Discontinuation of teriflunomide and dimethyl fumarate in a large Italian multicentre population: a 24-month real-world experience.

BACKGROUND: Teriflunomide (TRF) and Dimethyl fumarate (DMF) are licensed drugs for relapsing-remitting Multiple Sclerosis (RRMS). OBJECTIVES: We aimed to compare the rate and the time to discontinuation among persons with RRMS (pwRRMS), newly treated with TRF and DMF. MATERIALS AND METHODS: A retrospective study on prospectively collected data was performed in nine tertiary MS centers, in Italy. The 24-month discontinuation rate in the two cohorts was the primary study outcome. We also assessed the time to discontinuation and reasons of therapy withdrawn. Discontinuation of TRF and DMF was defined as a gap of treatment ≥ 60 days. RESULTS: A cohort of 903 pwRRMS (316 on TRF and 587 on DMF) was analyzed. During 24 months of follow-up, pwRRMS on TRF and DMF showed similar discontinuation rates. The analysis of predictors with Cox regression model showed differences between the two groups (p for log-rank test = 0.007); male gender [HR 2.21 (1.00-4.90); p = 0.01] and the number of previous switches [HR 1.47 (1.16-1.86); p = 0.01] were associated with higher hazard of discontinuation in the DMF group. CONCLUSIONS: In a real-world setting, pwRRMS on TRF and DMF had similar discontinuation rates over 24 months. Male pwRRMS on DMF with a previous history of therapeutic failure are at more risk of discontinuation therapy.

Anodal tDCS of the swallowing motor cortex for treatment of dysphagia in multiple sclerosis: a pilot open-label study.

Swallowing difficulties are a common symptom of multiple sclerosis (MS). The early detection and treatment of dysphagia is critical to prevent complications, including poor nutrition, dehydration, and lung infections. Recently, transcranial direct current stimulation (tDCS) has been proven to be effective in ameliorating swallowing problems in stroke patients. In this pilot study, we aimed to assess safety and efficacy of transcranial direct current stimulation (tDCS) in the treatment of dysphagia in MS patients. We screened 30 patients by using the 10-item DYsphagia in MUltiple Sclerosis (DYMUS) questionnaire, and patients at risk for dysphagia underwent a clinical and fiberoptic endoscopic evaluation of swallowing (FEES). Six patients who presented with mild to moderate dysphagia underwent the experimental procedures. These consisted of 5 sessions of anodal tDCS applied in consecutive days over the right swallowing motor cortex. Patients were followed-up at 1 week, 1 month and 3 months after treatment, and changes in the Dysphagia Outcome and Severity Scale (DOSS) score between baseline and post-tDCS were assessed. Our results showed that in all patients, the tDCS treatment determined a mild but significant clinical benefit (one-point improvement in the DOSS score) lasting up to 1 month. In conclusion, our preliminary results show that anodal tDCS has therapeutic potential in the treatment of swallowing problems in patients suffering with MS. However, future double-blind, randomized, and sham-controlled studies are needed to confirm the present findings.

VDBP, CYP27B1, and 25-Hydroxyvitamin D Gene Polymorphism Analyses in a Group of Sicilian Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a chronic demyelinating disease of central nervous system regarded as one of the most common causes of neurological disability in young adults. The exact etiology of MS is not yet known, although epidemiological data indicate that both genetic susceptibility and environmental exposure are involved. A poor vitamin D status has been proposed as the most attractive environmental factor. Several evidence have highlighted the importance of mutations in vitamin D-regulating genes for vitamin D status. The purpose of our study was to assess the genetic variants of VDBP and CYP27B1 in MS patients and in a control group. A total of 192 subjects, including 100 MS patients and 92 healthy controls, were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism analyses. Serum 25-hydroxyvitamin D levels were measured in MS patients and controls by high-performance liquid chromatography. We did not observe any statically significant difference in the distribution of genotypic VDBP variants between the study groups. 25(OH)D plasma levels were significantly higher in the control group versus MS patients; MS patients who carried Gc2 showed lower 25(OH)D plasma levels and those who carried Gc1f showed higher levels. We observed only wild-type allele for CYP27B1 mutations analyzed both in MS patients and in the control group. In conclusion, our findings do not support a role of an independent effect of the investigated vitamin D-related gene variants, VDBP and CYP27B1, in the risk of MS.

Vitamin D receptor polymorphisms and 25-hydroxyvitamin D in a group of Sicilian multiple sclerosis patients.

Multiple sclerosis (MS) is an auto-immune disease whose etiology remains controversial. Both genetic and environmental factors are thought to be involved in the risk of developing the disease. The purpose of our study was to assess the association of Vitamin D receptor (VDR) polymorphisms with MS and to investigate the interaction of these polymorphisms with vitamin D levels. A total of 179 Sicilian subjects, including 104 MS patients and 75 healthy controls, were studied. The most common VDR polymorphisms (Fok-I, Bsm-I, Taq-I and Apa-I) were genotyped by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analyses in both groups and serum 25-hydroxyvitamin D [25(OH)D] levels were determined in MS patients by high-performance liquid chromatography (HPLC). The distribution of genotype and allele frequencies of the four VDR polymorphisms did not differ significantly between MS patients and healthy controls, and were unrelated to the forms and the course of MS. Low serum levels of 25(OH)D were observed in MS patients but no association was observed between VDR and 25(OH)D levels except for Fok-I. Moreover, MS patients with FF and Ff genotype had a significantly lower serum levels of 25(OH)D compared with ff carriers (P < 0.05 FF vs Ff and Ff vs ff). Our findings showed no association between VDR polymorphisms and risk of MS. Interestingly, F allele could confer a genetic predisposition to lower 25(OH)D levels.

Clinical and magnetic resonance imaging predictors of disease progression in multiple sclerosis: a nine-year follow-up study.

OBJECTIVE: The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of multiple sclerosis (MS) patients. METHODS: A total of 241 relapsing-remitting (RR) MS patients were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4. RESULTS: We concluded that conversion from RR to SP (OR 0.79; CI 0.7-0.9), progression of EDSS (OR 0.85; CI 0.77-0.93), achievement of EDSS 4 (OR 0.8; CI 0.7-0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82-0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9-4.36), (OR 2.7; CI 1.7-4.2), (HR 3.86; CI 1.94-7.70)). CONCLUSIONS: BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients with a relatively long and mild disease.

Endovascular treatment of CCSVI in patients with multiple sclerosis: clinical outcome of 462 cases.

Although it is still debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients underwent endovascular treatment (ET) of CCSVI. The objective of the study is to evaluate the outcome and safety of ET in Italian MS patients. Italian MS centers that are part of the Italian MS Study Group were all invited to participate to this retrospective study. A structured questionnaire was used to collect detailed clinical data before and after the ET. Data from 462 patients were collected in 33 centers. ET consisted of balloon dilatation (93 % of cases) or stent application. The mean follow-up duration after ET was 31 weeks. Mean EDSS remained unchanged after ET (5.2 vs. 4.9), 144 relapses occurred in 98/462 cases (21 %), mainly in RR-MS patients. Fifteen severe adverse events were recorded in 3.2 % of cases. Given the risk of severe adverse events and the lack of objective beneficial effects, our findings confirm that at present ET should not be recommended to patients with MS.

Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone.

OBJECTIVES: To evaluate the incidence and dose-dependency of mitoxantrone (MTX)-associated acute myelocytic leukemia (AML) in the network of Italian multiple sclerosis (MS) clinics. METHODS: We performed a multicenter retrospective cohort study of patients treated with MTX in MS centers under the Italian national health care system between 1998 and 2008. Demographic, disease, treatment, and follow-up information were collected using hospital records. RESULTS: Data were available for 3,220 patients (63% women) from 40 Italian centers. Follow-up (mean ± SD) was 49 ± 29 months (range 12-140 months). We observed 30 cases of AML (incidence 0.93% [95% confidence interval 0.60%-1.26%]). The mean cumulative dose was higher in patients with AML (78 vs 65 mg/m(2), p = 0.028). The median interval from the start of therapy to AML diagnosis was longer than expected at 33 months (range 13-84 months); 8 patients (27%) developed AML 4 years or more after the first MTX infusion. The rate of mortality associated with AML was 37%. CONCLUSIONS: This higher than expected risk of AML and related mortality requires that treatment decisions must be made jointly between clinicians and patients who understand their prognosis, treatment options, and treatment-related risks. The now large exposed MS population must be monitored for hematologic abnormalities for at least 6 years from the end of therapy, to ensure the rapid actions needed for early diagnosis and treatment of AML.

Multiple sclerosis survival: a population-based study in Sicily.

BACKGROUND AND PURPOSE: There are few population-based surveys on multiple sclerosis (MS) survival. To investigate MS survival in MS patients recruited during surveys conducted in Sicily. METHODS: Multiple sclerosis patients identified during previous surveys were randomly matched to two referent subjects by residence, year of birth, and gender. Living status was obtained by municipality records (end of follow-up June, 30th 2007) and, for the deceased, date and causes of death were searched. Kaplan-Meier plots were used to calculate differences in mortality between MS patients and referent subjects. MS risks for mortality with 95% confidence intervals (CI) were also calculated. RESULTS: We included 194 MS patients and 388 matched persons. Thirty MS patients (15.5%) and 28 referents (7.2%) had died until the end of follow-up. Mean survival from onset of the disease to death was 20.6 years. Mean age at death was 55.5 for MS patients and 64.8 for the referents. Adjusted Hazard Ratios for mortality in MS was 1.81 (95% CI 1.36-2.40). Kaplan-Meier estimates showed a higher mortality amongst patients compared to referent subjects (P < 0.001). CONCLUSIONS: The present study confirms the higher mortality risk in MS patients with no significant gender difference. Causes of death are related to complications of high disability and to increasing age.

Real-life impact of early interferon beta therapy in relapsing multiple sclerosis.

OBJECTIVE: Recent findings support greater efficacy of early vs. delayed interferon beta (IFNbeta) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFNbeta treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFNbeta treatment with regard to the greatest benefits on disability progression. METHODS: A cohort of 2,570 IFNbeta-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFNbeta treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings. RESULTS: The lowest hazard ratios (HRs) for the three PS quintiles-adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR = 0.63; 95% CI = 0.48-0.85; p < 0.002), and the EDSS 4.0 milestone (HR = 0.56; 95% CI = 0.36-0.90; p = 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders. INTERPRETATION: Greater benefits on disability progression may be obtained by an early IFNbeta treatment in RRMS.

Post-marketing of disease modifying drugs in multiple sclerosis: an exploratory analysis of gender effect in interferon beta treatment.

BACKGROUND: There are a few and conflicting results from randomised controlled trials (RCTs) pertaining to the influence of gender in response to currently used disease modifying drugs in Multiple Sclerosis (MS). Observational studies may be especially valuable for answering effectiveness questions in subgroups not studied in RCTs. OBJECTIVE: To conduct a post-marketing analysis aimed to evaluate the gender effect on Interferon beta (IFNbeta) treatment response in a cohort of relapsing (RR) MS patients. METHODS: A cohort of 2570 IFNbeta-treated RRMS was prospectively followed for up to 7 years in 15 Italian MS Centers. Cox proportional hazards regression models were used to assess gender differences for risk of reaching 1st relapse and risk of progression by 1 point on Expanded Disability Status Scale (EDSS) score. Gender effects were also explored by a propensity score (PS) matching algorithm, and a tree-growing technique. RESULTS: The multivariate Cox Regression analyses showed that male patients had a significant (p=0.0097) lower risk for 1st relapse and a trend (p=0.0897) for a higher risk to reach 1 point EDSS progression than females. The PS matched multivariate Cox Regression confirmed these results. The RECPAM analysis showed that male sex conferred a significant reduction in the risk for 1st relapse (HR=0.86; 95% CI=0.76-0.98; p=0.0226) in the subgroup with a low pre-treatment number of bouts, and a significant increase in the risk for 1 point EDSS progression (HR=1.33; 95% CI: 1.00-1.76; p<0.05) in the subgroup with a delayed treatment, but a still young age at the start of treatment. CONCLUSION: The results of this exploratory analysis seem to suggest that male patients do not respond to IFNbeta treatment in the same way of females.

An exploration of anger phenomenology in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients are often emotionally disturbed. We investigated anger in these patients in relation to demographic, clinical, and mood characteristics. PATIENTS AND METHODS: About 195 cognitively unimpaired MS patients (150 relapsing-remitting and 45 progressive) were evaluated with the State Trait Anger Expression Inventory, the Chicago Multiscale Depression Inventory, and the State Trait Anxiety Inventory. The patients' anger score distribution was compared with that of the normal Italian population. Correlation coefficients among scale scores were calculated and mean anger scores were compared across different groups of patients by analysis of variance. RESULTS: Of the five different aspects of anger, levels of withheld and controlled Anger were respectively higher and lower than what is expected in the normal population. Although anger was correlated with anxiety and depression, it was largely independent from these mood conditions. Mean anger severity scores were not strongly influenced by individual demographic characteristics and were not higher in more severe patients. CONCLUSIONS: The presence of an altered pattern of anger, unrelated to the clinical severity of MS, suggests that anger is not an emotional reaction to disease stress. An alteration of anger mechanisms might be a direct consequence of the demyelination of the connections among the amygdale, the basal ganglia and the medial prefrontal cortex.

Brain atrophy evolution and lesion load accrual in multiple sclerosis: a 2-year follow-up study.

BACKGROUND: To investigate in a large cohort of patients with multiple sclerosis (MS), lesion load and atrophy evolution, and the relationship between clinical and magnetic resonance imaging (MRI) correlates of disease progression. METHODS: Two hundred and sixty-seven patients with MS were studied at baseline and two years later using the same MRI protocol. Abnormal white matter fraction, normal appearing white matter fraction, global white matter fraction, gray matter fraction and whole brain fraction, T2-hyperintense, and T1-hypointense lesions were measured at both time points. RESULTS: The majority of patients were clinically stable, whereas MRI-derived brain tissue fractions were significantly different after 2 years. The correlation between MRI data at baseline and their variation during the follow-up showed that lower basal gray matter atrophy was significantly related with higher progression of gray matter atrophy during follow-up. The correlation between MRI parameters and disease duration showed that gray matter atrophy rate decreased with increasing disease duration, whereas the rate of white matter atrophy had a constant pattern. Lower basal gray matter atrophy was associated with increased probability of developing gray matter atrophy at follow-up, whereas gray matter atrophy progression over 2 years and new T2 lesion load were risk factors for whole brain atrophy progression. CONCLUSIONS: In MS, brain atrophy occurs even after a relatively short period of time and in patients with limited progression of disability. Short-term brain atrophy progression rates differ across tissue compartments, as gray matter atrophy results more pronounced than white matter atrophy and appears to be a early phenomenon in the MS-related disease progression.

Body mass index does not change before Parkinson's disease onset.

BACKGROUND AND PURPOSE: Previous studies on the association between Parkinson's disease (PD) and body mass index (BMI) have reported conflicting results. We investigated the relationship between PD and BMI by a case-control study. METHODS: PD patients were randomly matched to healthy individuals by sex and age. BMI distribution in cases has been compared with BMI of controls and odd ratios (ORs) with 95% CI were calculated. RESULTS: We included 318 PD patients and 318 controls. We observed no association between PD and BMI. BMI distribution in cases and controls was similar also when we adjusted for diabetes, hypercholesterolemia and the time elapsed between PD onset and the interview (OR = 0.99; CI = 0.94-1.03; P = 0.51). CONCLUSIONS: These results did not confirm the previously reported association between PD and BMI. Population characteristics and methodological issues may partially account for the differences observed between the present study and the others.

Mortality in multiple sclerosis: a review.

This work was undertaken to evaluate studies on mortality caused by multiple sclerosis (MS), to evaluate if useful inferences can be drawn from survival studies that can be applied to clinical practice. A literature search was carried out to find epidemiological studies on MS prognosis, survival, mortality and causes of death relevant to our aim. The World Health Organization (WHO) reports on worldwide cause-specific mortality were also considered. Studies were evaluated according to the duration of the follow-up study, the year of publication and the methodology used. We evaluated MS survival from a methodological point of view and considered if time trends could be drawn from study results. We conclude that mortality is only slightly higher in MS patients when compared with that in the general population. Mortality is higher particularly for older patients and those with longer disease duration.

Autosomal dominant hereditary spastic paraplegia: report of a large Italian family with R581X spastin mutation.

We describe a large kindred with a typical pure form of autosomal dominant hereditary spastic paraplegia (ADHSP). On the basis of maximum LOD score of 1.94 at theta (max)=0 with marker D2S367, we obtained suggestive evidence for linkage of ADHSP to SPG4 locus. Denaturing high-performance liquid chromatography (DHPLC) and direct sequence analysis allowed us to identify a nonsense mutation (1741* C>T) in exon 17 of the Spastin gene. This transition, carried by all the affected family members and two apparently healthy individuals, lead to truncation of the last 36 amino acids in the C-terminus of the protein. These results confirm the existence of mutation in the SPG4 gene with a reduced penetrance, indicating that other genetic or environmental factors are required to trigger full-blown disease.

Treatment of multiple sclerosis with interferon beta in clinical practice: 2-year follow-up data from the South Italy Mobile MRI Project.

This follow-up study assessed the 2-year clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) originally enrolled in an MRI study conducted at eight centres in south Italy (the South Italy Mobile MRI Project). Of the 597 MS patients recruited at baseline, 391 returned for the follow-up study. Of these, 363 provided 2-year clinical and MRI follow-up data, and 215 were still undergoing treatment with one of four interferon beta regimens: Avonex, 30 mcg intramuscularly once weekly; Betaferon, 250 mcg subcutaneously (sc) every other day; Rebif 22 mcg sc three times weekly (tiw; Rebif 22); or Rebif 44 mcg sc tiw (Rebif 44). Over the 2-year follow-up period, patients receiving the higher dose of Rebif were more likely to remain free from relapses [odds ratio (OR) = 2.23] and from developing both new T2 (OR = 0.15) and new T1 black hole lesions (OR = 0.22), when compared with patients in the Avonex group. Despite some limitations in the trial design, the results from this follow-up study provide helpful clinical and MRI data on the efficacy of interferon beta regimens in MS patients treated in the clinical setting.

Cognitive dysfunction in patients with relapsing-remitting multiple sclerosis.

Cognitive dysfunction is considered one of the clinical markers of multiple sclerosis (MS). However, in the literature there are inconsistent reports on the prevalence of cognitive dysfunction, and separate data for the relapsing-remitting (RR) type of the disease are not always presented. In this study, we submitted 461 RRMS patients to a battery of neuropsychological tests to investigate their impairment in various cognitive domains. As a consequence of the exclusion criteria, the sample is not fully representative of the entire population of RRMS patients. In this selected sample, when only the eight scores of a core battery (Mental Deterioration Battery) were considered (with respective cutoffs), it emerged that 31% of the patients were affected by some degree of cognitive deficit. In particular, 15% had mild, 11.2% moderate and 4.8% had severe impairment. Information processing speed was the most frequently impaired area, followed by memory. When two other tests (SDMT and MCST) were added and cognitive domains were considered, it emerged that 39.3% of the patients were impaired in two or more domains. When four subgroups were obtained by means of cluster analysis and then compared, it emerged that information processing speed and memory deficits differentiated the still cognitively unimpaired from the mildly impaired MS patients. Significant associations were found between cognitive and clinical characteristics. However, due to the large sample size, clinically irrelevant relationships may also have emerged. Even with the limitations imposed by the sample selection and the possible underestimation of the prevalence and severity of cognitive dysfunction, these results seem to provide further evidence that information processing speed deficit may be an early and important marker of cognitive impairment in MS patients.

Long-term survival of Parkinson's disease: a population-based study.

In a set of a population- based study, long-term survival of 59 prevalent PD patients was compared with that of individuals free of neurological diseases matched 1:2 by sex and age of enrolment. PD individuals, compared with reference subjects, showed a two-fold increased risk of death (OR 2.1; 95 % CI 1.4, 3.1). Among causes of death, pneumonia and cachexia were significantly more frequent among PD patients than among individuals free of neurological diseases. We confirmed in a long-term follow-up study an increased mortality among PD individuals compared with that of the general population.

Brain atrophy and lesion load in a large population of patients with multiple sclerosis.

OBJECTIVE: To measure white matter (WM) and gray matter (GM) atrophy and lesion load in a large population of patients with multiple sclerosis (MS) using a fully automated, operator-independent, multiparametric segmentation method. METHODS: The study population consisted of 597 patients with MS and 104 control subjects. The MRI parameters were abnormal WM fraction (AWM-f), global WM-f (gWM-f), and GM fraction (GM-f). RESULTS: Significant differences between patients with MS and control subjects included higher AWM-f and reduced gWM-f and GM-f. MRI data showed significant differences between patients with relapsing-remitting and secondary progressive forms of MS. Significant correlations between MRI parameters and between MRI and clinical data were found. CONCLUSIONS: Patients with multiple sclerosis have significant atrophy of both white matter (WM) and gray matter (GM); secondary progressive patients have significantly more atrophy of both WM and GM than do relapsing-remitting patients and a significantly higher lesion load (abnormal WM fraction); lesion load is related to both WM and even more to GM atrophy; lesion load and WM and GM atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and brain atrophy); and GM atrophy is the most significant MRI variable in determining the final disability.

Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity.

BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.