Dimethyl fumarate for treating relapsing multiple sclerosis.

Introduction: Outcomes of two large double-blind placebo-controlled studies of oral dimethyl fumarate (DMF) in multiple sclerosis (MS) provided the basis for its marketing approval as Tecfidera® by the US FDA in early 2013 and the European Medicines Agency in February 2014. The safety of DMF is complemented by experience in the use of an oral mixture of fumaric acid esters, including DMF for psoriasis (Fumaderm®; DMF and monoethyl fumarate [DMF-MEF]) licensed in Germany in 1994.

Areas Covered: This article reviews the pivotal trials leading to the approval of DMF for MS and the pharmacological literature related to the extensive use of oral fumaric acid esters for psoriasis over the last quarter century.

Increased seroreactivity to human T cell lymphoma/leukemia virus-related endogenous sequence-1 Gag peptides in patients with human T cell lymphoma/leukemia virus myelopathy.

Previously, we had shown that although only 8% of patients with large granular lymphocytic leukemia (LGLL) were infected with human T cell lymphoma/leukemia virus (HTLV)-2, almost half had antibodies to HTLV Gag and Env peptides. Herein, we investigated whether this could be due to cross-reactive antibodies to two homologous peptides in the Gag protein of the endogenous retrovirus HTLV-related endogenous sequence-1 (HRES-1). In addition, we had previously shown that patients with HTLV neurodegenerative diseases had increased seroreactivity to homologous HERV-K10 endogenous retrovirus peptides.

Increased seroreactivity to HERV-K10 peptides in patients with HTLV myelopathy.

Background: Previously, we had shown that persons infected with human T-cell lymphoma leukemia virus 1 or 2 (HTLV-1 or 2) had an increased prevalence of antibodies to a peptide in the Pol protein of the retrovirus HERV-K10, homologous to a peptide in HTLV gp21 envelope protein. The prevalence rate was higher in those with myelopathy vs. non-myelopathy.

Multiple sclerosis and the spinal cord.

Many clinical manifestations of multiple sclerosis (MS) may be attributed to spinal cord disease. MS may have classic presentation or a more complex presentation. MS is mainly a relapsing remitting disease, but there is also an insidious form that is progressive, known as primary progressive MS (PPMS).

Association between paroxysmal tonic spasms and neuromyelitis optica.

Objective: To determine the frequency of the association between tonic spasms and neuromyelitis optica (NMO) at our center.

Design: An institutional review board-approved retrospective study of clinical, serological, and radiographic characteristics of patients with NMO.

Setting: Multiple sclerosis center.

Impact of rituximab on relapse rate and disability in neuromyelitis optica.

Background: Neuromyelitis optica (NMO) is a severe demyelinating disease often leading to serious disability. Accumulating evidence now implicates humoral mechanisms in its pathogenesis. In the absence of an approved therapy, anti-inflammatory/immunosuppressant drugs have been used empirically for more than three decades.

Human T-lymphotropic virus type I or II (HTLV-I/II) associated with recurrent longitudinally extensive transverse myelitis (LETM): two case reports.

We describe two patients with recurrent longitudinally extensive transverse myelitis (LETM) associated with human T-lymphotropic virus type I or II (HTLV-I/II) exposure, and with neuromyelitis optica (NMO) immunoglobulin G (IgG) antibody in one case. HTLV-I/II are well known retroviral agents of myelopathy and B-cell dysfunction in humans. NMO is an autoimmune, demyelinating disorder of the central nervous system (CNS), also linked to B-cell dysfunction.

LGL leukemia and HTLV.

Samples were obtained from 53 large granular lymphocytic leukemia (LGLL) patients and 10,000 volunteer blood donors (VBD). Sera were screened in an HTLV-1 enzyme immunoassay (EIA) and further analyzed in peptide-specific Western blots (WB). DNAs were analyzed by HTLV-1, -2, -3, and -4-specific PCR.

Evidence of platelet activation in multiple sclerosis.

Objective: A fatality in one multiple sclerosis (MS) patient due to acute idiopathic thrombocytopenic purpura (ITP) and a near fatality in another stimulated our interest in platelet function abnormalities in MS. Previously, we presented evidence of platelet activation in a small cohort of treatment-naive MS patients.

Methods: In this report, 92 normal controls and 33 stable, untreated MS patients were studied.

Chronic inflammatory demyelinating polyradiculoneuropathy associated with multiple sclerosis.

Objective: To describe temporal profile of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in patients with definite, relapsing multiple sclerosis (MS).

Background: Peripheral demyelinating neuropathy has been rarely reported in association with central nervous system demyelinating disorder indistinguishable from MS.

Methods: In addition to usual diagnostic studies for CIDP and MS in all 5 patients, we studied proximal segments of nerves using deep tendon reflex latency measurements of biceps reflex, patellar reflex, and ankle reflex.

Interferon-beta1a reduces plasma CD31+ endothelial microparticles (CD31+EMP) in multiple sclerosis.

Background: A correlation between plasma CD31+ endothelial microparticles (CD31+EMP) levels and clinical, as well as brain MRI activity, in multiple sclerosis (MS) patients has been previously reported. However, the effect(s) of treatment with interferon-beta1a (IFN-beta1a) on plasma levels of CD31+EMP has not been assessed. In a prospective study, we measured plasma CD31+EMP levels in 30 patients with relapsing-remitting MS.

The role of CD4+ T-cells in the development of MS.

Objective: Multiple sclerosis (MS) is a chronic, progressive central nervous system (CNS) disease with unknown cause. Considerable evidence supports an autoimmune origin with an important role for cellular immune responses in its pathogenesis.

Methods: We have reviewed the current literature dealing with lymphocyte responses and their interactions as it relates to MS and present supporting evidence from animal models.

The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications.

Multiple sclerosis (MS) has been recognised as a disease since the mid-19th century. The delineation of its CNS pathology, revealing the presence of inflammatory demyelination and relative sparing of axons, was originally interpreted as evidence of infection. Despite many studies, a primary infectious aetiology of MS has not been found.

Relapse rates and enhancing lesions in a phase II trial of natalizumab in multiple sclerosis.

Background: Natalizumab, a humanized monoclonal IgG4 antibody, is an alpha4-integrin antagonist, which inhibits the migration of inflammatory cells into the central nervous system, a key pathogenic mechanism in multiple sclerosis (MS). In a six month, phase II clinical trial of patients with relapsing MS, natalizumab significantly reduced the formation of new gadolinium-enhanced (Gd+) lesions and the number of clinical relapses.

Objective: To investigate the relationship of historical relapse rate and new Gd + lesion number with subsequent MS disease activity and natalizumab treatment in the phase II study.

Endothelial microparticles (EMP) bind and activate monocytes: elevated EMP-monocyte conjugates in multiple sclerosis.

Elevated plasma endothelial microparticles (EMP) have been documented in MS during exacerbation. However, the role of EMP in pathogenesis of MS remains unclear. We investigated the formation of EMP-monocyte conjugates (EMP-MoC) and their potential role in transendothelial migration of inflammatory cells in MS.

Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects.

Background: Relapses in multiple sclerosis (MS) can cause significant neurologic disability. Natalizumab (Antegren) is a humanized anti-alpha4-integrin antibody that inhibits the trafficking of leukocytes across endothelium by blocking binding of alpha4beta1-integrin to vascular cell adhesion molecule-1.

Objective: To assess the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses.

A controlled trial of natalizumab for relapsing multiple sclerosis.

Background: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.

Transient movement disorders and multiple sclerosis.

Movement disorders associated with multiple sclerosis (MS) are uncommon, except for tremor. We report two patients with relapsing-remitting MS, who developed either dystonia or chorea during clinical exacerbation of their MS. The movement disorders resolved during treatment with adrenocorticotropin hormone (ACTH).

Epidemiologic features of HTLV-II: serologic and molecular evidence.

Purpose: A literature review was performed of the three principal subpopulations most commonly associated with human T-cell lymphotropic virus type II (HTLV-II) with the view of identifying the prevalence and transmission routes of HTLV-II. These included blood donors (BDs), intravenous drug users (IVDUs), and Amerindians (Indian populations from the Americas). We used the major criterion of serological and molecular distinction between human T-cell lymphotropic virus types I (HTLV-I) and II (HTLV-II).

Perverted head-shaking nystagmus: a possible mechanism.

The authors describe a patient with acute MS who developed vertigo (tumbling) and downbeat nystagmus upon horizontal head oscillation (perverted head-shaking nystagmus). The only abnormality on brain MRI was a hyperintense signal in the caudal medulla that contains the nucleus Roller and nucleus intercalatus. These nuclei project to structures involved in the velocity storage system for horizontal vestibulocular reflex (VOR) and vertical VOR, and also to the vestibular cerebellum.

Elevated plasma endothelial microparticles in multiple sclerosis.

Objective: To assess endothelial dysfunction in patients with MS and to investigate whether plasma from patients with MS induces endothelial cell dysfunction in vitro.

Background: Endothelial cell dysfunction may contribute to the pathogenesis of MS. Elevations of soluble adhesion molecules intracellular adhesion molecule, vascular cell adhesion molecule, and platelet-endothelial cell adhesion molecule-1 (CD31) have been reported as markers of blood-brain barrier (BBB) damage in MS, but direct assay of endothelium has been difficult.

Glossopharyngeal neuralgia and MS.

Glossopharyngeal neuralgia (GPN) is characterized by a severe lancing pain in the posterior pharynx, tonsillar fossa, and base of the tongue. It is induced frequently by swallowing and yawning. GPN has not been described previously in MS patients.