NEDA) status in patients with relapsing-remitting multiple sclerosis (RRMS) from 7 multiple sclerosis outpatient clinics in Central Italy. METHODS: We analyzed data of patients with RRMS who started an oral agent, namely DMF or FNG, either as first treatment (naives) or after switching from self-injectable drugs (switchers). We performed a propensity score (PS)-based nearest-neighbor matching within a caliper of 0.05 to select patients with homogeneous baseline characteristics. Pairwise censoring was adopted to adjust for difference in length of follow-up between the 2 treatment groups. Comparisons were then conducted in matched samples with Cox models (stratified by center) with NEDA-3 as the main outcome. NEDA-3 was defined as no relapses, no disability worsening, and no MRI activity. RESULTS: Overall, 483 and 456 patients eligible for analysis started on FNG and DMF, respectively. The PS-matching procedure retained a total of 550 patients (275 per group). After a median on-study follow-up of 18 months, the proportions of patients with NEDA-3 were similar (FNG 73%, DMF 70%; hazard ratio [HR] 0.74, p = 0.078). Subgroup analyses showed a comparable effectiveness of the 2 drugs in naives (n = 170, HR 1.15, p = 0.689), whereas FNG was superior to DMF in the achievement of NEDA-3 status among switchers (n = 380, HR 0.57, p = 0.007). CONCLUSION: We found no significant difference between FNG and DMF on NEDA-3 status, while subgroup analyses suggest the superiority of FNG over DMF in patients switching from self-injectable drugs. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with RRMS, DMF and FNG have comparable efficacy in treatment-naive patients and that FNG is superior to DMF in patients switching from self-injectable drugs.

JC Virus-DNA Detection Is Associated with CD8 Effector Accumulation in Peripheral Blood of Patients with Multiple Sclerosis under Natalizumab Treatment, Independently from JC Virus Serostatus.

Although natalizumab (anti-α4 integrin) represents an effective therapy for relapsing remitting multiple sclerosis (RRMS), it is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). The aim of this study was to explore natalizumab-induced phenotypic changes in peripheral blood T-lymphocytes and their relationship with JCV reactivation. Forty-four patients affected by RRMS were enrolled. Blood and urine samples were classified according to natalizumab infusion number: 0 (N0), 1-12 (N12), 13-24 (N24), 25-36 (N36), and over 36 (N > 36) infusions. JCV-DNA was detected in plasma and urine. T-lymphocyte phenotype was evaluated with flow cytometry. JCV serostatus was assessed. Ten healthy donors (HD), whose ages and sexes matched with the RRMS patients of the N0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared to JCV-DNA negative patients (JCV-) (p < 0.01 and p < 0.001, resp.). Patients with CD8 E percentages above 10.4% tended to show detectable JCV-DNA in plasma and/or urine (ROC curve p = 0.001). The CD8 E was increased when JCV-DNA was detectable in plasma or urine, independently from JCV serology, for N12 and N24 groups (p < 0.01). As long as PML can affect RRMS patients under natalizumab treatment with a negative JCV serology, the assessment of CD8 E could help in the evaluation of JCV reactivation.

The Italian validation of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS) and the application of the Cognitive Impairment Index scoring procedure in MS patients.

Cognitive dysfunction occurs in almost 50-60% of patients with multiple sclerosis (MS) even in early stages of the disease and affects different aspects of patient's life. Aims of the present study were (1) to introduce and validate an Italian version of the minimal assessment of cognitive functions in MS (MACFIMS) battery and (2) to propose the use of the Cognitive Impairment Index (CII) as a scoring procedure to define the degree of impairment in relapsing-remitting (RRMS) and secondary-progressive (SPMS) patients. A total of 240 HC and 123 MS patients performed the Italian version of the MACFIMS composed by the same tests as the original except for the Paced Auditory Serial Addition Test. The CII was derived for each score of the 11 scales for participants of both groups. The results of the study show that cognitive impairment affects around 50% of our sample of MS patients. In RRMS group, only the 15.7% of patients reported a severe impairment, while in the group of SPMS, the 51.4% of patients felt in the "severely impaired" group. Results are in line with previously reported percentages of impairment in MS patients, showing that the calculation of the CII applied to the Italian version of the MACFIMS is sensitive and reliable in detecting different degrees of impairment in MS patients.

Sativex in resistant multiple sclerosis spasticity: Discontinuation study in a large population of Italian patients (SA.FE. study).

BACKGROUND: The approval of Sativex for the management of multiple sclerosis (MS) spasticity opened a new opportunity to many patients. In Italy, the healthcare payer can be fully reimbursed by the involved pharma company with the cost of treatment for patients not responding after a 4 week (28 days) trial period (Payment by Results, PbR), and 50% reimbursed with the cost of 6 weeks (42 days) treatment for other patients discontinuing (Cost Sharing, CS). The aim of our study was to describe the Sativex discontinuation profile from a large population of spasticity treated Italian MS patients. METHODS: We collected data of patients from 30 MS centres across the country starting Sativex between January 2014 and February 2015. Data were collected from the mandatory Italian Medicines Agency (AIFA) web-registry. Predictors of treatment discontinuation were assessed using a multivariate Cox proportional regression analysis. RESULTS: During the observation period 631 out of 1597 (39.5%) patients discontinued Sativex. The Kaplan-Meier estimates curve showed that 333 patients (20.8%) discontinued treatment at 4 weeks while 422 patients (26.4%) discontinued at 6 weeks. We found after adjusted modeling that a higher NRS score at T1 (adjHR 2.23, 95% 2.07-2.41, p<0.001) and a lower baseline NRS score (adjHR 0.51 95% CI 0.46-0.56, p<0.001) were predictive of treatment discontinuation. CONCLUSION: These data show that the first 6 weeks are useful in identifying those patients in which Sativex could be effective, thus avoiding the cost of longer term evaluation.

Identifying Relapses in Multiple Sclerosis Patients through Administrative Data: A Validation Study in the Lazio Region, Italy.

BACKGROUND: Relapse is frequently considered an outcome measure of disease activity in relapsing-remitting multiple sclerosis (MS). The objectives of this study were to identify relapse episodes in patients with MS in the Lazio region using health administrative databases and to evaluate the validity of the algorithm using patients enrolled at MS treatment centers. METHODS: MS cases were identified in the period between January 1, 2006 and December 31, 2009 using data from regional Health Information Systems (HIS). An algorithm based on HIS was used to identify relapse episodes, and patients recruited at MS centers were used to validate the algorithm. Positive and negative predictive values (PPV, NPV) and the Cohen's kappa coefficient were calculated. RESULTS: The overall MS population identified through HIS consisted of 6,094 patients, of whom 67.1% were female and the mean age was 41.5. Among the MS patients identified by the algorithm, 2,242 attended the centers and 3,852 did not. The PPV was 58.9%, the NPV was 76.3%, and the kappa was 0.36. CONCLUSIONS: The proposed algorithm based on health administrative databases does not seem to be able to reliably detect relapses; however, it may be a helpful tool to detect healthcare utilization, and therefore to identify the worsening condition of a patient's health.

NMR-based metabolomic approach to study urine samples of chronic inflammatory rheumatic disease patients.

The nuclear magnetic resonance (NMR)-based metabolomic approach was used as analytical methodology to study the urine samples of chronic inflammatory rheumatic disease (CIRD) patients. The urine samples of CIRD patients were compared to the ones of both healthy subjects and patients with multiple sclerosis (MS), another immuno-mediated disease. Urine samples collected from 39 CIRD patients, 25 healthy subjects, and 26 MS patients were analyzed using 1H NMR spectroscopy, and the NMR spectra were examined using partial least squares-discriminant analysis (PLS-DA). PLS-DA models were validated by a double cross-validation procedure and randomization tests. Clear discriminations between CIRD patients and healthy controls (average diagnostic accuracy 83.5 ± 1.9%) as well as between CIRD patients and MS patients (diagnostic accuracy 81.1 ± 1.9%) were obtained. Leucine, alanine, 3-hydroxyisobutyric acid, hippuric acid, citric acid, 3-hydroxyisovaleric acid, and creatinine contributed to the discrimination; all of them being in a lower concentration in CIRD patients as compared to controls or to MS patients. The application of NMR metabolomics to study these still poorly understood diseases can be useful to better clarify the pathologic mechanisms; moreover, as a holistic approach, it allowed the detection of, by means of anomalous metabolic traits, the presence of other pathologies or pharmaceutical treatments not directly connected to CIRDs, giving comprehensive information on the general health state of individuals. Graphical abstract NMR-based metabolomic approach as a tool to study urine samples in CIRD patients with respect to MS patients and healthy controls.

Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in non-responders and in treatment-naïve patients with multiple sclerosis.

In this independent, multicentre post-marketing study we directly compared the effectiveness of natalizumab (NTZ), fingolimod (FNG) and self-injectable drugs (INJ), in non-responders to first immunomodulating treatment and in highly active treatment-naïve patients with multiple sclerosis. As main outcome measure we considered the proportions of patients with no evidence of disease activity (NEDA-3), defined as absence of relapses, disability worsening and radiological activity. A total of 567 non-responders to interferon beta (IFNB) or glatiramer acetate (GA) [dataset A] and 216 highly active treatment-naïves [dataset B] were followed up to 24 months from the beginning of NTZ, FNG or INJ, i.e. switching from IFNB to GA or viceversa (in the case of non-responders) or starting high-dose IFNB (in the case of highly active treatment-naïves). Propensity score matching in a 1:1:1 ratio was used to select only patients with similar baseline characteristics, retaining 330 and 120 patients in dataset A and B, respectively. In dataset A, the 24-month proportion with NEDA-3 was greater in both NTZ group (67%) and FNG group (42%) than in INJ group (35%) (p ≤ 0.016); however, NTZ was superior to FNG in promoting the attainment of NEDA-3 status (p = 0.034). In dataset B, the 24-month proportion with NEDA-3 was greater in NTZ group (75%) and FNG group (67%) than in INJ group (40%), but the small cohort sizes most likely prevented the detection of any statistically significant difference. Our study provides real-world evidence that NTZ was more effective than both FNG and INJ in non-responders, while it could seem that, in highly active treatment-naïves, NTZ was as effective as FNG and both were superior to INJ.

Natalizumab Affects T-Cell Phenotype in Multiple Sclerosis: Implications for JCV Reactivation.

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects.

Anti-GAPDH Autoantibodies as a Pathogenic Determinant and Potential Biomarker of Neuropsychiatric Diseases.

OBJECTIVE: To investigate the potential role of circulating autoantibodies specific to neuronal cell surface antigens in the pathophysiology of neuropsychiatric disorders. METHODS: Two different kinds of immunoscreening approaches were used to identify autoantigens associated with neuropsychiatric disorders in the serum of patients with schizophrenia. The presence of autoantibodies specific to the identified autoantigens was then tested in patients with various psychiatric disorders and in patients with systemic lupus erythematosus (SLE) and concomitant neuropsychiatric manifestations. Furthermore, the potential pathogenic role of these autoantibodies was assessed both in vitro and in vivo. RESULTS: GAPDH was identified as a novel autoantigen associated with neuropsychiatric disorders. Serum anti-GAPDH IgG was detected in the serum of 51% of patients with schizophrenia and 50% of patients with major depression. Moreover, SLE patients with comorbid psychiatric manifestations presented significantly higher serum levels of anti-GAPDH antibodies than did SLE patients without psychiatric manifestations (P = 0.004 by chi-square test). Of note, a significant positive correlation (R = 0.48, P = 0.0049, by Spearman's rank correlation test) was found between the levels of serum anti-GAPDH antibodies and cognitive dysfunction in patients with SLE. In vitro analysis of the effects of purified human anti-GAPDH autoantibodies on SH-SY5Y cells showed an immediate neurite retraction. Finally, in vivo administration of anti-GAPDH autoantibodies in the right cerebral ventricle of C57BL/6J mice resulted in specific behavioral changes associated with a detrimental cognitive and emotional profile. CONCLUSION: Overall, these data suggest that anti-GAPDH autoantibodies play a role in the pathogenesis of neuropsychiatric disorders, thus representing a potentially promising tool for the screening of individual vulnerability to these disabling conditions.

A 12-month prospective, observational study evaluating the impact of disease-modifying treatment on emotional burden in recently-diagnosed multiple sclerosis patients: The POSIDONIA study.

INTRODUCTION: Depression and anxiety are common among patients with multiple sclerosis (MS) and are frequently present at the time of MS diagnosis. METHODS: POSIDONIA was a 12-month, observational, prospective study conducted in Italy to evaluate the impact of disease-modifying treatment (DMT) on emotional burden in patients with recently-diagnosed MS. The Hospital Anxiety and Depression Scale (HADS), specifically HADS anxiety (HADS-A) and depression (HADS-D) subscale scores, the Short-Form 36 Health Survey (SF-36) and the Impact of Event Scale - Revised (IES-R) were used to measure patient-reported outcomes. The Hamilton Depression Rating Scale (HDRS), HDRS-17, was used as a measure of healthcare provider-reported outcomes. The primary study outcome was change from baseline in feelings of anxiety and depression over 12months (via HADS). RESULTS: Of 250 enrolled patients, 222 (88.8%) completed the study. At baseline, mean HADS total, HADS-A and HADS-D subscale scores were within the normal range. There were no significant changes over time in mean HADS total and HADS-A and HADS-D subscale scores, although the subgroup of patients with baseline scores indicative of anxiety or depression tended to improve over time. Both the HDRS and IES-R total scores improved over time, but there were no statistically significant changes in SF-36. CONCLUSION: In the patient population of the POSIDONIA study depression and anxiety were present in a minority of patients thus not allowing to detect the impact of starting DMT. However DMT appears to have a positive effect in patients with measurable anxiety or depression at baseline.

Prevalence of multiple sclerosis in the Lazio region, Italy: use of an algorithm based on health information systems.

Compared with other areas of the country, very limited data are available on multiple sclerosis (MS) prevalence in Central Italy. We aimed to estimate MS prevalence in the Lazio region and its geographical distribution using regional health information systems (HIS). To identify MS cases we used data from drug prescription, hospital discharge and ticket exemption registries. Crude, age- and gender-specific prevalence estimates on December 31, 2011 were calculated. To compare MS prevalence between different areas within the region, we calculated age- and gender-adjusted prevalence and prevalence ratios using a multivariate Poisson regression model. Crude prevalence rate was 130.5/100,000 (95 % CI 127.5-133.5): 89.7/100,000 for males and 167.9/100,000 for females. The overall prevalence rate standardized to the European Standard Population was 119.6/100,000 (95 % CI 116.8-122.4). We observed significant differences in MS prevalence within the region, with estimates ranging from 96.3 (95 % CI 86.4-107.3) for Latina to 169.6 (95 % CI 147.6-194.9) for Rieti. Most districts close to the coast showed lower prevalence estimates compared to those situated in the eastern mountainous area of the region. In conclusion, this study produced a MS prevalence estimate at regional level using population-based health administrative databases. Our results showed the Lazio region is a high-risk area for MS, although with an uneven geographical distribution. While some limitations must be considered including possible prevalence underestimation, HIS represent a valuable source of information to measure the burden of SM, useful for epidemiological surveillance and healthcare planning.

No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon ß1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study).

BACKGROUND: A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis. OBJECTIVES: The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis. METHODS: This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon ß1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months. RESULTS: A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months. CONCLUSIONS: Our results suggest that the combination of atorvastatin and interferon ß1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis.

Attention-related changes in short-term cortical plasticity help to explain fatigue in multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), pathophysiology of fatigue is only partially known. OBJECTIVE: The aim of this study was to investigate whether the attention-induced modulation on short- and long-term cortical plasticity mechanisms in primary motor area (M1) is abnormal in patients with MS-related fatigue. METHODS: All participants underwent 5-Hz repetitive transcranial magnetic stimulation (rTMS), reflecting short-term plasticity, and paired associative stimulation (PAS), reflecting long-term plasticity, and were asked to focus their attention on the hand contralateral to the M1 stimulated. A group of age-matched healthy subjects acted as control. RESULTS: In patients with MS, 5-Hz rTMS and PAS failed to induce the normal increase in motor-evoked potential (MEP). During the attention-demanding condition, 5-Hz rTMS- and PAS-induced responses differed in patients with MS with and without fatigue. Whereas in patients with fatigue neither technique induced the attention-induced MEP increase, in patients without fatigue they both increased the MEP response, although they did so less efficiently than in healthy subjects. Attention-induced changes in short-term cortical plasticity inversely correlated with fatigue severity. CONCLUSION: Short-term and long-term plasticity mechanisms are abnormal in MS possibly owing to widespread changes in ion-channel expression. Fatigue in MS reflects disrupted cortical attentional networks related to movement control.

Intradetrusorial Botulinum Toxin in Patients with Multiple Sclerosis: A Neurophysiological Study.

Patients with multiple sclerosis (MS) often complain of urinary disturbances characterized by overactive bladder syndrome and difficulties in bladder emptying. The aim of the study was to investigate the pathophysiology of bladder dysfunction and the neurophysiological effects of intradetrusorial incobotulinum toxin A (BoNT/A) in patients with MS having both brain and spinal MS-related lesions. Twenty-five MS patients with neurogenic detrusor overactivity (NDO) underwent clinical evaluation and soleus Hoffmann reflex (H reflex) study during urodynamics. Of the 25 patients, 14 underwent a further session one month after intradetrusorial BoNT/A injection. Eighteen healthy subjects acted as the control. In healthy subjects, the H reflex size significantly decreased at maximum cystometric capacity (MCC), whereas in MS patients with NDO, the H reflex remained unchanged. In the patients who received intradetrusorial BoNT/A, clinical and urodynamic investigations showed that NDO improved significantly. Volumes at the first, normal and strong desire to void and MCC increased significantly. Despite its efficacy in improving bladder symptoms and in increasing volumes for first desire, normal and strong desire to void, BoNT/A left the H reflex modulation during bladder filling unchanged. In the MS patients we studied having both brain and spinal MS-related lesions, the H reflex size remained unchanged at maximum bladder filling. Since this neurophysiological pattern has been previously found in patients with spinal cord injury, we suggest that bladder dysfunction arises from the MS-related spinal lesions. BoNT/A improves bladder dysfunction by changing bladder afferent input, as shown by urodynamic findings on bladder filling sensations, but its effects on H reflex modulation remain undetectable.