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Objective Evaluate the effect of subcutaneous interferon β-1a (sc IFN β-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 β-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 β-1a tiw or qw, versus placebo, reduced the overall number of new lesions (P P = 0.005) and new T1 iso-intense lesions (P P = 0.002) after 24 months; only sc IFN β-1a tiw was associated with fewer T1 hypo-intense lesions versus placebo (P P Conclusions In patients with an FCDE, treatment with sc IFN β-1a tiw for 24 months reduced the number of new lesions evolving into black holes.

Treatment with fingolimod for multiple sclerosis (MS) reduces the efficacy of COVID-19 vaccination. We evaluated by a multivariate linear regression model whether main lymphocyte subsets and demographic feature correlated to the subsequent increase in anti-SARS-CoV2 antibodies following the third dose of COVID-19 vaccination in fingolimod-treated MS patients. We found that number and proportion of peripheral blood CD19+ B lymphocytes before the third dose of vaccination in MS patients treated with fingolimod, predict the subsequent increase of anti-SARS-CoV2 antibodies (respectively p = 0.013; p = 0.015). This work suggests that evaluating the numbers of CD19+ B cells may be important to identify patients at risk of not producing SARS-CoV-2 antibodies, with possible reduced protection from COVID-19.

BACKGROUND AND PURPOSE: Demyelinating lesions in the anterior visual pathways represent an underestimated marker of disease dissemination in patients with MS. We prospectively investigated whether a dedicated high-resolution MR imaging technique, the 3D-T2-STIR-ZOOMit, improves demyelinating lesion detection compared with the current clinical standard sequence, the 2D-T2-STIR. MATERIALS AND METHODS: 3T MR imaging of the anterior visual pathways (optic nerves, chiasm, and tracts) was performed using 3D-T2-STIR-ZOOMit and 2D-T2-STIR, in patients with MS and healthy controls. Two experienced neuroradiologists assessed, independently, demyelinating lesions using both sequences separately. 3D-T2-STIR-ZOOMit scan-rescan reproducibility was tested in 12 patients. The Cohen κ was used for interrater agreement, and the intraclass correlation coefficient for reproducibility. Between-sequence detection differences and the effects of location and previous acute optic neuritis were assessed using a binomial mixed-effects model. RESULTS: Forty-eight patients with MS with (n = 19) or without (n = 29) past optic neuritis and 19 healthy controls were evaluated. Readers' agreement was strong (3D-T2-STIR-ZOOMit: 0.85; 2D-T2-STIR: 0.90). The 3D-T2-STIR-ZOOMit scan-rescan intraclass correlation coefficient was 0.97 (95% CI, 0.96–0.98; P < .001), indicating excellent reproducibility. Overall, 3D-T2-STIR-ZOOMit detected more than twice the demyelinating lesions (n = 89) than 2D-T2-STIR (n = 43) (OR = 2.7; 95% CI, 1.7–4.1; P < .001). In the intracranial anterior visual pathway segments, 33 of the 36 demyelinating lesions (91.7%) detected by 3D-T2-STIR-ZOOMit were not disclosed by 2D-T2-STIR. 3D-T2-STIR-ZOOMit increased detection of demyelinating lesion probability by 1.8-fold in patients with past optic neuritis (OR = 1.8; 95% CI, 1.2–3.1; P = .01) and 5.9-fold in patients without past optic neuritis (OR = 5.9; 95% CI, 2.5–13.8; P < .001). No false-positive demyelinating lesions were detected in healthy controls. CONCLUSIONS: Dedicated 3D-T2-STIR-ZOOMit images improved substantially the detection of MS disease dissemination in the anterior visual pathways, particularly in the intracranial segments and in patients without past optic neuritis.

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.

Background: Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage. Methods: In the CLARITY study ( ClinicalTrials.gov NCT00213135), the effect of 2 years’ treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS). Results: Compared with placebo (–0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (–0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (–0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p Conclusions: Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates.

Background Multiple sclerosis (MS) is an heterogenous disease whose prevalence varies in Europe. Hereby, we aimed to estimate prevalence of MS in the Campania Region of Italy. Methods To identify individuals with MS living in the Campania Region of Italy, we extracted data from the following healthcare administrative databases: hospital discharge records, regional drug registry, and specialist outpatient visits from Jan-2015 to 3Dec-2017. Individuals alive on the 1-Jan-2018 were included to capture prevalence on this date. Age-sex standardised prevalence rates were calculated using the direct standardisation method; the European population in 2018 was considered as reference population. To assess differences in the prevalence ratios across the five provinces of the region, standardised morbility ratios (SMR) were calculated. To calculate 95% confidence intervals (95%CI) for the standardised rates, the Byar’s approximation method based on the Poisson distribution was used. Results We identified 5,361 individuals with MS (females 64.5%, age 45.6±12.7 years). Standardised prevalence rate per 100,000 people was 90.0 cases (95%CI=87.60, 92.40) (112.07 for females [95%CI=108.36, 115.88] and 66.20 for males [95%CI=63.26, 69.25]). The SMR in the province of Naples, the most densely populated, was 0.90 (95%CI=0.86, 0.96), whereas the highest SMR was found in the province of Salerno (SMR=1.30; 95%CI=1.23, 1.38), and the lowest in the province of Caserta (SMR=0.89; 95%CI=0.82-0.96). Conclusions Prevalence of MS in the Campania Region is lower than previous estimates from smaller areas in the North of Italy, suggesting a longitudinal gradient. Differences within the Region could be explained by genetic/environmental background and healthcare organization (e.g., missing diagnoses). In the future, healthcare administrative databases could be used to monitor MS prevalence/incidence and to plan healthcare resource utilization. Key messages Prevalence of MS in the Campania Region is 90 cases per 100,000 people. It is lower than previous estimates from smaller areas in the North of Italy, suggesting a longitudinal gradient. Differences within the Region could be explained by genetic/environmental background and healthcare organization (e.g., missing diagnoses).

Background: The pandemic of the new type of corona virus infection 2019 [Covid-19] also affect people with Multiple Sclerosis (pwMS). Currently, the accumulating information on the effects of the infection regarding the & nbsp;& nbsp;demographic and clinical characteristics of the disease, as well as outcomes within different DMTs & cedil; enable us to have better practices on the management of the Covid-19 infection in pwMS. Objective: To investigate the incidence of coronavirus disease 2019 (Covid-19) and to reveal the relationship between the demographic-clinical and therapeutic features and the outcome of Covid-19 infection in a multi- center national cohort of pwMS.& nbsp; Methods: The Turkish Neurological Society-MS Study Group in association with the Italian MuSC-19 Study Group initiated this study. A web-based electronic Case Report Form (eCRF) of Study-MuSC-19 were used to collect the data. The demographic data and MS histories of the patients were obtained from the file tracking forms of the relevant clinics.& nbsp; Results: 309 MS patients with confirmed Covid-19 infection were included in this study. Two hundred nineteen (219) were females (70.9%). The mean age was 36.9, ranging from 18 to 66, 194 of them (62.8%) were under 40. The clinical phenotype was relapsing-remitting in 277 (89.6%) and progressive in 32 (10.4%). Disease duration ranged from 0.2 years to 31.4 years. The median EDSS was 1.5, ranging from 0 to 8.5. The EDSS score was

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) ( 3.5 ml) than in patients with high BPF (>0.85) and low T2-LV (

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.

Purpose Debate on adjunct screening in women with dense breasts has followed legislation requiring that women be informed about their mammographic density and related adjunct imaging. Ultrasound or tomosynthesis can detect breast cancer (BC) in mammography-negative dense breasts, but these modalities have not been directly compared in prospective trials. We conducted a trial of adjunct screening to compare, within the same participants, incremental BC detection by tomosynthesis and ultrasound in mammography-negative dense breasts. Patients and Methods Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts is a prospective multicenter study recruiting asymptomatic women with mammography-negative screens and dense breasts. Eligible women had tomosynthesis and physician-performed ultrasound with independent interpretation of adjunct imaging. Outcome measures included cancer detection rate (CDR), number of false-positive (FP) recalls, and incremental CDR for each modality; these were compared using McNemar’s test for paired binary data in a preplanned interim analysis. Results Among 3,231 mammography-negative screening participants (median age, 51 years; interquartile range, 44 to 78 years) with dense breasts, 24 additional BCs were detected (23 invasive): 13 tomosynthesis-detected BCs (incremental CDR, 4.0 per 1,000 screens; 95% CI, 1.8 to 6.2) versus 23 ultrasound-detected BCs (incremental CDR, 7.1 per 1,000 screens; 95% CI, 4.2 to 10.0), P = .006. Incremental FP recall occurred in 107 participants (3.33%; 95% CI, 2.72% to 3.96%). FP recall (any testing) did not differ between tomosynthesis (FP = 53) and ultrasound (FP = 65), P = .26; FP recall (biopsy) also did not differ between tomosynthesis (FP = 22) and ultrasound (FP = 24), P = .86. Conclusion The Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts’ interim analysis shows that ultrasound has better incremental BC detection than tomosynthesis in mammography-negative dense breasts at a similar FP-recall rate. However, future application of adjunct screening should consider that tomosynthesis detected more than 50% of the additional BCs in these women and could potentially be the primary screening modality.

Highlights • This paper shows that DMD boys could be grouped into classes sharing trajectories. • Using analysis accounting for trajectory classes, the variation was strongly reduced. • Reducing unexplained variation could help to improve DMD clinical trial design., High variability in patients' changes in 6 minute walk distance (6MWD) over time has complicated clinical trials of treatment efficacy in Duchenne muscular dystrophy (DMD). We assessed whether boys with DMD could be grouped into classes that shared similar ambulatory function trajectories as measured by 6MWD. Ambulatory boys aged 5 years or older with genetically confirmed DMD who were enrolled in a natural history study at 11 care centers throughout Italy were included. For each boy, standardized assessments of 6MWD were available at annual intervals spanning 3 years. Trajectories of 6MWD vs. age and trajectories of 6MWD vs. time from enrollment were examined using latent class analysis. A total of 96 boys were included. At enrollment, the mean age was 8.3 years (mean 6MWD: 374 meters). After accounting for age, baseline 6MWD, and steroid use, four latent trajectory classes were identified as explaining 3-year 6MWD outcomes significantly better than a single average trajectory. Patient trajectories of 6MWD change from enrollment were categorized as having fast decline (n = 25), moderate decline (n = 19), stable function (n = 37), and improving function (n = 15) during the 3-year follow-up. After accounting for trajectory classes, the standard deviation of variation in 6MWD was reduced by approximately 40%. The natural history of ambulatory function in DMD may be composed of distinct trajectory classes. The extent to which trajectories are associated with novel and established prognostic factors warrants further study. Reducing unexplained variation in patient outcomes could help to further improve DMD clinical trial design and analysis.

Background The treatment effects in multiple sclerosis (MS) clinical trials are often estimated by monitoring disease activity by the count of “active” plaques on T2-weighted or gadolinium (Gd)-enhanced T1-weighted magnetic resonance imaging (MRI). Objective To evaluate the relationship between the treatment effects estimated on T2-weighted or Gd-enhanced T1-weighted MRI. Methods Data were extracted from published randomized clinical trials in relapsing-remitting MS with frequent MRI, reporting both active T2 and Gd-enhancing lesions. A regression analysis was performed between the treatment effects estimated on the two different MRI endpoints. Results A strong association was found between the treatment effect on Gd-enhancing lesions and on active T2 lesions (R2 = 0.93), and the treatment effect estimates were almost the same (slope = 0.96). Conclusion Defining either active T2 or Gd-enhancing lesions as MRI endpoint seems to be not crucial for monitoring MRI activity in MS clinical trials. The choice of the best MRI endpoint should be based on different considerations (e.g., sensitivity, reproducibility, time for assessment, safety, and patients’ comfort). Further monitoring active T2 lesions could allow less expensive trials, without requiring injection of Gd-based contrast agents.

The importance of HLA donor-recipient matching in unrelated haematopoietic SCT (HSCT) is the subject of debate. In this retrospective study, we analyzed 805 adult patients from the Italian Registry receiving HSCT for a haematological malignancy from January 1999 to June 2006 and correlated the degree of HLA matching with transplant outcome. All patient-donor pairs had high-resolution typing at HLA-A, -B, -C, -DRB1 and -DQB1. There was a significantly higher risk of overall mortality, non-relapse mortality, graft failure and acute GVHD (aGVHD) for patients receiving HSCT from an unrelated donor with one or more low- or high-resolution mismatch/es (Mm/s). When only a single HLA Mm is present (9/10 matched pairs), mortality risk is higher than among 10/10 matched pairs in patients transplanted with acute leukaemia in the first CR ('early' patients) but not in the other patients ( advanced patients): HR 1.69, 95% CI 0.94-3.02, P = 0.08; HR = 1.03, 95% CI = 0.80-1.32, P = 0.82, for early and advanced patients, respectively. These results confirm that the advantage of a 10/10 match has a greater effect in early patients, thus suggesting that a 9/10 matched donor can be chosen in patients with advanced disease lacking a rapidly available 10/10 matched one. Bone Marrow Transplantation ( 2009) 44, 571-577; doi:10.1038/bmt.2009.67; published online 13 April 2009

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.

The gold standard for measuring treatment effects is the randomized controlled trial. In patients with multiple sclerosis (MS), trial durations are typically 2-3 years, and the long-term effects of drugs for MS can only be assessed through trial extensions or observational studies that take advantage of data from registries or large single-centre databases. The main limitation of observational studies is an unavoidable selection bias that is introduced through nonrandom assignment of the intervention. Propensity score methods can mitigate this bias by balancing the groups with respect to baseline covariates, but this approach cannot correct for unmeasurable confounding factors. Extensions of clinical trials are free from selection biases because of the initial randomization, but they can only provide an assessment of early versus delayed treatment effects. Here, we discuss these methodological issues and analyse how they have been managed in studies of the long-term effects of IFN-β in patients with MS.

Appropriate supportive care and identification of long-term sequels of therapy are of paramount importance in HIV-infected pediatric patients. As low bone mineral quality (BMQ) in patients can be considered a marker of possible degeneration in osteopenia and osteoporosis in adulthood, we evaluated bone features in a pediatric population. Forty-four patients (23 females, 21 males; aged 3-17 years) were compared with a control population (1227 healthy children: 568 females, 641 males; aged 3-18 years). Seven patients were CDC stage C, 18 B, and 18 A. All patients were vertically infected; four were naive to any antiretroviral treatment, seven were taking two NRTIs, and 32 were on HAART. BMQ was assessed by a quantitative ultrasound (QUS) technique. It measures the amplitude-dependent speed of sound (AD-SoS, m/sec) and the bone transmission time (BTT, microsec). QUS values were significantly lower in cases than in controls, even after adjustment for age and body size (AD-SoS: 1924.7 +/- 64.9 and BTT: 0.97 +/- 0.3 in controls; AD-SoS: 1879.7 +/- 57.2 and BTT: 0.80 +/- 0.32 in cases; por = 0.001). The associations of AD-SoS and BTT with gender, type of therapy, and CDC stages were not significant. AD-SoS and BTT were significantly associated with age (r = 0.59, p0.0001), skeletal age SDS (r = 0.46, p = 0.002), height (r = 0.66, p0.0001), and therapy duration (r = 0.31, p = 0.04). Both AD-SoS and BTT values in patients fell below mean values of controls. Follow-up of bone mineral density is important in patients to prevent long-term problems of skeletal status.

We have previously described a scoring system for patients undergoing hemopoietic stem cell transplantation (HSCT) based on day +7 blood urea nitrogen (BUN) and serum bilirubin levels. We have revised that scoring system using a formal multivariate approach based on a training phase (305 patients) and a validation phase (217 patients). Day +7 BUN, serum cholinesterase (CHE), total proteins (TP), gamma glutamyl transferase (gammaGT), donor type and cell dose at transplant were included in the new score. The score distribution identified three groups of patients in the training set (25, 25-75,75 percentile of the score) which were classified as low, intermediate and high risk. Their actuarial risk of transplant-related mortality (TRM) at 6 years was, respectively, 12, 38 and 60%. In the validation set the 6 year actuarial TRM was, respectively, 15, 40 and 69%. High risk patients had more graft-versus-host disease (GvHD) (P0.0001) and lower platelet counts (P0.0001). This study confirms that GvHD and TRM can be predicted on day +7 after HSCT: pre-emptive GvHD therapy may be one option for high-risk patients and is being tested in a prospective randomized trial. The score for single patients can be calculated on the web site http://213.26.110.20/lrm/day_seven_score.html.

Objectives – The present study was planned to investigate the relationship between the plasma lipid profile and disease activity in patients with a first clinical episode suggestive of multiple sclerosis (MS). Material and methods – Eighteen consecutive out-patients underwent a monthly brain magnetic resonance imaging (MRI), blood sample and neurological assessment over 6 months. Blood samples were used to evaluate total cholesterol and triglyceride levels as well as their lipoprotein fractions. Plasma total apolipoprotein E concentration was also determined. Results – We found a significant correlation between the mean number of enhancing lesions and the mean plasma level of both total and low density lipoprotein cholesterol. The total plasma cholesterol level increased on average by 4.4 mg/dl for each enhancing lesion. Conclusion – Our preliminary data suggest a potential role of plasma cholesterol level as a biological marker of disease activity after a first demyelinating event. Further studies need, however, to be designed to determine whether the plasma cholesterol level is of practical use in monitoring the disease course.

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

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.

Recent studies showed that rituximab, a chimeric anti-CD20 monoclonal antibody, reduces antibody levels and ameliorates neuropathy in two thirds of patients with neuropathy and anti-myelin-associated glycoprotein (MAG) monoclonal IgM.1–3 Few data are available on the long-term effects of this therapy.4 We report on the long-term follow-up of rituximab responders with anti-MAG polyneuropathy. ### Methods. Ten patients with anti-MAG polyneuropathy responding to rituximab, 375 mg/sq for four consecutive weekly infusions, were prospectively studied for 36 months. The effects of the initial treatment in 13 patients and the type of assessment were previously described.3 The baseline clinical and laboratory data of the 10 responding patients are reported in the table. All but one patient (no. 1) had an IgM monoclonal gammopathy of undetermined significance and a symptom duration of up to 2 years. Three patients had not been previously treated for the neuropathy, whereas seven were unresponsive to immune or cytostatic therapies. We considered as responders patients who improved at month 12 by at least one point in two clinical scales including MRC sumscore (appendix e-1 on the Neurology ® Web site at www.neurology.org), INCAT Disability Scale (appendix e-2), and INCAT sensory sumscore (ISS) …

In this study we assessed the safety, efficacy and cost-effectiveness of the use of triple dose gadolinium-DTPA (Gd) in serial monthly brain MRI of patients with multiple sclerosis, such as could be selected for clinical trials. The number of enhancing lesions, the number of new enhancing lesions and the number of active scans were used to evaluate the sensitivity of the contrast-enhanced MRI to disease activity. The dose of Gd, and the effect of introducing a delay between the contrast injection and the scan were both appraised. Every 4 weeks for 3 months, and in two separate sessions, scans were obtained from 40 patients with relapsing-remitting or secondary progressive multiple sclerosis, 5 min (early) and 20 min (delayed) after a standard dose (0.1 mmol/kg) or triple dose (0.3 mmol/kg) Gd injection. There were 435 enhancing lesions (242 of which were new) on the early standard dose scans, 479 (263 new) on the delayed standard dose, 772 (365 new) on the early triple dose and 827 (404 new) on the delayed triple dose. There were 109 scans revealing active disease on the early standard dose scans, 112 on the delayed standard dose, 119 on the early triple dose and 120 on the delayed triple dose. Statistical simulations indicated that the sample sizes needed for both cross-over and parallel-group trials with similar powers are lower if serial monthly triple dose MRI is used. No side-effects were reported and no significant changes in blood test parameters were found throughout the study. This study shows that the serial use of triple dose Gd is safe, and that it increases the sensitivity of serial monthly enhanced MRI in detecting multiple sclerosis activity significantly. Its use should enable preliminary trials of experimental therapies for multiple sclerosis to be conducted in small patient populations, over a short period of time.

To investigate the plasma levels of lopinavir by enzyme-linked immunosorbent assay (ELISA) in a cohort of patients who were vertically infected with human immunodeficiency virus 1 (HIV).Plasma levels of lopinavir (Cmin) were determined by ELISA test in patients treated with lopinavir/ritonavir-based combined antiretroviral therapy who had achieved virological response after 4 wk of therapy. Reference lopinavir concentrations were Cmin 1-8 μg/mL. Correlation between lopinavir plasma concentration and continuous variables was evaluated by mean of Pearson correlation coefficient. Differences in lopinavir (LPV) concentration for binary categorical variables were assessed by Mann-Whitney test, while for variables with more than two categories Kruskal-Wallis test was used.Thirty-four patients were enrolled; median age was 133 mo (15-265). The median lopinavir dose tested was 383.5 mg/kg (IQR: 266.6-400 mg/kg), with a median plasma concentration of 8.8 μg/mL (IQR: 5-14 μg/mL). Lopinavir Cmin was1 μg/mL in only one sample (2.9 %), while 14 samples had Cmin between 1 and 8 μg/mL (41.2 %) and 19 (55.9 %) 8 μg/mL. No significant correlations were found between plasma concentrations of lopinavir and the continuous variables considered in the study. A negative but, not completely significant, correlation was found between plasma drug concentration and body mass index (r = -0.29; p = 0.09).The use of a simple and relatively cost-effective methodology might render therapeutic drug monitoring (TDM) appeal in the daily clinical practice.

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.

Purpose of the study : Promising research suggest that maraviroc (MVC) has favourable clinical outcome in HIV-infected patients (pts). Aim of the study is to assess: durability, safety profile and immunovirological recovery in a large MVC-based cohort. Methods : All HIV pts treated with antiretroviral therapy (ART) containing MVC for at least 6 months (all viruses CCR-5 tropic analyzed by genotypic and phenotypic test) were recruited in an observational multicenter study. Eight Infectious Diseases Centers in Liguria and Piedmont (Italy) collected at baseline and every 3 months demographics, clinical and immunovirological data on a web-based system (by MedinfoDist, University of Genoa). We used SPSS for Pearson Chi square test and for generalized estimating equation (GEE); in this model for longitudinal data and frequency analysis we considered altered: TCD4+ ≤350/mmc, HIVRNA >50 cp/ml, total cholesterol >200 mg/dl, triglycerides >160 mg/dl, transaminase >40 mg/dl, creatinine >1.3 mg/dl and we divided data in 5 time periods: baseline, 1-6, 9-12, 15-24 and 24-45 months. Summary of results : We enrolled 55 pts: 36 (65%) males, median age 49.6 years (yrs) (range [r] 18.2-76.6, IQR 44.5-53.3), 11 (20%) HCVRNA-positive, 4 (7%) HBsAg-positive, 1 both infection. Twenty-four (44%) pts were classified as CDC C stage, median nadir TCD4+ was 219/mmc (r 11-529, IQR 125-317), median duration of ART was 15.3 yrs (r 1.3-27.3, IQR 12-16.8), median duration of treatment with MVC was 23 months (r 6-47, IQR 14-36). At baseline 42 (76%) pts had HIVRNA >50 cp/ml, 11 (20%) HIVRNA ≤50 cp/ml, 2 (4%) pts no data; on treatment at the last examination 53 pts (96%) had HIVRNA ≤50 cp/ml, 2 pts still had HIVRNA >50 cp/ml (CCR5 tropic) and median TCD4+ count was 469/mmc (r 73-1802, IQR 302-592). One pt died and only 2 pts shifted to X4. Chi square test at 9-12 months showed p=0.0001 and the 80% of pts had TCD4+ >350/mmc; at the same observation time 83.3% of pts had HIVRNA ≤50 cp/ml (p=0.0001). About cholesterol, triglycerides, transaminase and creatinine no significative differences were found and the median value showed no changes. Conclusions : In our study a majority of pts treated with ART containing MVC achieved a count of TCD4 >350/mmc and HIVRNA undetectable within 9-12 months. This regimen is a safe, feasible option and in pts with a poor immunological stage, MVC offered a remarkable TCD4+ count gain with limited X4 strains onset. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Dentone C et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18265 http://www.jiasociety.org/index.php/jias/article/view/18265 | http://dx.doi.org/10.7448/IAS.15.6.18265

Chronic GVHD (cGVHD) has been associated with reduced risk of relapse after allo-SCT for onco-hematological disease due to a graft-vs-malignancy effect. Here we retrospectively analyzed a series of 802 adult patients transplanted from unrelated donors and found that cGVHD was associated with significantly lower relapse and that the limited form was associated with a survival advantage: hazard ratio for OS=0.63 (0.46-0.87); P=0.004; this was due to combination of relapse reduction and similar non-relapse mortality with respect to patients without cGVHD. Importantly, the graft-vs-malignancy effect observed here did not differ when PBSC or BM were used as stem cell source, thus suggesting that the protective effect of limited cGVHD is similar after PBSC- or BM-based transplantation. These findings could have practical implications and suggest no qualitative difference between cGVHD occurring after transplantation performed with different stem cell sources.

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.

The risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab for multiple sclerosis (MS) is a serious concern. The presence of anti-JC virus antibodies is a risk factor for PML development, but 2.5 % of the patients result falsely-negative, while the prognostic relevance of testing JCV-DNA in biological fluids of treated patients is debated. Aim of this work was to evaluate the utility of testing JCV-DNA, together with anti-JCV antibodies, in biological samples of treated patients as a tool for PML risk stratification. 126 subjects from 5 MS Centers in Italy were included in the study. We performed a cross-sectional study in 63 patients testing JCV-DNA in blood, peripheral blood cells and urine. We longitudinally assessed the presence of JCV-DNA in a cohort of 33 subjects, one of which developed PML. We could test retrospectively serum samples from another PML case occurred during natalizumab therapy. Anti-JCV antibodies and urinary JCV-DNA were both tested in 73 patients. No changes in JCV-DNA status occurred during natalizumab treatment. The subject who developed PML in the longitudinal cohort had detectable JCV-DNA in urine at all time-points while serum or blood from both PML patients were always negative before the onset of disease and, in one case, after. Four subjects with JCV-DNA in urine and undetectable anti-JCV antibodies were retested for anti-JCV antibodies and three out of four resulted positive. In conclusion, testing JCV-DNA in urine is complementary to testing anti-JCV antibodies in identifying patients at risk of PML.

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 m 2 . 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 m 2 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 = 0.0 1), 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.

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.

BACKGROUND AND PURPOSE: Reliable markers to monitor PPMS are still needed. We investigated whether conventional and DTI measures of thalamic damage are predictive of long-term disability accumulation in PPMS. MATERIALS AND METHODS: Brain conventional and DTI scans were obtained at baseline and after a mean follow-up of 15 months in 54 patients with PPMS and 8 healthy controls. Patients were reassessed clinically after 5 years. At baseline and follow-up, measures of lesion load, brain atrophy, and NTV were obtained. MD and FA histograms of the NAWM, the whole GM without the thalami, and the thalami were obtained. A multivariate analysis evaluated the predictors of long-term neurologic deterioration. RESULTS: At follow-up, 35 patients showed disability worsening. At baseline, compared with healthy controls, patients with PPMS had lower NTV (P < .001) and thalamic FA (P = .002) and higher thalamic (P = .002) and whole GM without the thalami (P = .005) MD. During follow-up, the change of thalamic FA was higher in PPMS versus healthy controls (P = .01). Baseline NTV and thalamic DTI quantities differed significantly between patients with PPMS with and without thalamic lesions. Baseline thalamic quantities were significantly correlated with the extent of brain T2 lesions and the severity of NAWM damage. The multivariate model included average NAWM MD (OR = 1.46, P = .005) and FA thalamic change (OR = 0.84, P = .02) as independent predictors of EDSS score deterioration (Nagelkerke R(2) = 0.55). CONCLUSIONS: Short-term accrual of thalamic damage and the severity of NAWM involvement predict the long-term accumulation of disability in PPMS.

Objective: In multiple sclerosis (MS), the aim of therapies is to prevent the accumulation of irreversible disability. This is difficult to assess given the short time course of clinical trials. MRI markers and relapses are often used as surrogate of disability in MS studies, but their validity remains controversial. We sought to validate, at the individual patient level, MRI lesions and relapses as surrogates for disability progression over the course of MS trials. Methods: Individual patient data from a large, placebo-controlled trial of interferon β-1a in relapsing-remitting MS (RRMS) were analyzed. The Prentice criteria were applied to evaluate surrogacy of 1-year MRI active lesions and relapses for disability worsening (Expanded Disability Status Scale [EDSS]) over the 2-year follow-up. Results: All Prentice criteria were satisfied. Treatment reduced by 31% the odds of having EDSS worsening over 2 years, reducing the mean number of MRI lesions by 61% and the mean number of relapses by 36% over 1 year. Both 1-year MRI lesion activity and relapses, when considered independently, accounted for more than 60% of the treatment effect on 2-year EDSS worsening. A combination of 1-year MRI lesion activity and relapses explained 100% of the treatment effect on EDSS worsening over 2 years. Conclusions: A combined measure of 1-year changes in MRI lesions and relapses after interferon therapy fully estimated the corresponding effect on 2-year EDSS worsening. This short-term combined measure appears to be a surrogate for disability progression over a longer term when evaluating the effect of interferon in RRMS.

1477-0970 (Electronic) 1352-4585 (Linking) Journal Article; This study was performed to assess the temporal evolution of damage within lesions and the normal-appearing white matter, measured using frequent magnetization transfer (MT) MRI, in relapsing-remitting multiple sclerosis (RRMS). The relationship of MT ratio (MTR) changes with measures of lesion burden, and the sample sizes needed to demonstrate a treatment effect on MTR metrics in placebo-controlled MS trials were also investigated. Bimonthly brain conventional and MT MRI scans were acquired from 42 patients with RRMS enrolled in the placebo arm of a 14-month, double-blind trial. Longitudinal MRI changes were evaluated using a random effect linear model accounting for repeated measures, and adjusted for centre effects. The Expanded Disability Status Scale (EDSS) score remained stable over the study period. A weak, but not statistically significant, decrease over time was detected for normal-appearing brain tissue (NABT) average MTR (-0.02% per visit; p = 0.14), and MTR peak height (-0.15 per visit; p = 0.17), while average lesion MTR showed a significant decrease over the study period (-0.07% per visit; p = 0.03). At each visit, all MTR variables were significantly correlated with T2 lesion volume (LV) (average coefficients of correlation ranging from -0.54 to -0.28, and p-values from

Objective: To evaluate whether the effects on potential surrogate endpoints, such as MRI markers and relapses, observed in trials of experimental treatments are able to predict the effects of these treatments on disability progression as defined in relapsing-remitting multiple sclerosis (RRMS) trials. Methods: We used a pooled analysis of all the published randomized controlled clinical trials in RRMS reporting data on Expanded Disability Status Scale (EDSS) worsening and relapses or MRI lesions or both. We extracted data on relapses, MRI lesions, and the proportion of progressing patients. A regression analysis weighted on trial size and duration was performed to study the relationship between the treatment effect observed in each trial on relapses and MRI lesions and the observed treatment effect on EDSS worsening. Results: A set of 19 randomized double-blind controlled trials in RRMS were identified, for a total of 44 arms, 25 contrasts, and 10,009 patients. A significant correlation was found between the effect of treatments on relapses and the effect of treatments on EDSS worsening: the adjusted R 2 value of the weighted regression was 0.71. The correlation between the treatment effect on MRI lesions and EDSS worsening was slightly weaker ( R 2 = 0.57) but significant. Conclusions: These findings support the use of commonly used surrogate markers of EDSS worsening as endpoints in multiple sclerosis clinical trials. Further research is warranted to validate surrogate endpoints at the individual level rather than at the trial level, to draw important conclusions in the management of the individual patient.

OBJECTIVE: To compare the efficacy, tolerability, and safety of IV methylprednisolone (IV MP) vs oral methylprednisolone (oMP) at equivalent high doses in patients with multiple sclerosis (MS) experiencing a recent relapse.METHODS: Patients with a clinical relapse within the previous 2 weeks and at least 1 gadolinium (Gd)-enhancing lesion on a screening brain MRI scan were included. Forty patients with MS were randomized to receive either 1 g/day for 5 days of oMP (20 patients) or 1 g/day for 5 days of IV MP (20 patients). Expanded Disability Status Scale (EDSS) and brain MRI (dual-echo and postcontrast T1-weighted scans) were assessed at baseline and at weeks 1 and 4. The study primary research question (endpoint) was to compare the efficacy of the 2 treatment routes in reducing the number of Gd-enhancing lesions after 1 week from treatment initiation. Secondary outcomes were safety, tolerability, and clinical efficacy profiles of the 2 routes of administration.RESULTS: The 2 groups showed a reduction of Gd-enhancing lesions over time (p = 0.002 for oMP and p = 0.001 for IV MP) with a "non-inferiority effect" between the 2 routes of administration at week 1. Both groups showed an improvement of EDSS over time (p < 0.001) without between-group difference at week 4. Both treatments were well-tolerated and adverse events were minimal and occurred similarly in the 2 treatment arms.CONCLUSIONS: Oral methylprednisolone (oMP) is as effective as IV methylprednisolone in reducing gadolinium-enhancing lesions in patients with MS soon after an acute relapse with similar clinical, safety, and tolerability profiles. This study provides class III evidence that 1 g oMP x 5 days is not inferior to 1 g IV MP x 5 days in reducing the number of gadolinium-enhancing lesions over a period of 1 week (mean difference in lesion reduction comparing IV MP to oMP is -20%, 95% confidence interval -48% to + 5%).

Traditionally, the clinical endpoints used to monitor clinical trials in multiple sclerosis (MS) are the occurrence of relapses (usually expressed as a rate over time), and the degree of disability, most commonly evaluated using the Expanded Disability Status Scale (EDSS) [1].

Objective . The aim of the study was to evaluate the pattern of the lymphoid organization in the synovial tissue of patients affected with juvenile idiopathic arthritis (JIA). Methods . A total of 40 JIA patients who underwent synoviectomy or synovial biopsies were enrolled. The mean age at surgery was 15.1 yrs (range 6–30 yrs) and the mean disease duration was 6.7 yrs (range 3 months to 22.2 yrs). Tissue specimens were grouped according to the following criteria: (i) diffuse perivascular infiltrate without lymphoid organization, (ii) T cell–B cell aggregates with or without germinal centre reaction. Results . Synovial tissues from 12 JIA patients did not show any sign of lymphoid organization, whereas 28 patients displayed a variable number of T–B cell aggregates. Typical features consistent with a germinal centre reaction were present in two JIA patients only. Lymphoid organization in JIA patients did not correlate with the duration and severity of the disease or with the degree of synovial inflammation, but did positively correlate with the presence of anti-nuclear antibodies. Moreover, a diffuse lymphocyte infiltration was significantly related to the presence of an acute phase of inflammation and the presence of lymphoid aggregates correlated with the degree of plasma cells infiltration. Conclusions . Lymphoid neogenesis in JIA represents a phase in the immunopathological process that characterize the development of inflammatory synovitis. It is not related to disease activity or severity, but appears to be more frequent in patients with circulating anti-nuclear antibodies.

Reliable prognostic markers of primary progressive (PP) multiple sclerosis evolution are still needed. Diffusion tensor (DT) MRI can quantify normal-appearing white matter (NAWM) and grey matter (GM) damage in multiple sclerosis patients. We investigated whether conventional and DT-MRI-derived measures can predict the long-term clinical evolution of PP multiple sclerosis. In 54 PP multiple sclerosis patients, conventional and DT-MRI scans of the brain and T-1-weighted scans of the cervical cord were acquired at baseline and after a median follow-up of 15 months. Another clinical evaluation was performed, 56 months after baseline, in 52 patients. Measures of lesion load, brain and cord atrophy were obtained. Histograms of the mean diffusivity (MD) and fractional anisotropy (FA) values from the NAWM and GM were analysed. At follow-up, 35 patients (65%) experienced a confirmed disability progression. Baseline expanded disability status scale score and average GM MD were independent predictors of subsequent clinical deterioration in a multivariable model (Nagelkerke R-2: 0.44; discriminating ability: 81%). A lower level of disability and a more severe GM damage identify PP multiple sclerosis patients with an increased risk of disease progression over the subsequent 5 years. These data may be relevant to select patients for future exploratory phase II trials.

This study aimed at evaluating the influence of a different slice orientation on brain magnetic resonance imaging (MRI) lesion load in multiple sclerosis (MS). Fifteen MS patients were scanned obtaining both axial and sagittal conventional spin echo (24 slices; TR 2400, TE 30/80) brain MRI. The total lesion load (TLL) was assessed twice for each scan, using a semi-automated local thresholding technique and the same marked hardcopies. The mean TLL was 22734 mm3 for axial and 22003 mm3 for sagittal scans. The mean intra-observer coefficient of variation (COV) was 4.65% for the axial acquisitions and 4.52% for the sagittal acquisitions. This difference was not statistically significant (one-way ANOVA, P> 0.1). The lesion load was significantly higher from axial MRI as compared to the intra-observer variability (two-way ANOVA, P =0.01), but the fluctuations around this average difference between axial and sagittal scan TLL were significantly large (test for interaction, P < 0.00I). Our data indicate that the use of sagittal conventional MRI scans does not seem to be worthwhile for the quantitative assessment of lesion load in MS patients.

Objective: To define the nature and the temporal evolution of neuronal/ axonal injury in patients at the earliest clinical stage of multiple sclerosis (MS), using whole brain N-acetylaspartate (WBNAA) proton MR spectroscopy (H-1-MRS). Methods: Thirty-five patients at presentation with clinically isolated syndromes (CIS) and MRI evidence of disease dissemination in space were studied. The following scans of the brain were acquired within 3 months from the onset of the disease and after 12 months: 1) dual-echo; 2) WBNAA H-1-MRS; 3) pre- and postcontrast T1-weighted. The same scans were obtained in 12 age-matched healthy subjects, without contrast administration. In patients, conventional MRI scans were also repeated 3 months after the first scanning session, to assess the presence of early disease dissemination in time (DIT). Results: Over the study period, 24 patients showed MRI evidence of disease DIT, thus fulfilling the criteria for a diagnosis of MS. The average WBNAA amount was lower in CIS patients than in controls both at baseline (13.7 vs 16.9 mM, p < 0.001) and at 1-year follow-up (12.6 vs 16.2 mM, p < 0.001), but the average yearly percentage change of WBNAA did not differ between the two groups. No MRI or H-1-MRS quantities were significantly associated with the disease DIT over the study period. Conclusion: Irreversible brain damage associated with axonal dysfunction occurs at a very early stage in patients with clinically isolated syndromes, but it does not seem to be related with the disease evolution in the subsequent short-term period.

Little is known about the temporal evolution of gray matter damage occurring early in the course of multiple sclerosis (MS). The authors investigated the evolution of gray matter volume loss in 117 patients with relapsing-remitting MS, scanned monthly for a 9-month period. Time-trend analysis revealed a decrease of gray matter volumes over the study period (p < 0.001). This study shows that gray matter damage in relapsing-remitting MS evolves markedly over a short period of observation.

The 6 min walk test (6MWT) has been recently chosen as the primary outcome measure in several international multicenter clinical trials in Duchenne muscular dystrophy (DMD) ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment and with age and 6MWT values at baseline. 96 patients from 11 centers were assessed at baseline and 1, 2 and 3 years after baseline. Three boys (3%) lost the ability to perform the test within 12 months, another 13 between 12 and 24 months (14%) and other 11 between 24 and 36 months (12%). The 6MWT showed an average overall decline of −15.8 (SD 77.3) meters in the first year, of −58.9 (SD 125.7) in the second year and −104.22 (SD 146.2) in the third year. The changes were significantly different in the two baseline age groups and according to the baseline 6MWT values (below and above 350 m) (test for interaction, p

The authors estimated the sample sizes needed for exploratory trials of MS assessing the efficacy of new treatments in reducing the number of new enhancing lesions vs those of interferon-beta or glatiramer acetate. The sample sizes per arm ranged from 868 (effect: 20%) to 94 (effect: 50%) for patients with relapsing-remitting MS and from 2,484 (effect: 20%) to 361 (effect: 50%) for patients with secondary progressive MS. In MS, exploratory trials of new vs available therapies require large numbers of patients, even when MR end-points are used.

The clinical endpoints that are conventionally used in clinical trials in multiple sclerosis (MS) are: (a) occurrence of exacerbations often expressed as a rate, and (b) disability, usually evaluated by means of the Expanded Disability Status Scale (EDSS) [1]. These two endpoints represent the two fundamental dimensions affecting the evolution of the disease and the quality of life of MS patients. However, from a statistical viewpoint, they have several drawbacks. First of all, they cannot be assessed objectively, and their reproducibility is low [2]. As a consequence, in treatment trials both the patient and the physician in charge of assessing the clinical endpoint should be blinded to the assigned treatment. This is not always possible, depending on the study design or the toxicity of the experimental treatment. Second, their correlation with the pathological changes associated with the activity of the disease is poor [3, 4]. Finally, the sensitivity of EDSS to change is moderate [5], and often trials lasting much longer than 2–4 years would be needed to establish the effect of a new treatment on EDSS. All these limitations decrease the statistical power and the reliability of clinical trials based on these two clinical endpoints, with implications on the size and duration of MS trials, as well as on their design.