Event-related potentials and deep grey matter atrophy in multiple sclerosis: Exploring the possible associations with cognition.

BACKGROUND: Event-related potentials (ERPs) have been proposed as a neurophysiological biomarker to capture cognitive dysfunction in multiple sclerosis (MS). Few studies have evaluated the relationships between ERPs and brain atrophy as known marker of structural brain damage related to cognitive impairment (CI). OBJECTIVES: To explore the relationships of brain atrophy, including of the cortex and deep grey matter, with ERP abnormalities and cognitive function, as defined using the Brief Repeatable Battery of Neuropsychological Tests (BRBN). RESULTS: Seventy-eight patients with relapsing-remitting MS were enroled, of which 38 (48.7%) had CI. Independent t-test comparisons of the ERP parameters found a significant difference in P300 wave latency, with a latency of 343.7 ± 32.6 ms in the CI group vs. 320.3 ± 16.5 ms in the cognitively preserved (CP) group (p = 0.001). Significant differences in the MRI measurements, including the cortex (p = 0.02) and deep grey matter structures [thalamus (p = 0.001), amygdala (p = 0.030), and nucleus accumbens (p = 0.004)) were observed, with lower measurements in the CI group. Regression models were also performed to explore the impact of brain volumes on ERP parameters. This showed a relationship between P300 latency and the lower amygdala (p = 0.02) and hippocampus (p = 0.03) volumes, while the amplitude of the P300 was significantly associated with a lower cortex volume (p = 0.01). CONCLUSION: Cortex volume emerged as the most significant predictor of the P300 amplitude. The amygdala and hippocampal volumes were found to influence P300 latency, highlighting the role of deep grey matter atrophy in ERPs for the first time. The combination of structural MRI and neurophysiological techniques, sensitive to diverse aspects of MS pathology, could improve the understanding of CI in MS and its neurodegenerative and inflammatory substrate.

Assessing the burden of vascular risk factors on brain atrophy in multiple sclerosis: A case- control MRI study.

BACKGROUND: Some studies have indicated the importance of considering the presence of vascular comorbidities as negative prognostic factors for MRI outcomes in multiple sclerosis (MS). This study aimed to evaluate the possible influence of the most frequent vascular risk factors on brain volume in MS, also exploring the burden of their combined effects. METHODS: MS patients with at least one vascular risk factor and a control group of MS patients were enrolled. Patients underwent brain MRI and the volumes of the whole brain (WB), white matter (WM), grey matter (GM), and cortical GM were estimated by SIENAX. Longitudinal atrophy was assessed by SIENA. RESULTS: The sample included 326 MS patients, of these 49 (15%) had diabetes mellitus, 44 (13.4%) hypertension and 50 (15.3%) were active smokers. Multiple regression analyses revealed that diabetes mellitus was associated with significant reductions in WB (p = 0.03), GM and cortical GM (p = 0.01) volumes. Similarly, reduced cortical GM volume was associated with hypertension (p < 0.05). A strong relationship between the co-occurrence of multiple vascular risk factors and lower cortical GM volume (p = 0.007) was also identified. Ninety patients were included in the longitudinal study and a greater annualized brain volume loss was found in those with at least one vascular risk factor than in the control group (-1.05% vs. -0.58%, p = 0.005). CONCLUSIONS: Our results show that the vascular comorbidities affect brain atrophy, indicating that these conditions should be carefully monitored in patients with MS with a focus on limiting brain damage.

Performance in daily activities, cognitive impairment and perception in multiple sclerosis patients and their caregivers.

BACKGROUND: The relationship between cognitive assessment results in multiple sclerosis (MS) and performance in daily activities (DAs) remains unclear. Our study aimed to evaluate the relationship between cognitive functions (CF) measured by tests, performance in DAs, and the perception of CF in patients and their caregivers (CG) in MS. METHODS: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery was used to evaluate cognitive status. We created an ad hoc questionnaire (DaQ) to assess performance in DAs not requiring specific motor skills. We used the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) to measure each patient self-judgment and caregiver's perception of CF. RESULTS: Forty-nine patients and their caregivers were included in the study. Significant correlations were found between the BICAMS and the DaQ (Symbol Digit Modalities Test (SDMT): r = - 0.48, p < 0.001; California Verbal Learning Test (CVLT): r = - 0.33, p = 0.01; Brief Visual Memory Test (BVMT-R): r = - 0.42; p = 0.002); patients self-judgment (SDMT: r = - 0.38, p = 0.004; CVLT: r = - 0.26, p = 0.03); caregiver perception of patient's CF (SDMT: r = - 0.52, p < 0.001; CVLT: r = - 0.3, p = 0.01; BVMT-R: r = - 0.42, p = 0.002). The difference in perception between the patients and their caregivers was related to patient age (p = 0.001) and severity of cognitive impairment (p = 0.03). CONCLUSIONS: Cognitive assessment results show a significant correlation with performance in daily activities and with patients and, especially, caregiver perception of cognitive impairment. These data support the importance of a routine evaluation of cognitive function in MS that includes an anamnestic evaluation of patients, and, when possible, consideration of the caregiver's point of view.

Pregnancy planning and outcomes in patients with multiple sclerosis after mitoxantrone therapy: a monocentre assessment.

BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) have many pregnancy-related doubts and fears. Careful counselling is thus important. Mitoxantrone (MITO) is used in patients with aggressive MS and may affect reproductive capacity. The aim of this study was to investigate pregnancy planning and outcomes in patients with MS treated with MITO, both before and after the treatment. METHODS: Patients with MS previously treated with MITO were recruited. Clinical, demographic and treatment data were recorded. A questionnaire regarding the planning and outcomes of all pregnancies was administered. Parametric and non-parametric tests were performed using SPSS 22 software. RESULTS: A total of 238 patients (female/male, 158/80) were included; 106 subjects planned a pregnancy before MITO and 40 after MITO. Of these, respectively, 102 (97%) and 35 (85%) resulted in conception, 19 (19%) and 7 (18%) in miscarriage, 6 (6%) and 1 (3%) in abortion and 98 (96%) and 32 (91%) were full-term pregnancies. A total of 96 patients (40%) planned a pregnancy only before MITO (and not after), whereas 30 (13%) planned a pregnancy only after MITO (and not before) (P < 0.01). A total of 103 patients did not plan a pregnancy before MITO and 198 did not plan a pregnancy after MITO. The reasons included lack of interest or a partner, fear of MS and infertility. All of the babies born were healthy until the end of follow-up. CONCLUSIONS: Mitoxantrone does not affect the ability to conceive or pregnancy outcomes. We found no differences in pregnancies, abortions or miscarriages before and after MITO. The tendency to plan pregnancies decreased significantly after MITO. Our findings may be useful for improving the quality of life of patients and the approach taken by neurologists.

Adult brain volume in multiple sclerosis: The impact of paediatric onset.

BACKGROUND: Paediatric onset multiple sclerosis (POMS) is associated with reduced brain and deep grey matter volume in comparison with that in healthy controls and individuals with adult onset multiple sclerosis (AOMS). The aim of our study was to evaluate the impact of POMS on adult brain volume with adjustment for other parameters, such as disease duration. PATIENTS AND METHODS: We recruited 20 POMS and 40 AOMS patients and 20 healthy controls matched for age and sex. All study participants were adults at the time of inclusion in the study. All study subjects underwent brain magnetic resonance imaging (MRI) to evaluate whole brain, white matter, grey matter, cortical, and deep grey matter volumes. Clinical features, such as the Expanded Disability Status Scale (EDSS) score and disease duration, were also assessed. RESULTS: Brain (p = 0.01), grey matter (p = 0.01), and deep grey matter volume (p = 0.03) was significantly lower in POMS patients than in AOMS patients, while no differences were detected in the volume of white matter or cortical grey matter. A multiple linear regression analysis showed a relationship between brain volume (dependent variable) and the independent variables age (p < 0.000) and paediatric onset (p < 0.001), while other independent variables, including disease duration, sex, and disability, were not significantly different among groups. There were significant differences in thalamic volume among POMS and AOMS patients and healthy controls. CONCLUSION: Our data support the previous findings that POMS patients have reduced brain and deep grey matter volume, particularly thalamic volume, compared with sex- and age-matched AOMS patients and healthy controls. These findings appear to be independent of disease duration and other clinical features.

Cognition in multiple sclerosis: Between cognitive reserve and brain volume.

BACKGROUND: Several correlations between cognitive impairment (CI), radiologic markers and cognitive reserve (CR) have been documented in MS. OBIECTIVE: To evaluate correlation between CI and brain volume (BV) considering CR as possibile mitigating factor. METHODS: 195 relapsing MS patients underwent a neuropsychological assessment using BICAMS. BV was estimated using SIENAX to obtain normalized volume of brain (NBV), white matter (NWV), gray matter (NGV) and cortical gray matter (CGV). CR was estimated using a previously validated tool. RESULTS: Pearson test showed a correlation between the symbol digit modality test (SDMT) score and NBV (r=0.38; p<0.000) NGV(r=0.31; p<0.000), CGV (r=0.35; p<0.000) and CRI score(r=0.42; p<0.000). Linear regression (dependent variable:SDMT) showed a relationship with CR scores (p=0.000) and NGV(p<0.000). A difference was detected between cognitive impaired and preserved patients regarding mean of NBV(p=0.002), NGV(p=0.007), CGV(p=0.002) and CR Scores (p=0.007). Anova showed a association between the presence of CI (dependent variable) and the interaction term CRIQ × CGV (p=0.004) whit adjustment for age and disability evaluated by EDSS. CONCLUSIONS: Our study shows a correlation between cognition and BV, in particular gray matter volume. Cognitive reserve is also confirmed as an important element playing a role in the complex interaction to determine the cognitive functions in MS.

Brain volume in early MS patients with and without IgG oligoclonal bands in CSF.

BACKGROUND: Oligoclonal bands of IgG (OB) are proposed as an early prognostic factor of the disease. Growing attention is directed towards brain volume evaluation as a possible marker of the severity of MS. Previous studies found that MS patients lacking OB have less brain atrophy. AIM: to evaluate a possible relationship between OB and cerebral volume in a cohort of early MS patients. METHODS: Inclusion criteria were: diagnosis of relapsing-remitting MS; CSF analysis and MRI acquired simultaneously and within 12 months from clinical onset. A total of 15 healthy controls underwent MRI. RESULTS: In 20 MS patients, CSF analysis did not show OB synthesis (OB negative group). A control group of 25 MS patients in whom OB was detected was also randomly recruited (OB positive group). T test showed a significant difference in NWV between the OB positive and OB negative groups (P value = 0.01), and between the OB positive group and the healthy controls (P value = 0.001). No differences were detected between OB negative group and healthy controls. Multivariable linear regression showed a relationship between NWV and OB synthesis (P value = 0.02) controlling for age, gender, and EDSS. CONCLUSIONS: Our preliminary results suggest that OB positive patients show more atrophy of white matter since early phases of the disease, supporting the role of CSF analysis as a prognostic factor in MS.

'Timed up and go' and brain atrophy: a preliminary MRI study to assess functional mobility performance in multiple sclerosis.

Motor and cognitive disabilities are related to brain atrophy in multiple sclerosis (MS). 'Timed up and go' (TUG) has been recently tested in MS as functional mobility test, as it is able to evaluate ambulation/coordination-related tasks, as well as cognitive function related to mobility. The objective of this study is to evaluate the relationship between brain volumes and TUG performances. Inclusion criteria were a diagnosis of MS and the ability to walk at least 20 m. TUG was performed using a wearable inertial sensor. Times and velocities of TUG sub-phases were calculated by processing trunk acceleration data. Patients underwent to a brain MRI, and volumes of whole brain, white matter (WM), grey matter (GM), and cortical GM (C) were estimated with SIENAX. Sixty patients were enrolled. Mean age was 41.5 ± 11.6 years and mean EDSS 2.3 ± 1.2. Total TUG duration was correlated to lower WM (ρ = 0.358, p = 0.005) and GM (ρ = 0.309, p = 0.017) volumes. A stronger association with lower GM volume was observed for intermediate (ρ = 0.427, p = 0.001) and final turning (ρ = 0.390, p = 0.002). TUG is a useful tool in a clinical setting as it can not only evaluate patients' disability in terms of impaired functional mobility, but also estimate pathological features, such as grey atrophy.

Muscle elastography: a new imaging technique for multiple sclerosis spasticity measurement.

Multiple sclerosis (MS) spasticity is currently evaluated on the basis of neurological examinations such as Ashworth Scale (AS) and 0-10 NRS. Severity of spasticity is difficult to quantify. We investigated the use of real time elastography (RTHE) ultrasounds for evaluating objectively the muscle fibers status in MS spasticity patients and their changes after a new antispasticity treatment. Two studies were performed. In study A, 110 MS patients underwent a neurological evaluation based on the AS and RTHE. The RTHE images were scored with the new 1-5 muscle fibers rigidity imaging scale, here called MEMSs (Muscle Elastography Multiple Sclerosis Score). The correlation between AS and MEMSs was found to be statistically significant. In study B, 55 MS patients treated with THC:CBD oromucosal spray for their resistant spasticity were followed prospectively. MS spasticity was evaluated by the 0-10 NRS scale at baseline and after 4 weeks of treatment. MEMSs' figures were obtained at both timepoints. Responders to THC:CBD oromucosal spray (pre-defined as an improvement ≥20% in their 0-10 NRS spasticity score vs. baseline) were 65% of sample. These patients had a mean 0-10 NRS reduction of 1.87 and a MEMSs reduction of 1.97 (P values <0.0001). The remaining 35% of patients, classified as clinically non-responders, showed still a significant mean reduction in MEMSs (0.8, P = 0.002). Our overall results showed that RTHE, operativized throughout MEMSs, could be an objective gold standard to evaluate MS muscle spasticity as well as the effectiveness of antispasticity therapy.

Combining HLA-DRB1-DQB1 and Mycobacterium Avium Subspecies Paratubercolosis (MAP) antibodies in Sardinian multiple sclerosis patients: associated or independent risk factors?

BACKGROUND: Amongst Sardinians the human leukocyte antigen (HLA) DRB1-DQB1 haplotypes *15:02-*06:01, *16:01-*05:02, *14:01-4-*05:03 are protective for multiple sclerosis (MS), while *13:03-*03:01, *04:05-*03:01, *03:01-*02:01, *15:01-*06:02 and Mycobacterium avium subspecies paratubercolosis (MAP) are predisposing factors. We studied the correlation between MAP and HLA. METHODS: Five hundred thirty-one patients were searched for anti-MAP2694 antibodies, DRB1-DQB1 genotyping was performed. The haplotypes were classified as predisposing, neutral or protective. RESULTS: Anti-MAP2694 were found in 23 % of subjects carrying one protective HLA versus 32 % without (p = 0.04). CONCLUSIONS: We showed a lower frequency of Abs in patients with protective HLA. These haplotypes could have a protective role for both MS and MAP.

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.

BACKGROUND: The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. METHODS: We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. RESULTS: A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%). CONCLUSIONS: Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

An unusual infection in MS patient treated with dimethyl fumarate: A case report of omphalitis.

BACKGROUND: Notoriously the treatment of multiple sclerosis (MS) is based on the use of several different drugs, characterized by a diverse mechanism of action, efficacy and safety. Recently, progress has been made towards developing new oral immunotherapies, and dimethyl fumarate is the third oral agent approved for the treatment of relapsing-remitting forms. CASE: A 24-year-old patient, affected by relapsing remitting multiple sclerosis, started treatment in December 2014 with dimethyl fumarate. The common side effects (flushing and gastrointestinal events) of dimethyl fumarate occurred at the beginning of treatment, but resolved after 1 month. Six months later, the patient presented with serious recrudescence of the gastrointestinal event. In addition to this symptom, he had developed acute omphalitis-a very rare infection in adults. CONCLUSION: The pathogenic role of dimethyl fumarate to induce this rare infection was probably related to changes in immunological surveillance as well as to the irritant effect of this agent on the gastrointestinal epithelium. Therefore, post-marketing studies in clinical practice are still needed to provide the necessary long-term safety data.

Use of herbal remedies by multiple sclerosis patients: a nation-wide survey in Italy.

Though recent progress in multiple sclerosis (MS) treatment is remarkable, numerous unmet needs remain to be addressed often inducing patients to look for complementary and alternative medicines (CAM), especially herbal remedies (HR). HR use, scarcely investigated in MS, may cause adverse reactions (AR) and interfere with conventional treatment. We performed a survey aimed at evaluating use and attitudes towards HR and factor associated to HR use. Other CAM use and attitudes have been investigated as well. Multiple-choice questionnaires were distributed to MS out patients attending 14 Italian referral Centers. Multivariable logistic regression was used to identify HR use determinants. Present/past HR use for either MS or other diseases was reported in 35.6 % of 2419 cases (95 % CI 36.0-40.0 %). CAM use was reported in 42.5 % of cases. Independent predictors of HR use were represented by higher education, geographic area, dissatisfaction with conventional treatment of diseases other than MS and benefit perception from CAM use. Both HR and CAM use were not always disclosed to the healthcare professional. In conclusion, HR and other CAM appear to be popular among MS patients. The involvement of the healthcare professionals appears to be scarce with potential risk of AR or interference with conventional treatments.

Facial synkinesis as a first symptom of multiple sclerosis.

A 39-year-old woman was admitted to hospital because of a sensory hemisyndrome caused by a contrast-enhancing demyelinating lesion of the cervical cord. MRI, CSF examination and subsequent clinical and neuroradiological follow-up led to the diagnosis of multiple sclerosis. The patient had noticed an involuntary contraction of a small muscle fascicle on the right side of the chin for a year. Electromyographic and video recordings confirmed the synkinesis between the orbicularis oculi and lower facial muscles, a finding distinct from the myokymic discharges reported in multiple sclerosis and more similar to the synkinesis associated with hemifacial spasm.

Diagnostic tools for assessment of urinary dysfunction in MS patients without urinary disturbances.

Many guidelines are available for the management of lower urinary tract symptoms (LUTSs) in multiple sclerosis (MS) patients, but no agreement exists on the best approach for subjects without LUTSs. The objective of this study was to evaluate whether LUTSs can be detected in MS patients asymptomatic for urinary dysfunction, comparing three different tools [measure of post-void residual volume (PRV), bladder diary (BD), a focused questionnaire (IPSS)], and whether disability, disease duration and signs of pyramidal involvement are linked to their subclinical presence. 178 MS patients (118 women) have been included (mean age 41.2 years, mean disease duration 11.3 years, mean EDSS 2.2), and tested with the above-mentioned tools. PRV was abnormal in 14 subjects (7.8%), associated to abnormal findings at IPSS in 3 cases, at BD in 2 cases, at both in 1. BD was abnormal in 37 subjects (20.8%), with concomitant abnormal PRV in 2, abnormal IPSS in 10 cases, abnormal IPSS and BD in 1. IPSS was ≥ 9 in 43 subjects (24.1%). At least one test was abnormal in 76 patients (42.7%): 1 in 57 patients (32.0%), 2 in 17 (9.5%), and 3 tests in 2 (1.1%). Patients with at least one abnormal urinary variable, compared to patients without urinary abnormalities, had a more frequent pyramidal involvement (69.5 vs. 16.8%, χ(2) = 48.6, p < 0.00001), a more frequent occurrence of EDSS ≥2 (83.1 vs. 23.5%, χ(2) = 56.9, p < 0.00001), and a longer disease duration (15.7 ± 7.3 vs. 9.1 ± 7.1, t = 5.7, p < 0.00001). Asymptomatic LUTS were frequent but none of the tests used permitted to better identify asymptomatic patients.

Walking improvements with nabiximols in patients with multiple sclerosis.

Recently, nabiximols was approved as a treatment in MS spasticity. Data leading to approval and clinical use of nabiximols, although widely recognised, are based on subjective scales. Movement analysis procedures would obtain more detailed data about the impact on mobility. The aim of the study was to quantitatively assess the functional modification of gait patterns induced by nabiximols in MS. We evaluated three-dimensional gait analysis (spatial-temporal and kinematic) variation by means of one-way ANOVA. Twenty patients were enrolled-9 male and 11 female-with mean EDSS of 5.3 (SD ± 0.81) and mean reduction of numerical rating scale during nabiximols treatment of 1.88. The spatial-temporal parameters of gait revealed an increased speed (+15 %, p < 0.001), cadence (+6 %, p < 0.001) and stride length (+10 %, p < 0.001) after treatment. Regarding the kinematics data, the Gait Profile Score after treatment was reduced by 10 % (p < 0.001): Significant changes involved the pelvic area, hip rotation and knee flexion-extension. We found that nabiximols is able to improve the speed, cadence and stride length. Furthermore, the dynamics of the proximal segment of the legs and the knee movement results after treatment are closer to the physiologic values.

A genetic association study of two genes linked to neurodegeneration in a Sardinian multiple sclerosis population: the TARDBP Ala382Thr mutation and C9orf72 expansion.

Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by inflammation and accompanied and followed by neurodegeneration. Missense mutations of the TAR DNA Binding Protein gene (TARDBP) located in the chromosome 1p36.22 region, and the hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) are pathogenic in other neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Assuming that TARDBP Ala382Thr mutation and C9orf72 expansion may underlie MS, we evaluated their frequency in a large cohort of MS patients and controls from Sardinia, an island characterized by a very high frequency of MS and an unusual genetic background. Genomic DNA was extracted from peripheral blood and analyzed for the presence of a TARDBP Ala382Thr mutation and C9orf72 expansion. Difference in the frequency of these mutations between MS patients and controls was calculated using the χ(2) test with a standard 2×2 table. The Ala382Thr mutation in its heterozygous state was found in 27/1833 patients (1.4%) and 20/1475 controls (1.3%), whereas C9orf72 pathogenic repeat expansion was found in 6/1014 MS patients (0.6%) and 2/333 controls (0.6%). Individuals carrying the mutations did not present with other neurodegenerative conditions and any differences were reported between groups. TARDBP Ala382Thr mutation and C9orf72 expansion do not play a major role in MS pathogenesis in the Sardinian population. Further analyses on larger samples of MS patients from other populations are needed to better define the possible role of these genes in the complex interplay between neuroinflammation and neurodegeneration in MS.

A genetic study of the FMR1 gene in a Sardinian multiple sclerosis population.

Multiple sclerosis (MS) is a complex autoimmune disease originated from the interplay between genetic and environmental factors. An overlap of clinical and neuroradiological parameters has been described between MS and an adult-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). This syndrome is caused by a trinucleotide premutation expansion of a CGG sequence in the 55-200 repeat range, which is located in the fragile-X mental retardation 1 (FMR1) gene. Female premutation carriers have an increased propensity for immune-mediated disorders. Recently, a case of co-occurrence of MS and FXTAS was reported. Assuming that the premutation expansion may play a role in the MS susceptibility, we evaluated its frequency in a cohort of MS patients from Sardinia, an island characterized by a very high frequency of MS. Nuclear DNA was extracted by standard methods, purified with bisulfite treatment and then amplified twice by PCR with specific primers. Microsatellite analysis was performed and emizogotic subjects were sequenced. Clinical data of patients were also collected. Only 1/755 MS patients exhibited the premutation expansion with a heterozygosis pattern (30/58). No pathogenic repeat expansions (>200 repeats) were found in the entire cohort. Repeats labeled as the gray zone (45-60 repeats) were observed in 15/755 patients. No specific clinical features concerning disease course, disease activity, and disability were reported for these patients. Our results do not support a possible role for premutation or gray zone alleles in MS Sardinian patients. Further studies are needed to better understand the relationship between FXTAS and MS.

Induction and escalation therapies in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease affecting the central nervous system. Pharmacological therapy of MS includes symptomatic drugs, treatment for relapses (corticosteroid and intravenous immunoglobulin) and disease modifying drugs (DMDs) defined as pharmacological agents that have an impact on relapse rate, disability accumulation and radiological outcomes. Two different therapeutic approaches are widely used in MS: escalation and induction therapy. Escalation therapy consists of an early start with first line DMDs (beta interferon, glatiramer acetate, teriflunomide, dimethyl fumarate) and if DMDs are ineffective or partially effective, switching to second line drugs (mitoxantrone, natalizumab, fingolimod). Induction therapy consists of the early use of immunosuppressant drugs followed by long-term maintenance treatment, generally with immunomodulatory agents. While the use of natalizumab and fingolimod as first line drugs is indicated for aggressive forms of MS, the indication for mitoxantrone as an induction treatment arises from randomized studies demonstrating that induction therapy with mitoxantrone followed by DMD maintenance is more effective than monotherapy with beta interferon. However, the safety profile of induction drugs indicates this is not an acceptable therapeutic strategy for all MS patients in all phases of the disease. The upcoming challenge is to identify patients at high risk of disability development from their clinical characteristics, radiological findings or biomarkers. Furthermore, future studies to establish an individual safety profile stratification are needed.

Oral agents in multiple sclerosis.

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system. Disease-modifying drugs licensed for MS treatment have been developed to reduce relapse rates and halt disease progression. The majority of current MS drugs involve regular, parenteral administration, affecting long-term adherence and thus reducing treatment efficacy. Over the last two decades great progress has been made towards developing new MS therapies with different modes of action and biologic effects. In particular, oral drugs have generated much interest because of their convenience and positive impact on medication adherence. Fingolimod was the first launched oral treatment for relapsing-remitting MS; recently, Teriflunomide and Dimethyl fumarate have also been approved as oral disease-modifying agents. In this review, we summarize and discuss the history, pharmacodynamics, efficacy, and safety of oral agents that have been approved or are under development for the selective treatment of MS.