Assessing upper limb function in multiple sclerosis using an engineered glove.

BACKGROUND AND PURPOSE: The importance of upper limb function in multiple sclerosis (MS) is increasingly recognized, especially for the evaluation of patients with progressive MS with reduced mobility. Two sensor-engineered gloves, able to measure quantitatively the timing of finger opposition movements, were previously used to assess upper limb disability in MS. The aims of the present study were: (1) to confirm the association between glove-derived variables and standard measures of MS disability in a larger cohort; (2) to assess the correlation with quantitative magnetic resonance imaging (MRI) and quality of life (QoL) measures; and (3) to determine if the glove-derived variables offer advantages over the standard measure for assessing upper limb function in MS, namely, the Nine-Hole Peg Test (9HPT). METHODS: Sixty-five patients with MS, stable on disease-modifying treatment, were evaluated at baseline using the glove, and through clinical examination (Expanded Disability Status Scale, Symbol Digit Modalities Test, Timed 25-Foot Walk Test and 9HPT), MRI evaluation and QoL questionnaires. Correlations between the glove-derived variables and clinical, MRI and QoL variables were assessed using Spearman's rank correlation coefficient analysis. RESULTS: Glove-derived variables significantly differed between patients with relapsing-remitting and those with progressive MS, with similar or slightly higher correlations of the 9HPT with clinical variables. We found greater correlations of the QoL physical component with glove-derived variables than with the 9HPT, and a significant correlation of its mental component with the glove-derived variables but not with the 9HPT. CONCLUSION: The study results, confirming previous findings and showing advantages over the 9HPT, encourage the investigation of sensitivity to change in glove-derived variables in a longitudinal setting.

Subclinical motor impairment assessed with an engineered glove correlates with magnetic resonance imaging tissue damage in radiologically isolated syndrome.

BACKGROUND: An engineered glove measuring finger motor performance previously showed ability to discriminate early-stage multiple sclerosis (MS) patients from healthy controls (HCs). Radiologically isolated syndrome (RIS) classifies asymptomatic subjects with brain magnetic resonance imaging (MRI) abnormalities suggestive of multiple sclerosis. METHODS: Seventeen asymptomatic subjects with RIS and 17 HCs were assessed. They performed finger-to-thumb opposition sequences at their maximal velocity, metronome-paced bimanual movements and conventional and diffusion tensor MRI. RESULTS: Subjects with RIS showed lower (P = 0.005) maximal velocity and higher (P = 0.006) bimanual coordination impairment than HCs. In RIS, bimanual coordination correlated with T2-lesion volume, fractional anisotropy and radial diffusivity in the white matter. CONCLUSIONS: These findings point out the relevance of fine hand measures as a robust marker of subclinical disability.

Clinical activity after fingolimod cessation: disease reactivation or rebound?

BACKGROUND AND PURPOSE: There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS. METHODS: Patients with relapsing-remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis. RESULTS: A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound. CONCLUSIONS: The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described.

ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process. METHODS: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories - very high, high, low and very low - according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. RESULTS: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.

Identification of multiple sclerosis patients at highest risk of cognitive impairment using an integrated brain magnetic resonance imaging assessment approach.

BACKGROUND AND PURPOSE: While impaired cognitive performance is common in multiple sclerosis (MS), it has been largely underdiagnosed. Here a magnetic resonance imaging (MRI) screening algorithm is proposed to identify patients at highest risk of cognitive impairment. The objective was to examine whether assessment of lesion burden together with whole brain atrophy on MRI improves our ability to identify cognitively impaired MS patients. METHODS: Of the 1253 patients enrolled in the study, 1052 patients with all cognitive, volumetric MRI and clinical data available were included in the analysis. Brain MRI and neuropsychological assessment with the Brief International Cognitive Assessment for Multiple Sclerosis were performed. Multivariable logistic regression and individual prediction analysis were used to investigate the associations between MRI markers and cognitive impairment. The results of the primary analysis were validated at two subsequent time points (months 12 and 24). RESULTS: The prevalence of cognitive impairment was greater in patients with low brain parenchymal fraction (BPF) (<0.85) and high T2 lesion volume (T2-LV) (>3.5 ml) than in patients with high BPF (>0.85) and low T2-LV (<3.5 ml), with an odds ratio (OR) of 6.5 (95% CI 4.4-9.5). Low BPF together with high T2-LV identified in 270 (25.7%) patients predicted cognitive impairment with 83% specificity, 82% negative predictive value, 51% sensitivity and 75% overall accuracy. The risk of confirmed cognitive decline over the follow-up was greater in patients with high T2-LV (OR 2.1; 95% CI 1.1-3.8) and low BPF (OR 2.6; 95% CI 1.4-4.7). CONCLUSIONS: The integrated MRI assessment of lesion burden and brain atrophy may improve the stratification of MS patients who may benefit from cognitive assessment.

Relevance of asymptomatic spinal MRI lesions in patients with multiple sclerosis.

BACKGROUND: The impact of new asymptomatic spinal cord lesions (a-SL) in multiple sclerosis (MS) course is poorly characterized. OBJECTIVE: The objective of this research paper is to assess the prognostic value of a-SL in predicting MS course. METHODS: Relapsing-remitting MS patients who received serial MRI (brain and spinal) at baseline (t1) and within 12 to 36 months (t2) during clinical stability, and had a follow-up (t2-t3) ⩾24 months were included. Relapses and disability progression were evaluated between t2 and t3. RESULTS: Of 413 consecutive screened MS patients, 103 patients (65 females, median age 43 years) were included. After a median t1-t2 interval of 17 (IQR 13-26) months, 25.2% and 43.7% patients had ⩾1 new a-SL (a-SL+) and asymptomatic brain lesions (a-BL+), respectively. Relapse risk between t2 and t3 (median interval: 42 (IQR 32-57.5) months) was significantly increased in a-SL+ and/or a-BL+ vs a-BL- and a-SL- (HR = 2.31, 95% CI = 1.13-4.72, p = 0.02). No differences in the risk of disability progression were found in a-SL+ and/or a-BL+ vs a-SL- and a-BL-. CONCLUSION: a-SL occur in one-quarter of clinically stable RRMS, and combined with a-BL contribute significantly in predicting future disease course.

Fingolimod effect on brain volume loss independently contributes to its effect on disability.

BACKGROUND: Brain volume loss occurs in patients with relapsing-remitting MS. Fingolimod reduced brain volume loss in three phase 3 studies. OBJECTIVE: To evaluate whether the effect of fingolimod on disability progression was mediated by its effects on MRI lesions, relapses or brain volume loss, and the extent of this effect. METHODS: Patients (992/1272; 78%) from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study were analyzed. Month-24 percentage brain volume change, month-12 MRI-active lesions and relapse were assessed. The Prentice criteria were used to test surrogate marker validity. The proportion of treatment effect on disability progression explained by each marker was calculated. RESULTS: Two-year disability progression was associated with active T2 lesions (OR = 1.24; p = 0.001) and more relapses during year 1 (OR = 2.90; p < 0.001) and lower percentage brain volume change over two years (OR = 0.78; p < 0.001). Treatment effect on active T2 lesions, relapses and percentage brain volume change explained 46%, 60% and 23% of the fingolimod effect on disability. Multivariate analysis showed the number of relapses during year 1 (OR = 2.62; p < 0.001) and yearly percentage brain volume change over two years (OR = 0.85; p = 0.009) were independent predictors of disability progression, together explaining 73% of fingolimod effect on disability. CONCLUSIONS: The treatment effect on relapses and, to a lesser extent, brain volume loss were both predictors of treatment effect on disability; combining these predictors better explained the effect on disability than either factor alone.

Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials.

BACKGROUND AND PURPOSE: No subgroups of patients with higher treatment effects have been clearly detected in multiple sclerosis (MS). The aim of the present work was to evaluate whether there are subgroups of relapsing-remitting MS (RRMS) patients who are more responsive to treatments. METHODS: All published randomized clinical trials in RRMS reporting a subgroup analysis of treatment effect were collected. Two main outcomes, the annualized relapse rate (ARR) and the disability progression, were studied. The treatment effect in each subgroup was reported as a relative effect (RE), defined as the treatment effect in the subgroup relative to the overall effect. A meta-analysis was run to compare the RE between subgroups. RESULTS: Six trials (6693 RRMS patients) were included. Treatment effects on ARR were significantly higher in younger than in older subjects (RE = 0.83 vs. RE = 1.30, P < 0.001), in patients with than those without gadolinium activity (RE = 0.86 vs. RE = 1.15, P = 0.005) and in patients with lower than in those with higher Expanded Disability Status Scale (RE = 0.96 vs. RE = 1.23, P = 0.02), and on disability progression in younger than in older subjects (RE = 0.82 vs. RE = 1.28, P = 0.017). CONCLUSIONS: This study formally shows that in RRMS higher treatment effects are associated with characteristics of earlier (lower age and Expanded Disability Status Scale) and more active (higher gadolinium activity) disease.

Validation of 1-year predictive score of long-term response to interferon-ß in everyday clinical practice multiple sclerosis patients.

BACKGROUND AND PURPOSE: The Rio score (RS) and the modified Rio score (MRS) are two scoring systems that can identify the early predictive factors of disability progression in relapsing-remitting multiple sclerosis (RRMS) patients treated with interferon-ß (IFN-ß). The objective of the study was to validate the usefulness of the RS and MRS in a large cohort of multiple sclerosis patients treated with IFN-ß in daily clinical practice. METHODS: The analysis included a cohort of RRMS patients treated with different formulations of IFN-ß for at least 1 year. The RS and MRS were used to classify the patients after 1 year of treatment. Multivariate analysis was performed to identify predictive variables of suboptimal response at 5 years, defined as Expanded Disability Status Scale confirmed progression or switching to a second-line therapy. RESULTS: Sixty-nine of 416 included patients were considered as suboptimal responders at 5-year evaluation. The possible score range was 0-3. A higher risk of suboptimal response was found for RS and MRS in the presence of ≥2 scores (hazard ratio 3.0, P = 0.002, and hazard ratio 5.0, P < 0.0001, respectively). CONCLUSIONS: Our study confirmed, in a daily clinical setting, that MRS had a better specificity and accuracy than RS in identifying the patients who will have a poor response to long-term IFN-ß treatment.

Time to first relapse as an endpoint in multiple sclerosis clinical trials.

BACKGROUND: The increasing number of effective therapies to treat multiple sclerosis (MS) raises ethical concerns for the use of placebo in clinical trials, suggesting that new clinical trial design strategies are needed. OBJECTIVES: To evaluate time to first relapse as an endpoint for MS clinical trials. METHODS: A recently-developed model fitting the distribution of time to first relapse in MS was used for simulations estimating the sample sizes of trials using this as an outcome, and for comparison with the size of trials using the annualized relapse rate (ARR) as the primary outcome. RESULTS: Trials based on time to first relapse were feasible, requiring sample sizes that were similar or even smaller than if the study was based on ARR instead. In the case of low ARR (0.4 relapses/year), as is expected in future trials, the 1-year trials designed to detect a treatment effect of 30%, with 90% power, require fewer patients when based on time to first relapse (470 patients/arm) than if based on ARR (540 patients/arm). CONCLUSIONS: Our simulations show that time to first relapse is not less powerful than ARR in MS trials; thus, this measure would be a potentially useful primary outcome offering the advantage of an ethically sound design, as the patients randomized to placebo can then switch to the active drug, once they relapse. A potential drawback is the loss of information for other endpoints collected at fixed time points.

Scoring treatment response in patients with relapsing multiple sclerosis.

BACKGROUND: We employed clinical and magnetic resonance imaging (MRI) measures in combination, to assess patient responses to interferon in multiple sclerosis. OBJECTIVE: To optimize and validate a scoring system able to discriminate responses to interferon treatment in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Our analysis included two large, independent datasets of RRMS patients who were treated with interferons that included 4-year follow-up data. The first dataset ("training set") comprised of 373 RRMS patients from a randomized clinical trial of subcutaneous interferon beta-1a. The second ("validation set") included an observational cohort of 222 RRMS patients treated with different interferons. The new scoring system, a modified version of that previously proposed by Rio et al., was first tested on the training set, then validated using the validation set. The association between disability progression and risk group, as defined by the score, was evaluated by Kaplan Meier survival curves and Cox regression, and quantified by hazard ratios (HRs). RESULTS: The score (0-3) was based on the number of new T2 lesions (>5) and clinical relapses (0,1 or 2) during the first year of therapy. The risk of disability progression increased with higher scores. In the validation set, patients with score of 0 showed a 3-year progression probability of 24%, while those with a score of 1 increased to 33% (HR = 1.56; p = 0.13), and those with score greater than or equal to 2 increased to 65% (HR = 4.60; p < 0.001). CONCLUSIONS: We report development of a simple, quantitative and complementary tool for predicting responses in interferon-treated patients that could help clinicians make treatment decisions.

Observational case-control study of the prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis: results from the CoSMo study.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has been proposed as a possible cause of multiple sclerosis (MS). OBJECTIVES: The CoSMo study evaluated the association between CCSVI and MS. METHODS: The primary end-point of this multicentric, case-control study was to compare the prevalence of CCSVI between patients with MS, patients with other neurodegenerative diseases (ONDs) and healthy controls (HCs). Color-coded duplex sonography was performed by a sonologist and the images were sent to one of three central sonologists for a second reading. Agreement between local and central sonologists or, in case of disagreement, the predominant judgment among the three central readers, was required for a diagnosis of CCSVI. All readings, data collection and analysis were blinded. RESULTS: The study involved 35 MS centers across Italy and included 1874 subjects aged 18-55. 1767 (94%) were evaluable: 1165 MS patients, 226 patients with ONDs and 376 HCs. CCSVI prevalence was 3.26%, 3.10% and 2.13% for the MS, OND and HC groups, respectively. No significant difference in CCSVI prevalence was found amongst the three cohorts (MS versus HC, OR = 1.55, 95%CI = 0.72-3.36, p = 0.30; OND versus HC, OR = 1.47, 95%CI = 0.53-4.11, p = 0.46; MS versus OND, OR = 1.05, 95%CI = 0.47-2.39, p = 0.99). High negative and low positive agreement was found between the local and centralized readers. CONCLUSIONS: CCSVI is not associated with MS.

Temporal evolution of new T1-weighted hypo-intense lesions and central brain atrophy in patients with a first clinical demyelinating event treated with subcutaneous interferon ß-1a.

OBJECTIVE: Evaluate the effect of subcutaneous interferon ß-1a (sc IFN ß-1a) versus placebo on the evolution of T1-weighted MRI lesions and central brain atrophy in in patients with a first clinical demyelinating event (FCDE). METHODS: Post hoc analysis of baseline-to-24 month MRI data from patients with an FCDE who received sc IFN ß-1a 44 µg once- (qw) or three-times-weekly (tiw), or placebo, in REFLEX. Patients were grouped according to treatment regimen or conversion to clinically definite MS (CDMS) status. The intensity of new lesions on unenhanced T1-weighted images was classified as T1 iso- or hypo-intense (black holes) and percentage ventricular volume change (PVVC) was assessed throughout the study. RESULTS: In patients not converting to CDMS, sc IFN ß-1a tiw or qw, versus placebo, reduced the overall number of new lesions (P < 0.001 and P = 0.005) and new T1 iso-intense lesions (P < 0.001 and P = 0.002) after 24 months; only sc IFN ß-1a tiw was associated with fewer T1 hypo-intense lesions versus placebo (P < 0.001). PVVC findings in patients treated with sc IFN ß-1a suggested pseudo-atrophy that was ~ fivefold greater versus placebo in the first year of treatment (placebo 1.11%; qw 4.28%; tiw 6.76%; P < 001); similar findings were apparent for non-converting patients. CONCLUSIONS: In patients with an FCDE, treatment with sc IFN ß-1a tiw for 24 months reduced the number of new lesions evolving into black holes.

A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper.

BACKGROUND: Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1-2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing-remitting phase than in those in the secondary progressive stage. OBJECTIVES: An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments. CONCLUSIONS: Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS.

Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience.

BACKGROUND: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase. OBJECTIVES: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008. METHODS: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8-126) months. RESULTS: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing-remitting course (31%) had a 6-12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression. CONCLUSIONS: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing-remitting phase of the disease.

Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene.

OBJECTIVE: To analyze the long-term impact of the R92Q mutation of TNFRSF1A in children with periodic fever, in comparison with children with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with TNFRSF1A structural mutations and children with periodic fever of unknown origin fulfilling the criteria for periodic fever, aphthosis, pharyngitis, and adenitis syndrome (PFAPA). METHODS: The extracellular region of TNFRSF1A was analyzed in 720 consecutive children with periodic fever, using denaturing high-performance liquid chromatography and DNA sequencing. Followup data on 11 pediatric patients with TNFRSF1A structural mutations (cysteine or T50M), 23 pediatric patients with an R92Q substitution, and 64 pediatric patients with PFAPA were collected during routine clinic visits. The 50-item Child Health Questionnaire was used to assess health-related quality of life (HRQOL). RESULTS: The frequency of typical TRAPS-related clinical manifestations was significantly lower and the impact of the disease on HRQOL was significantly reduced in patients with the R92Q mutation compared with TRAPS patients carrying structural mutations of TNFRSF1A. Followup data on 11 TRAPS patients with TNFRSF1A structural mutations (mean followup 7.9 years), 16 patients with theR92Q substitution (mean followup 7.3 years), and 64 patients with PFAPA (mean followup 5.2 years) were available. Patients with R92Q mutations and patients with PFAPA displayed a higher rate of self-resolution or amelioration of the fever episodes than did TRAPS patients with structural mutations. CONCLUSION: Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.

Impairment in explicit visuomotor sequence learning is related to loss of microstructural integrity of the corpus callosum in multiple sclerosis patients with minimal disability.

Sequence learning can be investigated by serial reaction-time (SRT) paradigms. Explicit learning occurs when subjects have to recognize a test sequence and has been shown to activate the frontoparietal network in both contralateral and ipsilateral hemispheres. Thus, the left and right superior longitudinal fasciculi (SLF), connecting the intra-hemispheric frontoparietal circuits, could have a role in explicit unimanual visuomotor learning. Also, as both hemispheres are involved, we could hypothesize that the corpus callosum (CC) has a role in this process. Pathological damage in both SLF and CC has been detected in patients with Multiple Sclerosis (PwMS), and microstructural alterations can be quantified by Diffusion Tensor Imaging (DTI). In light of these findings, we inquired whether PwMS with minimal disability showed impairments in explicit visuomotor sequence learning and whether this could be due to loss of white matter integrity in these intra- and inter-hemispheric white matter pathways. Thus, we combined DTI analysis with a modified version of SRT task based on finger opposition movements in a group of PwMS with minimal disability. We found that the performance in explicit sequence learning was significantly reduced in these patients with respect to healthy subjects; the amount of sequence-specific learning was found to be more strongly correlated with fractional anisotropy (FA) in the CC (r=0.93) than in the left (r=0.28) and right SLF (r=0.27) (p for interaction=0.005 and 0.04 respectively). This finding suggests that an inter-hemispheric information exchange between the homologous areas is required to successfully accomplish the task and indirectly supports the role of the right (ipsilateral) hemisphere in explicit visuomotor learning. On the other hand, we found no significant correlation of the FA in the CC and in the SLFs with nonspecific learning (assessed when stimuli are randomly presented), supporting the hypothesis that inter-hemispheric integrity is specifically relevant for explicit sequence learning.

Magnetic resonance imaging as surrogate for clinical endpoints in multiple sclerosis: data on novel oral drugs.

Recent studies have provided evidence for using magnetic resonance imaging (MRI) active lesions as surrogate for relapses and disability progression in multiple sclerosis (MS). However, the validity of MRI metrics as surrogate endpoints in MS is controversial. Furthermore, the extrapolation of previous results to novel therapies is not warranted. We tested here the validity of MRI surrogacy in MS studies on recently published trials of oral drugs. The 92% of observed effects of oral drugs on clinical outcomes resulted close to those predicted by MRI active lesions. This further validates MRI surrogacy in MS, with important implications for future trials planning.

Pronounced focal and diffuse brain damage predicts short-term disease evolution in patients with clinically isolated syndrome suggestive of multiple sclerosis.

BACKGROUND: In clinically isolated syndrome (CIS), the role of quantitative magnetic resonance imaging (MRI) in detecting prognostic markers is still debated. OBJECTIVE: To evaluate measures of diffuse brain damage (such as brain atrophy and the ratio of N-acetylaspartate to creatine (NAA/Cr)) in patients with CIS, in addition to focal lesions, as predictors of 1-year disease evolution. METHODS: 49 patients with CIS underwent MRI scans to quantify T2-lesions (T2-L) and gadolinium-enhanced lesion (GEL) number at baseline and after 1 year. Along with 25 healthy volunteers, they also underwent combined MRI/magnetic resonance spectroscopy examination to measure normalized brain volumes (NBVs) and NAA/Cr. Occurrence of relapses and new T2-L was recorded over 1 year to assess disease evolution. RESULTS: Occurrence of relapses and/or new T2-L over 1 year divided patients with CIS into 'active' and 'stable' groups. Active patients had lower baseline NAA/Cr and NBV. Baseline T2-L number, GEL, NAA/Cr and NBV predicted subsequent disease activity. Multivariable logistic regression models showed that both 'focal damage' (based on T2-L number and GEL) and 'diffuse damage' (based on NBV and NAA/Cr) models predicted disease activity at 1 year with great sensitivity, specificity and accuracy. This was best when the four MRI measures were combined (80% sensitivity, 89% specificity, 83% accuracy). CONCLUSIONS: Quantitative MRI measures of diffuse tissue damage such as brain atrophy and NAA/Cr, in addition to measures of focal demyelinating lesions, may predict short-term disease evolution in patients with CIS, particularly when used in combination. If confirmed in larger studies, these findings may have important clinical and therapeutic implications.

Risk factors for chronic kidney disease among human immunodeficiency virus-infected patients: A European case control study.

OBJECTIVES: Renal dysfunction is a common complication in human immunodeficiency virus (HIV)-infected patients and can be attributed to direct viral damage, comorbidities or drug toxicity. The aim of this study was to assess cross-sectional correlates of renal damage in a contemporary European cohort of patients. METHODS: We performed a case-control study from our cohort of 750 HIV-infected adults over a period of 5 months. We assessed renal damage by either proteinuria (≥+ on urine dipstick), reduced creatinine clearance (< 60 ml/min) or reduced estimated glomerular filtration rate (eGFR) of < 60 ml/ min/1.73 m2. The characteristics of cases and controls were compared in analysis and in multivariate logistic regression models with stepwise selection. RESULTS: Approximately 50% of the screened 106 patients had a qualifying abnormality. Altogether, we identified 55 cases with 110 age- and gender-matched controls. Mean eGFR was 90.7 (4.8) for cases vs. 106.1 (2.3) ml/min/1.73 m2 for controls (p = 0.001). Cases had a longer duration of HIV infection, more complex regimen, longer exposure to antiretroviral therapy and a more frequent diagnosis of acquired immune-deficiency syndrome (AIDS) and hepatitis C virus (HCV) infection. In the logistic multivariate model, renal damage remained significantly associated with longer known duration of HIV infection (OR 2.88, 95% CI: 1.28 - 6.46, p = 0.01), AIDS defining condition (OR 1.09 95% CI: 1.03 - 1.16, p = 0.002) female gender (OR 2.01, 95% CI: 0.96 - 4.18, p = 0.06), and HCV infection (OR 2.12, 95% CI: 0.99 - 4.52, p = 0.05). CONCLUSIONS: Duration, antiretroviral regimen and coincidental HCV impacted the frequency of renal abnormalities in our patients.