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Altres ajuts: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The workshop on which the manuscript is based was supported in its entirety by the European Committee on Treatment and Research in Multiple Sclerosis (ECTRIMS). The natural history of multiple sclerosis (MS) is highly heterogeneous. A subgroup of patients has what might be termed aggressive MS. These patients may have frequent, severe relapses with incomplete recovery and are at risk of developing greater and permanent disability at the earlier stages of the disease. Their therapeutic window of opportunity may be narrow, and while it is generally considered that they will benefit from starting early with a highly efficacious treatment, a unified definition of aggressive MS does not exist and data on its treatment are largely lacking. Based on discussions at an international focused workshop sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), we review our current knowledge about treatment of individuals with aggressive MS. We analyse the available evidence, identify gaps in knowledge and suggest future research needed to fill those gaps. A companion paper details the difficulties in developing a consensus about what defines aggressive MS.

Altres ajuts: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The workshop on which the manuscript is based was supported in its entirety by the European Committee on Treatment and Research in Multiple Sclerosis (ECTRIMS). While the major phenotypes of multiple sclerosis (MS) and relapsing-remitting, primary and secondary progressive MS have been well characterized, a subgroup of patients with an active, aggressive disease course and rapid disability accumulation remains difficult to define and there is no consensus about their management and treatment. The current lack of an accepted definition and treatment guidelines for aggressive MS triggered a 2018 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on aggressive MS. The aim of the workshop was to discuss approaches on how to describe and define the disease phenotype and its treatments. Unfortunately, it was not possible to come to consensus on a definition because of unavailable data correlating severe disease with imaging and molecular biomarkers. However, the workshop highlighted the need for future research needed to define this disease subtype while also focusing on its treatment and management. Here, we review previous attempts to define aggressive MS and present characteristics that might, with additional research, eventually help characterize it. A companion paper summarizes data regarding treatment and management.

Open-label extensions [studies SP516 (NCT00501969) and SP715 (NCT00594386)] of the CLEOPATRA-PD and PREFER studies were conducted to evaluate the safety, tolerability and efficacy of the dopaminergic agonist, rotigotine, over several years of follow-up in patients with advanced Parkinson’s disease (PD). Eligible subjects completing the double-blind trials received open-label adjunctive rotigotine (≤16 mg/24 h) for up to 4 and 6 years in Studies SP516 and SP715, respectively. Safety and tolerability were assessed using adverse events, vital signs and laboratory parameters, and efficacy assessed using the unified Parkinson’s disease rating scale (UPDRS). Of the 395 and 258 patients enrolled in the SP516 and SP715 studies, 48 and 45 % completed, respectively. Adverse events were typically dopaminergic effects [e.g., somnolence (18–25 %/patient-year), insomnia (5–7 %/patient-year), dyskinesias (4–8 %/patient-year) and hallucinations (4–8 %/patient-year)], or related to the transdermal application of a patch (application site reactions: 14–15 %/patient-year). There were no clinically relevant changes in vital signs or laboratory parameters in either study. Mean UPDRS part II (activities of daily living) and part III (motor function) total scores improved from double-blind baseline during dose titration, then gradually declined over the maintenance period. In study SP516, mean UPDRS part II and III total scores were 0.8 points above and 2.8 points below double-blind baseline, respectively, at end of treatment. In study SP715, mean UPDRS part II and III total scores were 4.1 points above and 0.2 points below baseline, respectively, at end of treatment. In these open-label studies, adjunctive rotigotine was efficacious with an acceptable safety and tolerability profile in patients with advanced PD for up to 6 years.

Disseminated encephalomyelitis (DEM) is the acute or chronic response of the immune system to an antigen. It is noteworthy that it can affect simultaneously the central and peripheral portions of the nervous system, the latter clearly differentiating it from multiple sclerosis (MS). Pathologically there are differences and gradations in the type and severity of damage that are seen mostly, although not exclusively, in the white matter. Although DEM is generally considered to be a demyelinating disease, edema and inflammation, and even hemorrhage, are not only major constituents of the pathological response but may, in some instances, be its only manifestations. DEM can be seen following a wide variety of viral infections and vaccinations ; the acute phase generally occurs within one to three weeks after the precipitating event. In rare instances, it may occur in a matter of hours or days, or as late as several months, after a dated antigenic challenge such as a vaccination. Unfortunately, the recurrent or multiphasic, or the unusual progressive, forms of DEM are rarely recognized in adults in whom they are frequently misdiagnosed as MS, despite the fact that they are just as common as they are in children. Except for fever, headache, nausea and vomiting, alterations in the state of consciousness and cognitive abnormalities, the central nervous system symptoms of DEM, are very similar to those of MS. It is important to note that the triggering infection may be very mild or it may be subclinical and escape attention. Magnetic resonance imaging (MRI) has made it possible to correctly diagnose DEM in its acute, chronic, recurrent and multiphasic forms because, in most instances, the images are quite typical. Nevertheless, in clinical practice, the images of DEM and MS are often confused resulting in the former being misdiagnosed as the latter, resulting in the inappropriate initiation of long-term immunomodulatory treatment. This review will illustrate different clinical and MRI presentations of DEM in order to emphasize the features which help to differentiate it from MS.

Prolactine-Secreting Pituitary Carcinoma: Clinico- Pathological Correlations

Review of the recent medical literature raises doubts about the reliability of reported prevalence rates of multiple sclerosis (MS). Many published prevalence rates are inflated. Some studies have shown that relying on clinical information and MRI interpretation leads to one third of incorrect MS diagnoses. The most important error is failing to distinguish between the clinical and MRI characteristics of MS and of disseminated encephalomyelitis (DEM) in both their acute and relapsing forms. The diagnostic criteria in current usage, including those relating to imaging, do not differentiate between MS and other recurrent inflammatory demyelinating diseases of the central nervous system. Considering a second demyelinating episode following a clinically isolated symptom or acute DEM, as confirming MS, is another major source of error. Another is including cases with onset before they entered the study group or moved to the geographic area. Neuromyelitis optica (NMO) has long been considered an MS variant and in Far Eastern countries it is counted as the 'oriental' form of MS, falsely inflating prevalence rates of MS in those areas. Recent immunologic and radiologic evidence shows that at least some NMO cases represent instances of DEM

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Besides clinical findings and history, MRI is by far the single most important confirmatory examination available in the diagnosis of MS. Additional tests must be dictated by well founded suspicion of altewrnative diagnoses by history information.

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We analysed twelve models for the discrimination of transferred and locally synthesized protein fractions in cerebrospinal fluid and aqueous humor. Optimal parameters for the evaluation of intrathecal and intraocular protein synthesis have been deduced.

Recent data indicate that the apoptotic process, mediated by the CD95/Fas cell surface receptor, may be impaired in activated lymphocytes of patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to analyse the expression of CD95/Fas on peripheral blood (PB) CD4+ and CD8+ T lymphocytes and apoptosis of PB lymphocytes in RRMS patients in the relapse of the disease, immediately before and after pulse corticosteroid therapy (PCT), and in healthy individuals. The study included 27 patients (23 F, 4 M) with RRMS diagnosed by McDonald's criteria and 31 healthy controls (25 F, 6 M). Mean age of the patients was 36.85 +/- 7.52 years, mean duration of the disease 4.14 +/- 4.89 years, and average EDSS scale 3.24 +/- 1.18. Mean age of the controls was 36.54 +/- 10.72 years. The proportions of CD95+ T lymphocyte subsets were analysed by the use of monoclonal antibodies (anti-CD4-PE/Cy5, anti-CD8-FITC and anti-CD95-PE, DAKO) and flow cytometry (FACSscan cytometer and CellQuest software, Becton Dickinson). Apoptosis of lymphocytes was analysed by the use of annexin-V-FITC and PI labeling (Becton Dickinson), as well as flow cytometry. For statistical analysis nonparametric Mann-Whitney test for independent samples and Wilcoxon test for dependent samples were used. Results were presented as median (M) and range. The p values < 0.05 were considered as statistically significant. The proportion of CD4+CD95+ T lymphocytes was significantly higher in patients before therapy (M= 47.90 ; range 32.50 - 61.50), as compared to patients after therapy (M= 40.60 ; range 30.60 - 51.80, p< 0.01), and to controls (M= 36 ; range 30.40 - 40.10, p< 0.01). The proportion of CD8+CD95+ T lymphocytes was significantly higher in patients before therapy (M= 26 ; range 16.80 - 39.10), as compared to patients after therapy (M= 19.30 ; range 11-30, p< 0.01), and to controls (M= 19 ; range 12.30 - 25.50, p< 0.01). Apoptosis of lymphocytes was significantly lower in patients before therapy (M= 1.30 ; range 1- 4.70), as compared to patients after therapy (M= 5.60 ; range 3.10 - 48.80, p< 0.01), and to controls (M= 6.10 ; range 3.10 - 11.40, p< 0.01). Our results indirectly show that the process of apoptosis mediated by the CD95/Fas receptor is impaired in activated lymphocytes of RRMS patients. They also show that in those patients PCT influences on CD95/Fas expression on PB T lymphocytes, as well as on the lymphocyte apoptosis.