Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Advances in immunotherapy immunoregulatory properties of type-I interferons: Relevance to multiple sclerosis and the hypereosinophilic syndrome

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Dolutegravir-induced extrapyramidal syndrome in a young woman.

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Bilateral striatal necrosis associated with cerebral malaria

info:eu-repo/semantics/nonPublishe

Analysis of ballistic movements in ataxic hemiparesis following a pontine stroke

Although cerebellar-like ataxia is a well known component of the ataxic hemiparesis (AH), the mechanism of hypermetria in AH has not been established. We describe a patient presenting a left AH following a right pontine infarction. We investigated the ballistic flexion movements of both wrists and the associated agonist and antagonist electromyographic (EMG) activities, before and after addition of inertial loads. At the time of motion analysis, neurological examination showed cerebellar-like dysmetria of the left side but the patient had recovered a normal strength. In the basal state (without addition of loads), movements of the left wrist were hypermetric. The I duration of the agonist EMG activity was prolonged and the onset latency of the antagonist EMG activity was not delayed. Moreover, when a mass was added, the hypermetria was unchanged because the patient was unable to adapt appropriately neither the agonist, nor the g antagonist EMG activity. We suggest that the hypermetria was due to an imbalance between the duration of the agonist EMG activity (the launching force) and the duration of the antagonist EMG activity (the braking force).SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The idiopathic hypereosinophilic syndrome: clinical presentation, pathogenesis and therapeutic strategies

The idiopathic hypereosinophilic syndrome (HES) is a heterogenous disease entity characterized by persistent unexplained hypereosinophilia generally complicated by end-organ damage. Correct diagnosis and management are important in order to prevent long-term complications. Furthermore, it appears that HES represents a premalignant state in some patients, and close follow-up is necessary to detect early signs of malignant transformation. Previous studies of patient cohorts have led to the identification of a subgroup of patients with various clinical and biological features of primitive myeloproliferative disease. Patients in this subgroup have a clinically more aggressive disease in terms of organ damage and eventually develop acute myeloid leukemia. Among the remaining patients, it appears that some present an underlying T-cell disorder characterized by overproduction of Th2-type cytokines in vivo. Indeed, lymphocytes belonging to the Th2 subset are implicated in the maturation, activation and recruitment of eosinophils, essentially through the production of IL-5. Such patients appear to present a more benign disease at short term; however, they may develop T-cell lymphoma years after initial diagnosis. Therapy of HES includes glucocorticoids, hydroxyurea and more recently, interferon-alpha. Prednisone is generally recommended initially, followed by hydroxyurea in case of treatment failure. Until now, interferon-alpha has been reserved for refractory cases of HES. Our proposal for a new treatment strategy, based on current understanding of the pathogenesis of different subgroups of HES and on the mechanisms of action of the proposed therapeutic agents, which will be discussed in detail. Moreover, prevention of malignant transformation has become a new subject of concern when considering the beneficial effects of drugs.Journal Articleinfo:eu-repo/semantics/publishe

Lupus coagulation inhibitor associated neuropathy following cardiac surgery

info:eu-repo/semantics/nonPublishe

Antiphospholipid antibodies and ischemic neuropathy following cardiac surgery.

Sciatic nerve palsy is an uncommon complication of cardiac surgery and is thought to be induced by a combination of reduced femoral artery blood flow, small vessel vascular disease or prolonged hypoxia. We here describe a new case which is the first described with transient elevation of antiphospholipid antibodies. Although transient elevation of lupus coagulation inhibitor is known to occur frequently in patients treated in an intensive care unit, there are very few data about the possible role of antiphospholipid antibodies in the generation of ischemic neuropathies. We can not prove that the ischemic neuropathy in our case has been favored by the presence of lupus coagulation inhibitor and antiphospholipid antibodies as the occurrence of the symptoms seemed to precede the transient elevation of lupus coagulation inhibitor. This case suggests that antiphospholipid antibodies and lupus coagulation inhibitor should be included in the work up of patients who present nerve damage after cardiac surgery but further studies are needed to ascertain this association.Case ReportsJournal Articleinfo:eu-repo/semantics/publishe

IFN-beta interferes with the differentiation of dendritic cells form peripheral blood mononuclear cells: selective inhibition of CD40-dependent interleukin-12 secretion

info:eu-repo/semantics/publishe

Interferon-β inhibits Th1 responses at the dendritic cell level: Relevance to multiple sclerosis

Clinical studies have demonstrated beneficial effects of interferon-β (IFN-β) therapy in multiple sclerosis (MS) patients. However, the mechanism of action of IFN-β in MS remains unknown. IFN-β has even been demonstrated to enhance isolated T cell secretion of IFN-γ, a cytokine proven to be deleterious in MS. However, IFN-β inhibits IFN-γ secretion of T cells, when they are stimulated by antigen presenting cells (APC). We therefore decided to study the effects of IFN-β on the in vitro differentiation of dendritic cells (DC), a major class of APC. First, we found that the addition of IFN- β at the initiation of the differentiation did not modify DC morphology, but enhanced the expression of molecules involved in antigen presentation (HLA- DR, B7/1 and B7/2). However, DC, differentiated in the presence of IFN-β, secreted less interleukin-12 (IL-12) both spontaneously and upon activated by CD40-ligand bearing cells. As a consequence, DC differentiated in the presence of IFN-β induced less IFN-γ secretion by alloreactive T cells. We conclude that the direct action of IFN-β on DC results in inhibition of their ability to secrete IL-12 and to elicit Thelper-1 (Th-1) type responses. These results are of particular interest in MS, in which a critical role for IL-12 has recently been suggested by a number of clinical and experimental observations.SCOPUS: ar.jinfo:eu-repo/semantics/publishe