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1.  The brief international cognitive assessment for multiple sclerosis (BICAMS): normative values with gender, age and education corrections in the Italian population 
BMC Neurology  2014;14(1):171.
Background
BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) has been recently developed as brief, practical and universal assessment tool for cognitive impairment in MS subjects. It includes the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT2) and the Brief Visuospatial Memory Test–Revised (BVMT-R) . In this study we aimed at gathering regression based normative data for the BICAMS battery in the Italian population.
Methods
Healthy subjects were consecutively recruited among patient friends and relatives. Corrections for demographics were calculated using multivariable linear regression models. Test-retest reliability was assessed using the Pearson correlation coefficient.
Results
The BICAMS battery was administered to 273 healthy subjects (180 women, mean age 38.9 ± 13.0 years, mean education 14.9 ± 3.0 years). Test-retest reliability was good for all the tests.
Conclusions
The study provided normative data of the BICAMS for the Italian population confirming good test-retest reliability which can facilitate the use of the battery in clinical practice, also for longitudinal patient assessments.
doi:10.1186/s12883-014-0171-6
PMCID: PMC4172942  PMID: 25204350
Multiple sclerosis; Cognitive impairment; Assessment tool; Italian normative values
2.  Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study 
BMC Neurology  2014;14:114.
Background
Most of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD.
Methods
Structured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models.
Results
Seventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected.
Conclusions
Our data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.
doi:10.1186/1471-2377-14-114
PMCID: PMC4059028  PMID: 24884599
Multiple sclerosis; Paternity; Pregnancy; Interferon beta; Glatiramer acetate
3.  Increased CD8+ T cell responses to apoptotic T cell-associated antigens in multiple sclerosis 
Background
Here, we evaluated the hypothesis that CD8+ T cell responses to caspase-cleaved antigens derived from effector T cells undergoing apoptosis, may contribute to multiple sclerosis (MS) immunopathology.
Methods
The percentage of autoreactive CD8+ T effector cells specific for various apoptotic T cell-associated self-epitopes (apoptotic epitopes) were detected in the peripheral blood and cerebrospinal fluid (CSF) by both enzyme-linked immunospot and dextramers of class I molecules complexed with relevant apoptotic epitopes. Moreover, the capacity of dextramer+ CD8+ T cells to produce interferon (IFN)-γ and/or interleukin (IL)-17 in response to the relevant apoptotic epitopes was evaluated by the intracellular cytokine staining. Cross-presentation assay of apoptotic T cells by dendritic cells was also evaluated ex vivo.
Results
We found that polyfunctional (IFN-γ and/or IL-17 producing) autoreactive CD8+ T cells specific for apoptotic epitopes were represented in MS patients with frequencies significantly higher than in healthy donors. These autoreactive CD8+ T cells with a strong potential to produce IFN-γ or IL-17 in response to the relevant apoptotic epitopes were significantly accumulated in the CSF from the same patients. In addition, the frequencies of these autoreactive CD8+ T cells correlated with the disease disability. Cross-presentation assay revealed that caspase-cleaved cellular proteins are required to activate apoptotic epitope-specific CD8+ T cells ex vivo.
Conclusion
Taken together, these data indicate that apoptotic epitope-specific CD8+ T cells with strong inflammatory potential are recruited at the level of the inflammatory site, where they may be involved in MS immunopathology through the production of high levels of inflammatory cytokines.
doi:10.1186/1742-2094-10-94
PMCID: PMC3734107  PMID: 23890271
Apoptosis; CD8+ T cells; Multiple sclerosis
4.  Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: the Italian cohort study 
BMC Neurology  2012;12:165.
Background
Few studies have systematically addressed the role of epidural analgesia and caesarean delivery in predicting the post-partum disease activity in women with Multiple Sclerosis (MS).
The objective of this study was to assess the impact of epidural analgesia (EA) and caesarean delivery (CD) on the risk of post-partum relapses and disability in women with MS.
Methods
In the context of an Italian prospective study on the safety of immunomodulators in pregnancy, we included pregnancies occurred between 2002 and 2008 in women with MS regularly followed-up in 21 Italian MS centers. Data were gathered through a standardized, semi-structured interview, dealing with pregnancy outcomes, breastfeeding, type of delivery (vaginal or caesarean) and EA. The risk of post-partum relapses and disability progression (1 point on the Expanded Disability Status Sclae, EDSS, point, confirmed after six months) was assessed through a logistic multivariate regression analysis.
Results
We collected data on 423 pregnancies in 415 women. Among these, 349 pregnancies resulted in full term deliveries, with a post-partum follow-up of at least one year (mean follow-up period 5.5±3.1 years). One hundred and fifty-five patients (44.4%) underwent CD and 65 (18.5%) EA. In the multivariate analysis neither CD, nor EA were associated with a higher risk of post-partum relapses. Post-partum relapses were related to a higher EDSS score at conception (OR=1.42; 95% CI 1.11-1.82; p=0.005), a higher number of relapses in the year before pregnancy (OR=1.62; 95% CI 1.15-2.29; p=0.006) and during pregnancy (OR=3.07; 95% CI 1.40-6.72; p=0.005). Likewise, CD and EA were not associated with disability progression on the EDSS after delivery. The only significant predictor of disability progression was the occurrence of relapses in the year after delivery (disability progression in the year after delivery: OR= 4.00; 95% CI 2.0-8.2; p<0.001; disability progression over the whole follow-up period: OR= 2.0; 95% CI 1.2-3.3; p=0.005).
Conclusions
Our findings, show no correlation between EA, CD and postpartum relapses and disability. Therefore these procedures can safely be applied in MS patients. On the other hand, post-partum relapses are significantly associated with increased disability, which calls for the need of preventive therapies after delivery.
doi:10.1186/1471-2377-12-165
PMCID: PMC3544735  PMID: 23276328
Epidural analgesia; Caesarean delivery; Multiple sclerosis; Pregnancy
5.  Relevance of Brain Lesion Location to Cognition in Relapsing Multiple Sclerosis 
PLoS ONE  2012;7(11):e44826.
Objective
To assess the relationship between cognition and brain white matter (WM) lesion distribution and frequency in patients with relapsing-remitting multiple sclerosis (RR MS).
Methods
MRI-based T2 lesion probability map (LPM) was used to assess the relevance of brain lesion location for cognitive impairment in a group of 142 consecutive patients with RRMS. Significance of voxelwise analyses was p<0.05, cluster-corrected for multiple comparisons. The Rao Brief Repeatable Battery was administered at the time of brain MRI to categorize the MS population into cognitively preserved (CP) and cognitively impaired (CI).
Results
Out of 142 RRMS, 106 were classified as CP and 36 as CI. Although the CI group had greater WM lesion volume than the CP group (p = 0.001), T2 lesions tended to be less widespread across the WM. The peak of lesion frequency was almost twice higher in CI (61% in the forceps major) than in CP patients (37% in the posterior corona radiata). The voxelwise analysis confirmed that lesion frequency was higher in CI than in CP patients with significant bilateral clusters in the forceps major and in the splenium of the corpus callosum (p<0.05, corrected). Low scores of the Symbol Digit Modalities Test correlated with higher lesion frequency in these WM regions.
Conclusions
Overall these results suggest that in MS patients, areas relevant for cognition lie mostly in the commissural fiber tracts. This supports the notion of a functional (multiple) disconnection between grey matter structures, secondary to damage located in specific WM areas, as one of the most important mechanisms leading to cognitive impairment in MS.
doi:10.1371/journal.pone.0044826
PMCID: PMC3489883  PMID: 23144775
6.  Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study 
BMC Neurology  2012;12:124.
Background
Only few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in multiple sclerosis (MS), we aimed to assess pregnancy and fetal outcomes after in utero exposure to GA, using the same dataset, with a specific focus on the risk of spontaneous abortion.
Materials and methods
We recruited MS patients, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002–2008. Patients were divided into 2 groups: drug-exposed pregnancies (EP: suspension of the drug less than 4 weeks from conception); non-exposed pregnancies (NEP: suspension of the drug at least 4 weeks from conception or never treated pregnancies). All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders. Multivariate logistic and linear models were used for treatment comparisons.
Results
Data on 423 pregnancies were collected, 17 were classified as EP to GA, 88 as EP to IFNB, 318 as NEP. Pregnancies resulted in 16 live births in the GA EP, 75 live births in the IFNB EP, 295 live births in the NEP. GA exposure was not significantly associated with an increased risk of spontaneous abortion (OR = 0.44;95% CI 0.044-4.51;p = 0.49). Mean birth weight and length were not significantly different in pregnancies exposed to GA than in non exposed pregnancies (p = 0.751). The frequency of preterm delivery, observed in 4 subjects exposed to GA (25% of full term deliveries), was not significantly higher in pregnancies exposed to GA than in those non exposed (p > 0.735). These findings were confirmed in the multivariate analysis. There were neither major complications nor malformations after GA exposure.
Conclusions
Data in our cohort show that mother’s GA exposure is not associated with a higher frequency of spontaneous abortion, neither other negative pregnancy and fetal outcomes. Our findings point to the safety of in utero GA exposure and can support neurologists in the therapeutic counselling of MS women planning a pregnancy.
doi:10.1186/1471-2377-12-124
PMCID: PMC3487812  PMID: 23088447
Glatiramer acetate; Multiple sclerosis; Pregnancy; Pregnancy outcome; In utero exposure
7.  Impact of Natalizumab on Cognitive Performances and Fatigue in Relapsing Multiple Sclerosis: A Prospective, Open-Label, Two Years Observational Study 
PLoS ONE  2012;7(4):e35843.
Background and Objectives
Natalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years.
Methods
Cognitive performances were examined by the Rao's Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patient's self-reported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively.
Results
After 1 year of treatment the percentage of CI patients decreased from 29% (29/100) at baseline to 19% (19/100) (p = 0.031) and the mean baseline values of CII (13.52±6.85) and FSS (4.01±1.63) scores were significantly reduced (10.48±7.12, p<0.0001 and 3.61±1.56, p = 0.008). These significant effects were confirmed in the subgroup of patients treated up to two years.
Conclusions
These results demonstrate that a short-term NTZ treatment may significantly improve cognitive performances and fatigue in RRMS patients.
doi:10.1371/journal.pone.0035843
PMCID: PMC3338465  PMID: 22558238
8.  Improving the Characterization of Radiologically Isolated Syndrome Suggestive of Multiple Sclerosis 
PLoS ONE  2011;6(4):e19452.
Objective
To improve the characterization of asymptomatic subjects with brain magnetic resonance imaging (MRI) abnormalities highly suggestive of multiple sclerosis (MS), a condition named as “radiologically isolated syndrome” (RIS).
Methods
Quantitative MRI metrics such as brain volumes and magnetization transfer (MT) were assessed in 19 subjects previously classified as RIS, 20 demographically-matched relapsing-remitting MS (RRMS) patients and 20 healthy controls (HC). Specific measures were: white matter (WM) lesion volumes (LV), total and regional brain volumes, and MT ratio (MTr) in lesions, normal-appearing WM (NAWM) and cortex.
Results
LV was similar in RIS and RRMS, without differences in distribution and frequency at lesion mapping. Brain volumes were similarly lower in RRMS and RIS than in HC (p<0.001). Lesional-MTr was lower in RRMS than in RIS (p = 0.048); NAWM-MTr and cortical-MTr were similar in RIS and HC and lower (p<0.01) in RRMS. These values were particularly lower in RRMS than in RIS in the sensorimotor and memory networks. A multivariate logistic regression analysis showed that 13/19 RIS had ≥70% probability of being classified as RRMS on the basis of their brain volume and lesional-MTr values.
Conclusions
Macroscopic brain damage was similar in RIS and RRMS. However, the subtle tissue damage detected by MTr was milder in RIS than in RRMS in clinically relevant brain regions, suggesting an explanation for the lack of clinical manifestations of subjects with RIS. This new approach could be useful for narrowing down the RIS individuals with a high risk of progression to MS.
doi:10.1371/journal.pone.0019452
PMCID: PMC3084867  PMID: 21559385
9.  Evidence-based assessment of potential use of fingolimod in treatment of relapsing multiple sclerosis 
Core Evidence  2011;6:13-21.
Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the central nervous system and represents one of the most common causes of chronic neurologic disability in young adults. All the current disease-modifying drugs are administered parenterally, and can be associated with varying degrees of injection site or infusion-related reactions. Together with other side effects, the parenteral route of administration is one of the key factors affecting adherence to therapy in multiple sclerosis. Fingolimod (FTY720) is an immunomodulator that acts on sphingosine 1-phosphate (S1P) receptors and is the first oral drug approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis. Downmodulation of S1P receptor type 1 (S1P1) slows the egress of lymphocytes from lymph nodes and recirculation to the central nervous system, reduces astrogliosis, and inhibits angiogenesis during chronic neuroinflammation. Fingolimod also regulates the migration of B cells and dendritic cells, and enhances endothelial barrier function. Results from Phase II and III clinical trials provide robust evidence of the efficacy of fingolimod in relapsing-remitting multiple sclerosis. While some caution should be exercised in terms of safety issues, the introduction of fingolimod represents a great advance in the treatment of relapsing-remitting multiple sclerosis. The pharmacologic data on fingolimod and its efficacy and safety in multiple sclerosis are reviewed in this paper.
doi:10.2147/CE.S10101
PMCID: PMC3065557  PMID: 21468239
FTY720; fingolimod; S1P receptors; oral treatment; multiple sclerosis
10.  Early prediction of the long term evolution of multiple sclerosis: the Bayesian Risk Estimate for Multiple Sclerosis (BREMS) score 
Aim
To propose a simple tool for early prediction of unfavourable long term evolution of multiple sclerosis (MS).
Methods
A Bayesian model allowed us to calculate, within the first year of disease and for each patient, the Bayesian Risk Estimate for MS (BREMS) score that represents the risk of reaching secondary progression (SP).
Results
The median BREMS scores were higher in 158 patients who reached SP within 10 years compared with 1087 progression free patients (0.69 vs 0.30; p<0.0001). The BREMS value was related to SP risk in the whole cohort (p<0.0001) and in the subgroup of 535 patients who had never been treated with immune therapies, thus reasonably representing the natural history of the disease (p<0.000001).
Conclusions
The BREMS score may be useful both to identify patients who are candidates for early or for more aggressive therapies and to improve the design and analysis of clinical therapeutic trials and of observational studies.
doi:10.1136/jnnp.2006.107052
PMCID: PMC2117665  PMID: 17220286

Results 1-10 (10)