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.

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.

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.

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.

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.

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.

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.

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.

Parkinson disease survival: a population-based study.

OBJECTIVE: To evaluate whether the survival of patients with Parkinson disease (PD) is shorter than that of the general population. DESIGN: Survival was investigated in a cohort of patients with PD previously identified during a population-based prevalence study (prevalence day, November 1, 1987, reference follow-up date, October 31, 1995). The survival of patients with PD was compared with that of a control sample randomly selected from the same population (2 controls for each case, matched for age, sex, and study municipality). The causes of death in the 2 groups were also compared. Both univariate and multivariate survival analyses were performed to investigate the association with disease-related variables. SETTING: A door-to-door 2-phase prevalence survey performed in 3 Sicilian municipalities. PATIENTS: Fifty-nine patients with PD and 118 controls. RESULTS: Patients with PD showed a high risk of death (relative risk, 2.3; 95% confidence interval, 1.60-3.39). Greater age at November 1, 1987, high Hoehn-Yahr score, and lack of levodopa therapy were associated with a lower survival on univariate analysis. Multivariate analysis confirmed the association between shorter survival among patients with PD and greater age on November 1, 1987. One-way analysis of variance indicated a different effect of levodopa therapy according to age. Multivariate analysis did not confirm this finding. Pneumonia was the cause of death most frequently associated with PD. CONCLUSION: This study indicates that patients with PD have a shorter survival time than the general population.

Prevalence of diabetic neuropathy with somatic symptoms: a door-to-door survey in two Sicilian municipalities. Sicilian Neuro-Epidemiologic Study (SNES) Group.

In a door-to-door survey conducted in two municipalities of Sicily, we ascertained the prevalence of diabetic neuropathy. Our case-finding was restricted to subjects with somatic symptoms. During phase 1, we administered a screening instrument for peripheral neuropathy to 14,540 persons residing in Santa Teresa di Riva (Messina Province) and Terrasini (Palermo Province). During phase 2, neurologists evaluated those subjects who had screened positive. Diagnoses were based on clinical criteria only, and were reviewed by an adjudication panel. We found 39 persons (27 women, 12 men) affected by diabetic neuropathy. The crude prevalence, as of November 1, 1987, was 268.2 cases per 100,000 population. The prevalence increased with advancing age for both sexes and was consistently higher in women. The most common type was distal symmetric polyneuropathy. The median time between diagnosis of diabetes mellitus and onset of diabetic neuropathy was 8 years, and almost all identified persons with diabetic neuropathy were under treatment for diabetes mellitus.

High incidence and increasing prevalence of MS in Enna (Sicily), southern Italy.

Twenty years after a first survey, a follow-up study was performed on the prevalence of MS in Enna (Sicily), southern Italy. The prevalence of definite MS rose from 53 to 120.2 per 100,000 population. The incidence of definite MS for the period 1986 to 1995 was 5.7 per 100,000 per year. The innermost part of Sicily shows an elevated prevalence of MS, second only to Sardinia in the Mediterranean area.

Prevalence of essential tremor: a door-to-door survey in Terrasini, Sicily. Sicilian Neuro-Epidemiologic Study Group.

As part of a door-to-door neuroepidemiologic survey, we investigated the frequency and distribution of essential tremor (ET) in a Sicilian municipality. During phase 1, we administered a screening instrument for tremor to 7,653 persons residing in Terrasini (Palermo province). During phase 2, neurologists evaluated those subjects who had screened positive. The diagnoses, based on specified clinical criteria, were reviewed to increase reliability across neurologists. We found 31 subjects affected by ET (17 men, 14 women); 11 patients (35.5%) reported a familial aggregation. The prevalence of ET as of November 1, 1987, was 405.1 per 100,000 for the total population, and 1,074.9 per 100,000 for those 40 years old or older. The prevalence increased with advancing age for both sexes and was slightly but consistently higher in men. Comparison with other studies suggests striking geographic variation, which may reflect genetic differences.

Prevalence and incidence of multiple sclerosis in the city of Monreale, Italy.

The prevalence and incidence of multiple sclerosis (MS) in the city of Monreale, southern Italy were ascertained 10 years after a preliminary study in the same area. The study was undertaken in a population of 26,256 people. The patients were classified according to Poser's criteria. The prevalence of MS on 31 December 1991 was 72.4 per 100,000 population. The incidence of MS for the period 1981-1991 was 3.3/100,000 per year. The mean period between onset and diagnosis of MS was 4.9 years for those patients found during this survey and 9.2 years for those in the first study. This study shows an increase of MS prevalence in Monreale city and a high incidence. The findings parallel the reduction of the lag time between onset and diagnosis.

Preparation, characterisation and photosensitivity studies of solid dispersions of diflunisal and Eudragit RS100 and RL100.

Solid dispersions of diflunisal (DIF) with Eudragit RS100 (RS) and RL100 (RL) with different drug-to-polymer ratios were prepared by a solvent method (coevaporates) and were characterised in the solid state in comparison with the corresponding physical mixtures. The work was aimed at characterising the interactions occurring between DIF and RS or RL polymers, along with their influence on the in-vitro drug-dissolution pattern. The findings suggest that the drug did not change its crystalline form within the polymer network. Drug dispersion in the polymer matrix strongly influences its dissolution rate, which appears slower and more gradual while increasing the polymer ratios. Moreover, DIF is known to be a photosensitive compound, and its photoproduct has been found to be a toxic agent. This can be evidenced by testing red blood cell membranes for their resistance to the osmotic shock induced by UVA irradiation in the presence of DIF. The presence of some DIF/RS coevaporates was shown to reduce significantly the drug photosensitization process towards cell membranes. This suggests the possibility of combining the design of a drug delivery system with a photoprotective strategy.

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.