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. We have now extended our observations to a cohort restricted to North America in whom the diagnosis of HTLV myelopathy was rigorously confirmed to also test for reactivity to another HERV-K10 peptide homologous to the HTLV p24 Gag protein. METHODS: Sera from 100 volunteer blood donors (VBD), 53 patients with large granular lymphocytic leukemia (LGLL), 74 subjects with HTLV-1 or 2 infection (58 non-myelopathy and 16 myelopathy) and 83 patients with multiple sclerosis (MS) were evaluated in ELISA assays using the above peptides. RESULTS: The HTLV myelopathy patients had a statistically significant increased prevalence of antibodies to both HERV-K10 peptides (87.5%) vs. the VBD (0%), LGLL patients (0%), MS patients (4.8%), and the HTLV positive non-myelopathy subjects (5.2%). CONCLUSION: The data suggest that immuno-cross-reactivity to HERV-K10 peptides and/or transactivation of HERV-K10 expression by the HTLV Tax protein may be involved in the pathogenesis of HTLV-associated myelopathy/tropical spastic paraparesis and spastic ataxia.

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. Recent evidence for a role of antibody to aquaporin-4 in the pathogenesis of NMO has led to the use of rituximab, a monoclonal antibody targeting the CD20 epitope on the entire B cell lineage. OBJECTIVES: To evaluate the impact of rituximab on the relapse rate and disability in NMO. METHODS: This is an IRB approved retrospective longitudinal study of NMO patients treated with rituximab. RESULTS: We identified 53 patients with NMO, 23 of whom had been treated with rituximab. These patients (2 males, 21 females) had a mean age of 37.1 ± 14.6 years at the time of diagnosis. Eight of the 23 treated with rituximab were treatment naïve. All 23 were scheduled to receive infusions every six or 12 months after treatment initiation with a minimum follow-up of six months (median 32.5 months, range 7-63 months). Median relapse rate declined significantly from 1.87 relapses/patient per year to 0.0 relapses/patient per year. Kurtzke Expanded Disability Status Scale (EDSS) scores stabilized or improved in all patients. Use of rituximab is associated with a significant reduction in relapses and disability in patents with NMO.

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. Therefore, the immunopathogenesis of NMO may in some cases be linked to human HTLV exposure. Awareness of a possible association with human retroviral exposure will contribute to the optimal diagnosis and management of patients presenting with LETM or NMO.

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. Platelet counts, measures of platelet activation [plasma platelet microparticles (PMP), P-selectin expression (CD62p), circulating platelet microaggragtes (PAg)], as well as platelet-associated IgG/IgM, were carried out. In addition, plasma protein S activity was measured. RESULTS: Compared to controls, PMP were significantly elevated in MS (p < 0.001) and CD62p expression was also markedly elevated (p < 0.001). Both are markers of platelet activation. Platelet-associated IgM, but not IgG, was marginally elevated in MS (p = 0.01). Protein S in MS patients did not differ significantly from normal values. CONCLUSION: Platelets are significantly activated in MS patients. The mechanisms underlying this activation and its significance to MS are unknown. Additional study of platelet activation and function in MS patients is warranted.

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. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

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. METHODS: Using flow cytometry, in a blinded study, we measured plasma CD31+EMP in 30 consecutive patients with relapsing-remitting MS (RRMS) prior to and 4, 12, 24 and 52 weeks after initiation of intramuscular therapy with interferon-beta1a (IFN-beta1a), 30 micrograms weekly. At each visit, clinical examination was performed and expanded disability status scale (EDSS) scores were assessed. RESULTS: Plasma levels of CD31+EMP were significantly reduced from 24 through 52 weeks following initiation of treatment with IFN-beta1a. CONCLUSION: Our data suggest that serial measurement of plasma CD31+EMP levels may be used as a surrogate marker of response to therapy with INF-beta1a. In addition, the decline in plasma levels of CD31+EMP further supports the concept that IFN-beta1a exerts stabilizing effect on the cerebral endothelial cells in pathogenesis of 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. RESULTS: Issues regarding CD4+ T-cell subpopulations, their functional differentiation and regulatory interactions as they relate to their presumed role in MS-related pathology have been updated with references to the current literature. DISCUSSION: The evidence reviewed supports an important role of CD4+ T-cells in the immunopathogenesis of MS. The successful outcome of blocking CD4 cells entry into the CNS of animals with experimental demyelinating disease and humans with MS is a strong support for other evidence of an important role of these cell populations in the pathogenesis of MS. The understanding of the specific roles of CD4+ T-cells in the development of MS is crucial for better disease management and the prevention of neurological disability.

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. However, the occurrence of acute demyelinating disease following a variety of infections and vaccinations, leading to MS in about a third of cases, provides evidence for the existence of an auto-allergic pathogenesis for the disease. Improved understanding of the role of the blood-brain barrier in protecting the CNS, and the mechanisms by which cells gain entry into the brain and spinal cord has advanced the understanding of MS. Evidence of the central role of the adhesion molecule alpha4beta1-integrin (very late activation antigen-4 [VLA-4]) for lymphocytes in endothelial transmigration into the CNS specifically, has provided a major insight into the pathogenesis of human demyelinating disease and its experimental model, experimental autoimmune encephalomyelitis (EAE). This finding has led to a new window of therapeutic opportunity in MS. Monoclonal antibodies to VLA-4 abrogate the development of EAE in sensitised animals and may actually reverse its clinical and pathological findings in manifest disease. Natalizumab, one such monoclonal antibody, which is administered intravenously, has been found to be a promising agent in the treatment of MS. Although single doses produced no improvement in the speed or quality of recovery from acute exacerbations of MS in a phase II trial, long-term administration (in phase II and phase III trials) have produced significant benefits with results showing both a marked reduction in the risk of new magnetic resonance imaging lesions and a significant reduction in the risk of exacerbations within 2 months of the initiation of therapy. Phase III double-blinded controlled trials have provided additional evidence of safety and a favourable impact on exacerbation rates over the 1 year of administration. Unfortunately, the success of natalizumab has been curtailed by three cases of progressive multifocal leukoencephalopathy, which have prompted the manufacturer to voluntary withdraw the drug from the market. An independent review board is currently investigating the safety of the drug to determine whether it should return to the market. The demonstration that selective modulation (blocking) of the adhesion molecule VLA-4 by natalizumab in MS, resembling that observed in experimental disease, represents a major advance in rational therapy.

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. Anecdotal reports of serious adverse reactions to DMF-MEF are also reviewed in this report. EXPERT OPINION: DMF is generally safe and well tolerated. Flushing and gastrointestinal side effects are relatively common for the approved DMF dose but are ordinarily mild and self-limited. No increase in malignancies has been reported despite theoretical concerns. Although progressive multifocal encephalopathy has been reported anecdotally in 5 of > 196,000 patient-years of experience with fumaric acid esters, none of the 65,000 DMF MS patients treated in the first year has been affected. Appendix to the abstract: Subsequent to the acceptance of this article for publication, the manufacturer has notified physicians of the death of one patient from PML complicating use of DMF in the DEFINE study extension (ENDORSE). This does not alter the expert opinion rendered regarding the safety of DMF. We await the outcomes and recommendations from the ongoing investigation into this case.

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. Hence, in this study we also examined whether these patients had increased seroreactivity to the aforementioned HRES-1 Gag peptides. Sera from 100 volunteer blood donors (VBD), 53 patients with LGLL, 74 subjects with HTLV-1 or 2 infection (58 nonmyelopathy and 16 myelopathy), and 83 patients with multiple sclerosis (MS) were evaluated. The HTLV-positive myelopathy (HAM) patients had a statistically increased prevalence of antibodies to both HRES-1 Gag peptides (81%) vs. the VBD (0%), LGLL patients (13%), and MS patients (1%), and the HTLV-positive nonmyelopathy subjects (21%). The data suggest that cross-reactivity to HRES-1 peptides could be involved in the pathogenesis of HAM. The difference between the VBD and LGLL patients was also statistically significant, also suggesting a possible association in a minority of patients.

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. EMP-MoC were assayed in 30 MS patients in exacerbation, 20 in remission and in 35 controls. EMP-leukocyte conjugation was investigated flowcytometrically by employing alpha-CD54 or alpha-CD62E for EMP, and alpha-CD45 for leukocytes. EMP-MoC were characterized by identifying adhesion molecules involved and their effect on monocyte function. In vivo (clinical): EMP-MoC were markedly elevated in exacerbation vs. remission and controls, correlating with presence of GD+ MRI lesions. Free CD54+ EMP were not elevated but free CD62E+ EMP were. In vitro: EMP bound preferentially to monocytes, less to neutrophils, but little to lymphocytes. Bound EMP activated monocytes: CD11b expression increased 50% and migration through cerebral endothelial cell layer increased 2.6-fold. Blockade of CD54 reduced binding by 80%. Most CD54+ EMP bound to monocytes, leaving little free EMP, while CD62+ EMP were found both free and bound. These results demonstrated that phenotypic subsets of EMP interacted differently with monocytes. Based on our observations, EMP may enhance inflammation and increase transendothelial migration of monocytes in MS by binding to and activating monocytes through CD54. EMP-MoC were markedly increased in MS patients in exacerbation compared to remission and may serve as a sensitive marker of MS disease activity.

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). Three questions were formulated in addressing the possibility that HTLV-II might be responsible for the reported prevalence and transmission of this virus in these groups. Question One: Which population groups have the highest HTLV-II seroprevalence rates? Question Two: Are worldwide HTLV infection rates among the three sub-populations associated predominantly with the HTLV-II retrovirus type? Question three: What are the principal modes of transmission of HTLV-II? METHODS: Since earlier epidemiologic studies did not routinely use assays capable of distinguishing between HTLV-I and HTLV-II antibodies, their findings are necessarily inaccurate. However, with the more recent development of enhanced serologic assays, using recombinant antigens that are capable of accurately making this differentiation, it is now possible to more precisely define the epidemiology of HTLV-II. We reviewed only those studies where serological and molecular methods of accurately distinguishing between the two retroviruses were utilized. Initially, we located 36 studies, which met this particular review criterion. Of the five different assays we identified, the most prevalent were the polymerase chain reaction (PCR) (n = 14) and the synthetic peptide-based enzyme-linked immunoassay (Synth EIA) (n = 13). Our BD, IVDU, and Amerindian groups were also evaluated according to this differentiation schema. We were able to locate over 100 prevalence studies where focus was on some aspect of analysis of at least one or more of these three groups. By using many search terms - such as HTLV-II endemic population, seroepidemiological, as well as case control and cohort studies - we were able to create a comprehensive bibliographic database. RESULTS: The two groups identified with high HTLV-II prevalence rates are the IVDUs and Amerindian population. The importance of breast-feeding, IVDU, and contaminated blood products in the HTLV-II transmission process is confirmed. Sexual intercourse, however, as a mode of HTLV-II transmission remains problematic. CONCLUSIONS: By confining our evaluation to only those studies that used serological and/or molecular methods capable of distinguishing between the two retroviruses, we have been able to establish with confidence that there are consistent emerging patterns of HTLV-II infection in these populations.

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). Acute exacerbations of MS may be associated with transient movement disorders, which are responsive to ACTH.

Multiple sclerosis and the cerebellum.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease that has unpredictable symptomatology and severity. Cerebellar manifestations in MS can be present at any time of the clinical course. Early cerebellar findings are a predictor of disability and disease progression. Most patients have cerebellar manifestations once they enter the progressive stages of the disease. Of the cerebellar findings, tremor is by far the most common.

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). PPMS may not be identified for extended periods of time and should be on the differential of chronic myelopathies. Early diagnosis of MS rests on awareness of a clinically isolated syndrome and the required magnetic resonance imaging criteria. Early diagnosis results in early institution of treatment and a superior response.

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. PATIENTS: Patients with NMO treated at our center between 1990 and 2008. MAIN OUTCOME MEASURE: Records were examined for documentation of tonic spasms. RESULTS: Of 110 patients with International Classification of Diseases code 341, 57 patients met diagnostic criteria for NMO. Of these, 8 patients (14%) had documented typical tonic spasms (median age at onset, 39.5 years; range, 13.8-54.2 years). Of those patients, 4 were African American, 3 were Hispanic, and 1 was white. Only 1 was male. The NMO-IgG antibody was found in 1 of 6 patients tested. Tonic spasms appeared after a mean of 24.6 months (range, 0-91 months). In 2 of 57 patients meeting NMO criteria, tonic spasms accompanied their initial episodes. Seven of 8 patients who had tonic spasms responded to treatment with carbamazepine within 1 week. CONCLUSION: Tonic spasms are associated with NMO more commonly than with multiple sclerosis and may be a presenting sign in both diseases.

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. Forty four percent of LGLL patients vs. 0.12 % of VBD had anti-HTLV antibodies via EIA (p < 0.001). WB and PCR revealed that four LGLL patients (7.5%) vs. one VBD patient (0.01%) were infected with HTLV-2 (p < 0.001), suggesting an HTLV-2 etiology in a minority of cases. No LGLL patient was positive for HTLV-1, -3, or -4, whereas only one EIA-positive VBD was positive for HTLV-1 and none for HTLV-3 or -4. The HTLV EIA-positive, PCR-negative LGLL patients' sera reacted to epitopes within HTLV p24 gag and gp21 env. Other then the PTLV/BLV viruses, human endogenous retroviral element HERV K10 was the only sequence homologous to these two HTLV peptides, raising the possibility of cross-reactivity. Although three LGLL patients (5.7%) vs. none of 110 VBD patients tested positive for antibodies to the homologous HERV K10 peptide (p = 0.03), the significance of the anti-HTLV seroreactivity observed in many LGLL patients remains unclear. Interestingly, out of 36 HTLV-1-positive control subjects, 3 (8%) (p = 0.014) were positive for antibodies to HERV K10; all three had myelopathy. Out of 64 HTLV-2-positive control subjects 16 (25%) (p = <0.001) were positive for HERV K10 antibodies, and 4 (6%) of these had myelopathy. Out of 22 subjects with either HTLV-1 or -2 myelopathy, 7 (31.8%) were positive for HERV K10 antibodies, and out of 72 HTLV-infected subjects without myelopathy, 12 (16.7%) were positive for anti-HERV K10 antibodies (p = 0.11). The prevalence of anti-HERV K10 antibodies in these populations and the clinical implications thereof need to be pursued further.

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. RESULTS: All patients with MS subsequently (4-22 years) developed definite CIDP. Two of these patients developed multiple cranial nerve and spinal root enhancement on subsequent imaging without new intraparenchymal enhancement after a diagnosis of CIDP. The deep tendon reflex latencies were prolonged at more than 2 sites in all patients. Cerebral spinal fluid protein increased (70 +/- 19 to 144.8 +/- 17.4 mg/dL, P = 0.0001) at time of diagnosis of CIDP. Clinical improvement was observed in all patients after intravenous immunoglobulin therapy. CONCLUSIONS: When patients with MS develop CIDP, manifestations of central and peripheral disease involvement seem to respond to intravenous immunoglobulin. These cases suggest that there may be common antigenic targets in central and peripheral nervous system in this subset of patients.