An "all-wheel drive" proposal to accelerate clinical research in common and rare neurological diseases.

The complex biology of neurological diseases calls for collaborative efforts that may increase the success rate of clinical research. Models have been proposed, but concrete actions remain insufficient. Based on recent considerations from basic science, from science of patient input and from an analysis of scientific resources in Italy, we here explain why our country may represent an appropriate environment for such actions. Furthermore, we sketch operational framework and business model to be applied in order to accelerate, in parallel, the development of therapies in common and rare diseases.

Autologous hematopoietic stem cell transplantation in neuromyelitis optica: a registry study of the EBMT Autoimmune Diseases Working Party.

BACKGROUND: Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the central nervous system, hallmarked by pathogenic anti-aquaporin 4 antibodies. NMO prognosis is worse compared with multiple sclerosis. OBJECTIVE: The European Group for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) conducted a retrospective survey to analyze disease outcome following autologous stem cell transplantation (ASCT). METHODS: This retrospective multicenter study assessed the efficacy and safety of ASCT in 16 patients suffering from refractory NMO reported to the EBMT registry between 2001 and 2011. RESULTS: Fifteen patients were successfully mobilized with cyclophosphamide (Cy) and G-CSF, one with G-CSF alone. All patients received an unmanipulated autologous peripheral blood stem cell graft, after conditioning with BEAM plus anti-thymocyte globulin (ATG, n = 9 patients), thiotepa-Cy (n = 3) or Cy (200 mg/kg) plus ATG (n = 4). After a median follow-up of 47 months, three of 16 cases were progression and treatment free, while in the remaining 13 patients further treatments were administered for disability progression or relapse after ASCT. Altogether, relapse-free survival at three and five years was 31% and 10%, respectively, while progression-free survival remained 48% at three and five years. CONCLUSIONS: In these NMO patients, highly resistant to conventional treatment, ASCT allows for temporary control of the disease, despite a tendency to progress or relapse in the long term.

Economic impact of multiple sclerosis in Italy: focus on rehabilitation costs.

The study estimates the cost of multiple sclerosis (MS) in Italy quantifying the impact of the rehabilitation on cost of illness. Patients with MS were enrolled at MS clinical centres, in rehabilitation units and among members with MS of the Italian MS Society across the Italy. The MS costs were captured with a questionnaire and were estimated taking into account both healthcare and non-healthcare costs as well as the productivity losses. Mean total annual costs per patients were €37,948, increasing for different disease severity: from €22,750 at an EDSS score of 0-3 to €63,047 at an EDSS score equal to or more than 7. €3,418 was due to rehabilitation (about 26.7% of direct healthcare costs) and of these 44% was attributable to admission to rehabilitation. The multivariate analysis showed a consistent trend toward increased total cost with progressive severity of MS, with presence of relapses, while the total cost decreases with a better quality of life. The burden increases as the MS becomes more severe and with relapse occurrence, moreover we observed high costs due to admission to rehabilitation suggesting that different rehabilitation setting might be considered to reduce the financial burden and increase the quality of life for person with MS.

Postpartum relapses increase the risk of disability progression in multiple sclerosis: the role of disease modifying drugs.

OBJECTIVE: To assess relapses, disability progression and the role of disease modifying drugs (DMDs) in the year after delivery in women with multiple sclerosis (MS). METHODS: We prospectively followed-up pregnancies occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centres. The risk of relapses and disability progression in the year after delivery was assessed using time-dependent Cox regression analysis. RESULTS: 350 out of 423 pregnancies were assessed (pregnancies not resulting in live birth and with a postpartum follow-up period shorter than 1 year were excluded from the analysis). 148 patients (42.3%) had at least one relapse in the year after delivery. An Expanded Disability Status Scale (EDSS) score at conception ≥2.0 (HR=1.4; 95% CI 1.1 to 2.0; p=0.046) and a higher number of relapses before (HR=1.5; 95% CI 1.2 to 1.8; p<0.001) and during pregnancy (HR=2.3; 95% CI 1.6 to 3.4; p<0.001) were related to a higher risk of postpartum relapses. On the contrary, early DMD resumption after delivery marginally reduced the risk of postpartum relapses (HR=0.7, 95% CI 0.4 to 1.0; p=0.079). Moreover, 44/338 women progressed by at least one point on the EDSS. Disability progression was associated with a higher number of relapses before (HR=1.4, 95% CI 1.1 to 1.9; p=0.047) and after delivery (HR=2.7, 95% CI 1.4 to 5.2; p=0.002). CONCLUSIONS: Our findings show an increased risk of postpartum relapses and disability accrual in women with higher disease activity before and during pregnancy. Since it may reduce the risk of postpartum relapses, early DMD resumption should be encouraged, particularly in patients with more active disease.

Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study.

BACKGROUND: Most of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD. METHODS: Structured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models. RESULTS: Seventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected. CONCLUSIONS: Our data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.

Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: the Italian cohort study.

BACKGROUND: Few studies have systematically addressed the role of epidural analgesia and caesarean delivery in predicting the post-partum disease activity in women with Multiple Sclerosis (MS).The objective of this study was to assess the impact of epidural analgesia (EA) and caesarean delivery (CD) on the risk of post-partum relapses and disability in women with MS. METHODS: In the context of an Italian prospective study on the safety of immunomodulators in pregnancy, we included pregnancies occurred between 2002 and 2008 in women with MS regularly followed-up in 21 Italian MS centers. Data were gathered through a standardized, semi-structured interview, dealing with pregnancy outcomes, breastfeeding, type of delivery (vaginal or caesarean) and EA. The risk of post-partum relapses and disability progression (1 point on the Expanded Disability Status Sclae, EDSS, point, confirmed after six months) was assessed through a logistic multivariate regression analysis. RESULTS: We collected data on 423 pregnancies in 415 women. Among these, 349 pregnancies resulted in full term deliveries, with a post-partum follow-up of at least one year (mean follow-up period 5.5±3.1 years). One hundred and fifty-five patients (44.4%) underwent CD and 65 (18.5%) EA. In the multivariate analysis neither CD, nor EA were associated with a higher risk of post-partum relapses. Post-partum relapses were related to a higher EDSS score at conception (OR=1.42; 95% CI 1.11-1.82; p=0.005), a higher number of relapses in the year before pregnancy (OR=1.62; 95% CI 1.15-2.29; p=0.006) and during pregnancy (OR=3.07; 95% CI 1.40-6.72; p=0.005). Likewise, CD and EA were not associated with disability progression on the EDSS after delivery. The only significant predictor of disability progression was the occurrence of relapses in the year after delivery (disability progression in the year after delivery: OR= 4.00; 95% CI 2.0-8.2; p<0.001; disability progression over the whole follow-up period: OR= 2.0; 95% CI 1.2-3.3; p=0.005). CONCLUSIONS: Our findings, show no correlation between EA, CD and postpartum relapses and disability. Therefore these procedures can safely be applied in MS patients. On the other hand, post-partum relapses are significantly associated with increased disability, which calls for the need of preventive therapies after delivery.

B-cell-activating factor in rituximab-treated patients with anti-MAG polyneuropathy.

BACKGROUND: Antimyelin-associated glycoprotein (MAG) polyneuropathy is a slowly progressive distal form of mixed motor-sensory polyneuropathy that is scarcely responsive to conventional immunosuppressive therapy. Rituximab, a B-cell depleting antibody, is a promising therapeutic choice for anti-MAG polyneuropathy, and the evaluation of factors, such as B-cell-activating factor (BAFF), that control B-cell homeostasis is important to understand how this drug works. METHODS: Using an ELISA method, the authors measured serum BAFF concentrations in 23 patients with anti-MAG polyneuropathy, before and after rituximab therapy, in 20 neurological controls and in 14 healthy subjects. The patients were followed up over a mean period of 38±12 months and categorised as responders/non-responders, and, between the responders, as relapsing/non-relapsing. RESULTS: Pretherapy serum BAFF concentrations in non-responders were higher than in responders (cut-off 1665 pg/ml; sensitivity 71.4%; specificity 93.7%; likelihood ratio 11.4), with the highest post-therapy increases in responders. In the responders who relapsed, relapses occurred when serum BAFF concentrations returned to baseline values, 1-2 years after blood B-cell reappearance. CONCLUSIONS: Before and during therapy, measurements of serum BAFF in rituximab-treated patients with anti-MAG polyneuropathy may help predict the response to the therapy. The findings in this study also provide information about rituximab-induced modifications on B-cell homeostatic regulation.

Hand rehabilitation with sonification techniques in the subacute stage of stroke.

After a stroke event, most survivors suffer from arm paresis, poor motor control and other disabilities that make activities of daily living difficult, severely affecting quality of life and personal independence. This randomized controlled trial aimed at evaluating the efficacy of a music-based sonification approach on upper limbs motor functions, quality of life and pain perceived during rehabilitation. The study involved 65 subacute stroke individuals during inpatient rehabilitation allocated into 2 groups which underwent usual care dayweek) respectively of standard upper extremity motor rehabilitation or upper extremity treatment with sonification techniques. The Fugl-Meyer Upper Extremity Scale, Box and Block Test and the Modified Ashworth Scale were used to perform motor assessment and the McGill Quality of Life-it and the Numerical Pain Rating Scale to assess quality of life and pain. The assessment was performed at baseline, after 2 weeks, at the end of treatment and at follow-up (1 month after the end of treatment). Total scores of the Fugl-Meyer Upper Extremity Scale (primary outcome measure) and hand and wrist sub scores, manual dexterity scores of the affected and unaffected limb in the Box and Block Test, pain scores of the Numerical Pain Rating Scale (secondary outcomes measures) significantly improved in the sonification group compared to the standard of care group (time*group interaction < 0.05). Our findings suggest that music-based sonification sessions can be considered an effective standardized intervention for the upper limb in subacute stroke rehabilitation.

Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations.

Mutations in the gene MPZ, encoding myelin protein zero (MPZ), cause inherited neuropathies collectively called Charcot-Marie-Tooth type 1B (CMT1B). Based on the age of onset, clinical and pathological features, most MPZ mutations are separable into two groups: one causing a severe, early-onset, demyelinating neuropathy and a second, causing a late-onset neuropathy with prominent axonal loss. To investigate potential pathomechanisms underlying the two phenotypes, we transiently transfected HeLa cells with two late-onset (T95M, H10P) and two early-onset (H52R, S22_W28 deletion) mutations and analyzed their effects on intracellular protein trafficking, glycosylation, cell viability and intercellular adhesion. We found that the two late-onset mutations were both transported to the cell membrane and moderately reduced MPZ-mediated intercellular adhesion. The two early-onset mutations caused two distinct abnormalities. H52R was correctly glycosylated and trafficked to the plasma membrane, but strongly affected intercellular adhesion. When co-expressed with wild-type MPZ (wtMPZ), a functional dominant negative effect was observed. Alternatively, S22_W28 deletion was retained within the cytoplasm and reduced both adhesion caused by wtMPZ and cellular viability. Since the same trafficking patterns were observed in transfected murine Schwann cells, they are not an artifact of heterologous cell expression. Our results suggest that at least some late-onset mutations cause a partial loss of function in the transfected cells, whereas multiple abnormal gain of function pathways can result in early-onset neuropathy. Further characterization of these pathways will lead to a better understanding of the pathogenesis of CMT1B and a rational basis for treating these debilitating inherited neuropathies.

Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies.

Clinical investigation of autologous hematopoietic stem cell transplantation (HSCT) as therapy for multiple sclerosis (MS) has been ongoing for over a decade. While several phase II studies have been finalized or are in progress, no definitive prospective randomized studies comparing HSCT versus alternative therapies for MS have been completed. In this conference report of North American and European experts who are involved in the care of MS patients, including neurologists and HSCT physicians, and representatives of the Center for International Blood and Marrow Transplant Research (CIBMTR) and European Group for Blood and Marrow Transplantation (EBMT), we (1) critically review progress to date in HSCT for MS; (2) describe current registry based projects including long-term follow-up studies in HSCT for MS and harmonization of the MS disease-specific research forms that will be used in future by both databases; (3) discuss challenges in study design for a prospective randomized clinical trial of HSCT versus alternative therapy for MS such as feasibility, and the importance of multidisciplinary clinical teams, need for a large sample size and duration of observation required for outcomes assessment; and (4) address future directions in HSCT therapy for MS. To undertake a definitive multicenter clinical trial in autologous HSCT for MS, it will be important to begin well in advance to assemble the team, evaluate proposals for study design, and consider options for the infrastructure and logistical support that will be needed. International collaboration, including partnership with the CIBMTR and EBMT, may be desirable and may in fact be critical for successful completion of a definitive comparative study.

Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach.

OBJECTIVE: The aim of this work was to evaluate whether the treatment effects on magnetic resonance imaging (MRI) markers at the trial level were able to predict the treatment effects on relapse rate in relapsing-remitting multiple sclerosis. METHODS: We used a pooled analysis of all the published randomized, placebo-controlled clinical trials in relapsing-remitting multiple sclerosis reporting data both on MRI variables and relapses. We extracted data on relapses and on MRI "active" lesions. A regression analysis weighted on trial size and duration was performed to study the relation between the treatment effect on relapses and the treatment effect on MRI lesions. We validated the estimated relation on an independent set of clinical trials satisfying the same inclusion criteria but with a control arm other than placebo. RESULTS: A set of 23 randomized, double-blind, placebo-controlled trials in relapsing-remitting multiple sclerosis was identified, for a total of 63 arms, 40 contrasts, and 6,591 patients. A strong correlation was found between the effect on the relapses and the effect on MRI activity. The adjusted R(2) value of the weighted regression line was 0.81. The regression equation estimated using the placebo-controlled trials gave a satisfactory prediction of the treatment effect on relapses when applied to the validation set. INTERPRETATION: More than 80% of the variance in the effect on relapses between trials is explained by the variance in MRI effects. Smaller and shorter phase II studies based on MRI lesion end points may give indications also on the effect of the treatment on relapse end points.

Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years' experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases.

BACKGROUND: Autologous hematopoietic stem cell transplantation has been used since 1996 for the treatment of severe autoimmune diseases refractory to approved therapies. We evaluated the long-term outcomes of these transplants and aimed to identify potential prognostic factors. DESIGN AND METHODS: In this observational study we analyzed all first autologous hematopoietic stem cell transplants for autoimmune diseases reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 1996-2007. The primary end-points for analysis were overall survival, progression-free survival and transplant-related mortality at 100 days. RESULTS: Nine hundred patients with autoimmune diseases (64% female; median age, 35 years) who underwent a first autologous hematopoietic stem cell transplant were included. The main diseases were multiple sclerosis (n=345), systemic sclerosis (n=175), systemic lupus erythematosus (n=85), rheumatoid arthritis (n=89), juvenile arthritis (n=65), and hematologic immune cytopenia (n=37). Among all patients, the 5-year survival was 85% and the progression-free survival 43%, although the rates varied widely according to the type of autoimmune disease. By multivariate analysis, the 100-day transplant-related mortality was associated with the transplant centers' experience (P=0.003) and type of autoimmune disease (P=0.03). No significant influence of transplant technique was identified. Age less than 35 years (P=0.004), transplantation after 2000 (P=0.0015) and diagnosis (P=0.0007) were associated with progression-free survival. CONCLUSIONS: This largest cohort studied worldwide shows that autologous hematopoietic stem cell transplantation can induce sustained remissions for more than 5 years in patients with severe autoimmune diseases refractory to conventional therapy. The type of autoimmune disease, rather than transplant technique, was the most relevant determinant of outcome. Results improved with time and were associated with the transplant centers' experience. These data support ongoing and planned phase III trials to evaluate the place of autologous hematopoietic stem cell transplantation in the treatment strategy for severe autoimmune diseases.

Structural connectivity influences brain activation during PVSAT in Multiple Sclerosis.

To assess the influence of white matter pathology on cortical reorganization, we probed the fronto-parietal attention network in Multiple Sclerosis (MS) patients by combining the Paced Visual Serial Addition Test (PVSAT) with fMRI-guided fiber tractography (FT). During the PVSAT, the control subjects activated the left inferior parietal lobule, superior temporal gyrus, precuneus, precentral gyrus, and medial and middle frontal gyri; while the precuneus and the inferior parietal lobule gyrus bilaterally, the left precentral and angular gyri and the right superior parietal lobule were activated in the MS group. At fMRI-guided FT, the superior longitudinal fasciculus (SLF) was the main white matter tract connecting areas active during the PVSAT. We then identified two subgroups of MS patients according to the SLF mean Fractional Anisotropy, used as indicator of integrity. The activations of the MS patients with a less damaged tract were in the left hemisphere, similarly to controls; while the patients with a more damaged SLF showed bilateral cortical activations. The MS subgroups, however, did not differ in PVSAT performance. This approach could be useful to investigate the relationship between brain structural and functional plastic changes and to identify different MRI endophenotypes related to the same level of cognitive impairment.

Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis.

OBJECTIVE: To summarize the evidence on immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) to manage severe and treatment-refractory multiple sclerosis (MS). METHODS: We collected all the published studies of aHSCT in any form of MS from 1995 to 2016, carefully excluding reports that were updated in subsequent studies. Endpoints were transplant-related mortality (TRM), rate of disease progression, and no evidence of disease activity (NEDA) status. A weighted metaregression based on a Poisson model was run, assessing whether there were study-specific characteristics with an effect on TRM and progression. RESULTS: Fifteen studies including 764 transplanted patients were pooled in the meta-analysis. The pooled estimate of TRM was 2.1% (95% confidence interval [CI] 1.3%-3.4%). TRM was higher in older studies (p = 0.014) and in studies with a lower proportion of patients with relapsing-remitting MS (RRMS) (p = 0.028). A higher baseline Expanded Disability Status Scale (p = 0.013) was also significantly associated with a higher TRM. Pooled rate of progression was 17.1% at 2 years (95% CI 9.7%-24.5%) and 23.3% (95% CI 16.3%-31.8%) at 5 years. Lower 2-year progression rate was significantly associated with higher proportions of patients with RRMS (p = 0.004). The pooled proportion of NEDA patients at 2 years was 83% (range 70%-92%) and at 5 years was 67% (range 59%-70%). CONCLUSIONS: The emerging evidence on this therapeutic approach in MS indicates that the largest benefit/risk profile form this therapeutic approach can be obtained in patients with aggressive MS with a relapsing-remitting course and who have not yet accumulated a high level of disability.

Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells.

In multiple sclerosis (MS), dendritic cells (DCs) recruited to the central nervous system (CNS) are thought to be involved in the regulation of autoimmune responses directed against myelin antigens. To better understand the role of DCs in CNS inflammation, we performed a detailed immunohistochemical analysis of DC maturation markers and of DC relationship to CNS-infiltrating T cells in autopsy brain tissue of patients with MS. We also investigated the presence of DCs containing myelin debris in MS lesions. Myeloid DC subsets were identified using the following markers: CD1a for immature DCs; DC-SIGN for immature and mature DCs; and fascin, CD83, DC-LAMP, and CCR7 for mature DCs. The most common finding was the presence of cells expressing DC-SIGN and containing myelin components in the perivascular cuffs of early active and chronic (both active and inactive) MS lesions. Perivascular CD1a DCs were detected in active lesions in only one of 10 patients with MS who were examined. Although less numerous than DC-SIGN DCs, cells expressing mature DC markers were consistently detected in the inflamed meninges and perivascular cuffs of most active lesions examined. CCR7 immunostaining was predominantly confined to activated microglia at the lesion edges. Some perivascular DC-SIGN cells were found in close proximity to or contacting rare proliferating lymphocytes, most of which expressed the DC-SIGN ligand ICAM-3 and CD8. These data suggest that DCs recruited and maturing in MS lesions, where self-antigens are made available by continuous myelin destruction, may contribute to the local activation and expansion of presumably pathogenic T cells.

Risk of Occupational Accidents in Workers with Obstructive Sleep Apnea: Systematic Review and Meta-analysis.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is the single most important preventable medical cause of excessive daytime sleepiness (EDS) and driving accidents. OSA may also adversely affect work performance through a decrease in productivity, and an increase in the injury rate. Nevertheless, no systematic review and meta-analysis of the relationship between OSA and work accidents has been performed thus far. METHODS: PubMed, PsycInfo, Scopus, Web of Science, and Cochrane Library were searched. Out of an initial list of 1,099 papers, 10 studies (12,553 participants) were eligible for our review, and 7 of them were included in the meta-analysis. The overall effects were measured by odds ratios (OR) and 95% confidence intervals (CI). An assessment was made of the methodological quality of the studies. Moderator analysis and funnel plot analysis were used to explore the sources of between-study heterogeneity. RESULTS: Compared to controls, the odds of work accident was found to be nearly double in workers with OSA (OR = 2.18; 95% CI = 1.53-3.10). Occupational driving was associated with a higher effect size. CONCLUSIONS: OSA is an underdiagnosed nonoccupational disease that has a strong adverse effect on work accidents. The nearly twofold increased odds of work accidents in subjects with OSA calls for workplace screening in selected safety-sensitive occupations. COMMENTARY: A commentary on this article appears in this issue on page 1171.

Screening, diagnosis, and management of obstructive sleep apnea in dangerous-goods truck drivers: to be aware or not?

OBJECTIVE: The aims of this study were: to evaluate a homogeneous sample of truck drivers of dangerous goods (TDDGs) in order to assess the prevalence of obstructive sleep apnea (OSA), and to verify the secondary risk of motor vehicle accidents (MVAs) and near miss accidents (NMAs) in this population. METHODS: A sample of 283 male TDDGs was evaluated. None of the subjects reported OSA symptoms before screening. Clinical and physical evaluation, Epworth Sleepiness Scale (ESS), and the items on OSA from the Sleep Disorder Score (SDS) questionnaire were used to select subjects with suspicion of OSA. Polysomnography (PSG) was performed to confirm the diagnosis of OSA. The frequency of MVAs and NMAs was assessed at baseline for the whole sample, and also for the drivers with severe OSA after two years of continuous positive airway pressure (CPAP) treatment. RESULTS: The mean age of the sample was 42.3 ± 8.3 years. A total of 139 (49.1%) subjects had suspected OSA, and the PSG study confirmed the diagnosis in 35.7%. A significant association between OSA severity and NMAs was observed, and subjects with severe OSA showed a near five-fold increased risk of NMAs (OR = 4.745, 95% CI 1.292-17.424, p = 0.019). After two years of CPAP treatment, the rate of NMAs was comparable with drivers without OSA, showing the efficacy of therapy. CONCLUSION: This study showed an unexpected high prevalence of OSA in TDDGs. Untreated subjects with severe OSA had a significantly increased risk of NMAs. In professional drivers, screening, treatment, and management of OSA are mandatory for reducing road accident risk and improving road safety.

Neurological research in Europe, as assessed with a four-year overview of neurological science international journals.

This paper analyses all the peer-reviewed articles published by European authors in 161 neurological journals screened by ISI in accordance with Current Contents/Life Science and Current Contents/Clinical Medicine in the period 1995-1998. Our aim was to report the amount and quality of neurological research in the different countries of the European Union (EU), the USA and the world. The number of papers, the impact factors (IF), the population of the source country and gross domestic product (GDP), were downloaded. Data show that in the EU there is a progressive increase in the number of published papers from 1995 to 1998 and that large countries such as Germany, the United Kingdom, France and Italy rank at the top four places for absolute number of papers. The gap in the number of papers between the USA and the EU significantly diminished in the examined period, from a difference of 14 % to 6 %. However, when the IF is considered, the USA performed better than EU, although excellent results have been obtained by the United Kingdom, Ireland, Netherlands and Sweden. When the number and quality of papers are plotted against the number of inhabitants or GDP, Sweden, the Netherlands and Finland are the leading countries in Europe. The present study demonstrates that neurological research in the EU is active and productive, is steadily increasing and is now a relevant part of all biomedical world research.

Magnetization transfer and diffusion tensor MR imaging of acute disseminated encephalomyelitis.

BACKGROUND AND PURPOSE: Patients with acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) have a similar pattern of abnormalities on conventional MR images. We used magnetization transfer and diffusion tensor MR imaging to quantify normal-appearing brain tissue and cervical cord disease in patients with ADEM and to compare findings with those in healthy volunteers and patients with MS. METHODS: Brain dual-echo, T1-weighted magnetization transfer, and diffusion tensor images were obtained in eight patients with ADEM, in 10 patients with MS, and in 10 healthy volunteers. Fast short-tau inversion recovery, T1-weighted, and magnetization transfer cervical cord images were also obtained. We identified lesions on the images and quantified their volumes. We performed histogram analysis of the magnetization transfer ratio (MTR) and average mean histogram analysis of the diffusivity (D) in normal-appearing brain tissue and MTR in the cervical cord. RESULTS: Histogram analysis of normal-appearing brain tissue in patients with MS showed significantly lower MTRs and peak positions and significantly higher D averages compared with those in patients with ADEM. Patients with MS had significantly lower MTRs and D peak heights and significantly higher average D compared with those in healthy volunteers. Between patients with ADEM and control subjects, normal-appearing brain tissue MTR and D histogram metrics did not differ significantly. Cervical cord MTRs did not differ between control subjects and patients with ADEM, whereas the average MTR and histogram peak position was significantly lower in patients with MS than in the other groups. CONCLUSION: Outside the acute phase of disease and as opposed to what happens in MS, the normal-appearing brain tissue and cervical cord in patients with ADEM are spared in the pathologic process.