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Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

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.

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.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.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 of196,000 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.

Classically, multiple sclerosis (MS) is characterized by relapses of neurological deficits followed by remission. At present mechanisms of progressive aspects of the disease are currently undergoing increasing attention. Updated diagnostic criteria and improved diagnostic techniques, particularly in the field of magnetic resonance imaging (MRI), have facilitated diagnosis and monitoring of MS patients. Advances in immunology, particularly regarding the role of Th17 helper cells and B cells, together with increasing insight into genetics of MS, continue to improve our knowledge of the disease mechanisms underlying MS.

Intrathecal IgG synthesis (IT IgG Syn) is an established biomarker used for the diagnosis of multiple sclerosis (MS). Earlier studies used this biomarker to assess the impact of 2 different synthetic forms of interferon alpha (IFN-α) in chronic progressive MS. Unexpectedly, IT IgG synthesis was increased by this treatment. For the first time, we have assessed this parameter in relapsing-remitting patients to measure the impact of natural IFN-α treatment in a doseranging study in six dosage groups (5, 10, 15, 20, 25, & 30 MIU). We have found that IFN-α normalized IT IgG Synthesis at 12 weeks treatment for all dosage groups. Two weeks after stopping IFN-α results rose slightly. At 52 weeks, 28 weeks after stopping IFN-a results revealed cessation of IT IgG Synthesis in half of the patients (15, 20, 25 MIU weekly). These results reflect different outcomes for relapsing-remitting patients vs. chronic progressive patients. They may, however, reflect differences in the biological properties of the interferon products used. An optimal range of dosage with natural human IFN-α dosage for MS is suggested by the results.

This chapter is arranged with three sections. The introduction ( Section 1 ) includes subsections dealing with the history of experimental allergic encephalomyelitis (EAE) and of the development of copolymer −1, which led to the development of glatiramer acetate as a pharmacological product. Section 2 introduces glatiramer as an immunomodulator, with two subsections. The first outlines the impact on adaptive immune responses, and the second, the so-called “shift” from Th1 to Th2 helper T cell responses. Section 3 deals with the drug as a neuroprotective agent. The first subsection deals with induction of neurotrophic molecules by glatiramer and the second deals with the drugs impact on the innate immune system; a new focus for research on mechanisms of “switching off” damage by macrophages and microglial cells and “turning on” repair and regeneration of axons and myelin. Figures 1 and 2 show the relationships of the elements of immune function discussed in this chapter.

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.

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 =

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.

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.

Background: Natalizumab, a humanized monoclonal IgG4 antibody, is an a4-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. Methods: Patients who participated in the phase II study were stratified into subgroups according to: (i) the number of relapses in the two years prior to entry into the study: 2 relapses (n=108), 3 relapses (n=57), and-3 relapses (n=48); (ii) the number of new Gd+ lesions at baseline (Month 0): 0 (n=129), 1-2(n=50), and >2(n=33). Relapses and new Gd+ lesions during the treatment phase of the trial were determined and compared for each subgroup. Results: Both the prestudy relapse rate and number of new Gd+ lesions at baseline were related to the subsequent risk of a relapse; baseline number of Gd+ lesions was related to the likelihood of subsequent new Gd+ lesion formation. There was a lower proportion of subjects with an on-study relapse and fewer new Gd+ lesions in all natalizumab-treated subgroups when compared with their placebo counterpart; the difference was most apparent in the subgroups of patients with >3 relapses in the two years prior to study entry and >2 new Gd+ lesions at Month 0. Conclusions: There was a lower proportion of subjects with an on-study relapse in natalizumab-treated patients, particularly in those with a more active disease at study entry. Larger ongoing phase III studies will allow more definitive investigation of these preliminary subgroup findings.

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.To assess the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses.In this randomized, double-blind, multicenter trial, the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses were assessed. MS patients (n = 180) in acute relapse were randomly assigned to receive a single dose of natalizumab 1 or 3 mg/kg or placebo and were followed for 14 weeks.There was no difference in Expanded Disability Status Scale (EDSS) score change over time between treatment and placebo groups. In all three groups, approximately half of patients showed EDSS improvement after 2 weeks, rising to 67% by 8 weeks. EDSS improved by a mean value of 0.8 point at week 1, 1.2 points at week 4, and 1.6 points at week 8 in the natalizumab group compared with EDSS improvement of 1.0 point at week 1, 1.6 points at week 4, and 1.6 points at week 8 in the placebo group. A significant decrease in Gd-enhancing lesion volume was seen in both active treatment groups at weeks 1 and 3 compared with placebo.A single dose of IV natalizumab did not hasten clinical recovery after relapse, although a significant decrease in Gd-enhancing lesion volume was observed at 1 and 3 weeks after treatment. These MRI findings are consistent with prior studies of natalizumab and support its further investigation as an agent for the treatment of MS.

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.

To assess endothelial dysfunction in patients with MS and to investigate whether plasma from patients with MS induces endothelial cell dysfunction in vitro.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. Endothelial cells release microparticlesapproximately 1.5 microm (EMP) during activation or apoptosis. The authors developed a flow cytometric assay of EMP and studied EMP as markers of endothelial damage in MS.Platelet-poor plasma (PPP) from 50 patients with MS (30 in exacerbation and 20 in remission) and 48 controls were labeled with fluorescein isothiocyanate (FITC)-conjugated anti-CD31 and anti-CD51 (vitronectin receptor) antibodies, and two classes of EMP (CD31+ and CD51+) were assayed by flow cytometry. For in vitro studies, patients' plasma was added to the microvascular endothelial cell (MVEC) culture and release of CD31+ and CD51+ EMP were measured in the supernatant.Plasma from patients in exacerbation had 2.85-fold elevation of CD31+ EMP as compared with healthy controls, returning to near control value during remission. The CD31+ EMP concentration showed a positive association with gadolinium enhancement in patients with MS. In contrast, CD51+ EMP remained elevated in both exacerbation and remission. This suggests that CD31+ EMP is a marker of acute injury, whereas CD51+ EMP reflects chronic injury of endothelium. MS plasma induced release of both CD31+ and CD51+ EMP from MVEC culture in vitro.Endothelial dysfunction is evident during exacerbation of MS, evidenced by shedding of EMP expressing PECAM-1 (CD31). The in vitro data indicate contribution of one or more plasma factors in endothelial dysfunction of MS.

Devic's disease, which is characterized by attacks of optic neuritis and myelitis (often severe and associated with limited recovery), represents a major therapeutic challenge. We report our clinical observations of eight Devic's disease patients who were treated with prednisone and methotrexate or with cyclophosphamide alone. Four patients were stabilized with methotrexate and prednisone. Of the four patients treated with intravenous cyclophosphamide, only one was stabilized. Three patients who failed cyclophosphamide were subsequently stabilized on methotrexate and prednisone. Further investigations, such as multicenter controlled trials of methotrexate and prednisone in Devic's disease, would strengthen the conclusions from this small series.

Anti-alpha4 integrin antibody, natalizumab (Antegren), is a monoclonal antibody to a4b1 integrin adhesion molecules expressed on activated monocytes and CD4 cells. A 1-year followup of 28 patients with relapsing multiple sclerosis, randomized to 3 groups in a double-blind pharmacokinetic study, are presented. One group received placebo, a second group low doses (0.01–0.3 mg/kg) of natalizumab, and a third group high doses (1–3 mg/kg) of natalizumab. The observed reduction of relapses in all natalizumab-treated patients with multiple sclerosis suggests a potential range of doses to induce stabilization of the disease.

Earlier virologic studies established that human T-cell lymphotropic virus type II (HTLV-II) is the predominant retrovirus type found among Seminole Indians in southern Florida. We studied 46 members of the Seminole tribe living on 3 reservations to determine the risk factors for HTLV-II and to investigate disease association with the virus. The donors’ plasma samples were evaluated with the enzyme-linked immunosorbent and Western blot assays. DNA extracted from their peripheral blood mononuclear cells were analyzed by type-specific polymerase chain reaction amplification and detection of the HTLV pol gene using the primer pair SK110/SK111, and the probes SK112 or SK188. One of 46 (2%) subjects was identified as HTLV-I positive and 11 (24%) were identified as HTLV-II positive. Restriction fragment length polymorphism and sequence analyses indicated that all of the HTLV-II strains were subtype b. Mitochondrial DNA analyses indicated that all of the HTLV-II-positive subjects had an Amerindian haplotype. HTLV-II was more prevalent in Indians who were >45 years of age or female, had multiple sex partners or had received a blood transfusion. However, only the latter risk factor was statistically significant. Three of the HTLV-II-positive Indians demonstrated signs and symptoms of an ataxic neuropathy. The data support that HTLV-IIb is endemic among the Seminoles and that they will be a key population for further virologic studies.

Background: Recombinant human interferon beta-1b has been recently approved for the treatment of multiple sclerosis. A significant proportion of patients treated with this medication experienced cutaneous reactions. Objective: We describe the clinical and histologic features of cutaneous reactions to recombinant human interferon beta-1b. Methods: Consecutive patients with cutaneous reactions to recombinant interferon beta-1b were evaluated clinically and by biopsy. Results: Clinical lesions varied from subtle uninflamed sclerotic dermal plaques to erythematous plaques to cutaneous ulcers at injection sites. The nonsclerotic lesions were frequently painful. The firm plaques showed fibrosis histologically, whereas nonsclerotic inflammatory lesions demonstrated a consistent pattern of vascular thrombosis. Hematologic evaluation demonstrated platelet activation in most patients with inflammatory lesions, a feature also noted before interferon treatment in some patients. Conclusion: Therapy with recombinant interferon beta-1b is associated with a spectrum of cutaneous reactions and vascular thrombosis. (J Am Acad Dermatol 1997;37:553-8.)

Background: Spasticity is a serious problem in multiple sclerosis (MS) and many patients do not achieve a satisfactory response to currently available oral antispasticity drugs. Tizanidine hydrochloride, an α2-noradrenergic agonist, has been shown to have an antispasticity effect in single center trials of patients with MS. Objective: To compare plasma concentrations of tizanidine with objective measures of muscle tone in patients with MS with moderate to severe spasticity. Setting: Ten centers, all tertiary referral centers for the specialized treatment of patients with MS, in the United States and Canada. Design: A randomized, double-blind, placebo-controlled, dose-response study of tizanidine hydrochloride (8 or 16 mg). Patients: One hundred forty-two patients with spastic MS who were not taking any interfering medication, such as an antispasticity drug or other α-noradrenergic agonist, entered the trial. Results: Tizanidine treatment reduced muscle tone significantly, as shown by improved Ashworth scores and increased knee swing amplitude recorded by the pendulum test, both of which correlated significantly with plasma concentration. Placebo had no significant effect on muscle tone. Dizziness, drowsiness, dry mouth, and fatigue were reported most often in the group treated with tizanidine at peak plasma concentration. Conclusions: Tizanidine reduces spasticity in MS, and both therapeutic effects and side effects are related to the plasma drug levels.

We present a case of a woman with natalizumab associated progressive multifocal leukoencephalopathy (PML) who developed an immune reconstitution inflammatory syndrome (IRIS) 9 weeks after natalizumab withdrawal. She responded well to a small dose of steroids intravenously, without plasma exchange, and has returned to her baseline status within one year of her initial symptoms and MRI abnormality.

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.

A total of 113 patients with infection due to human T-cell leukemia virus type 1 (HTLV-I) were evaluated at the University of Miami from January 1988 to March 1993. Forty patients were identified with adult T-cell leukemia/lymphoma (ATLL) and 63 with HTLV-I-associated myelopathy (HAM). Three had concomitant ATLL and HAM. Two HAM patients co-infected with human immunodeficiency virus type 1 (HIV-I) developed clonal lymphoproliferative disease during the study period. Patients with ATLL have a poor prognosis; multiple chemotherapy regimens including high-dose cytotoxic agents have been utilized with a small impact on survival. Most of our patients are currently treated with experimental regimens. Rheumatologic or autoimmune illnesses were identified, mostly in HAM patients, and a small number developed immunodeficiencies in the absence of other definable etiologic factors. Most of the patients were immigrants from areas of endemicity in the Caribbean basin, although many Americans were also recognized. HTLV-I/II infection was diagnosed serologically and typed as HTLV-I by polymerase chain reaction (PCR) or a modified Western blot when a DNA sample was not available. In 24 of 40 patients with ATLL, Southern blot hybridization performed on DNA extracted from peripheral blood lymphocytes or tumor tissue demonstrated clonal HTLV-I integration. In South Florida, ATLL and HAM are now seen frequently. Since HTLV-I infection is associated with a 4% lifetime risk of developing ATLL and an additional 0.25% lifetime risk for developing HAM, a large pool of asymptomatically infected individuals must exist here.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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. The authors offer possible mechanisms for perverted nystagmus in this patient.

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.

We describe a 33-year-old homosexual man with a steroid-responsive, remitting and relapsing leukoencephalopathy associated with recent human immunodeficiency virus type 1 (HIV-1) seroconversion. Biopsy of a parieto-occipital lesion revealed demyelination and astrogliosis with focal necrosis. Detailed investigations demonstrated no pathogens in the brain other than HIV-1. This patient illustrates that a neurological disorder clinically indistinguishable from multiple sclerosis may be the presenting manifestation of HIV-1 infection and may occur in the absence of clinically significant immunosuppression.

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-β1a (IFN-β1a) 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-β1a (IFN-β1a), 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-β1a. 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-β1a. In addition, the decline in plasma levels of CD31+EMP further supports the concept that IFN-β1a exerts stabilizing effect on the cerebral endothelial cells in pathogenesis of MS.

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.

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.

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.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.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 (P0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P0.001). 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).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.

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.

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. The authors report four MS patients with GPN. Three responded to carbamazepine and one resolved during treatment with adrenocorticotrophin hormone (ACTH) and cyclophosphamide. Withdrawal of carbamazepine after 1 week in one patient resulted in recurrence of pain. GPN may be associated with MS and responds to carbamazepine.

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.

Jamaican Neuropathy of the ataxic type (tropical ataxic neuropathy [TAN] and spastic type (tropical spastic paraparesis [TSP]) have been recognized for over a century in Jamaica. The recent association of TSP with HTLV-I (TSP/HAM) is now well established. We now present evidence for a possible association between a TAN-like illness with HTLV-II in four females aged 34-49. All presented with ataxic gait and all four have prominent mental changes. Three of the four also have minor motor deficits with urinary frequency and two have nocturnal leg cramps. All have serum antibody and all had PCR evidence of HTLV-II infection. Antibody to HTLV-II is present in CSF from two subjects. The distinctive picture of prominent ataxia and altered mental status in these subjects contrasts with a predominantly myelopathic picture seen in TSP/HAM.

Human T-cell lymphotropic virus type one (HTLV-1) is associated with tropical spastic paraparesis or HTLV-I--associated myelopathy. We report 2 women with a spastic ataxic illness similar to HTLV-I--associated myelopathy infected solely with HTLV-II. Identification of HTLV-II infection was made serologically, by polymerase chain reaction, and by viral culture (in 1 woman). One woman, treated with 200 mg of danazol orally, three times daily, had pronounced improvement in ambulation, nocturnal spasticity, and nighttime urinary frequency. It appears that infection with HTLV-II may cause an illness similar to HTLV-I--associated myelopathy, but distinguished by the presence of ataxia.

An American family of English origin with an unusually early onset and long-duration form of Creutzfeldt-Jakob disease (CJD) had a heterozygous insert mutation in the region of repeating octapeptide coding sequences between codons 51 and 91 of the PRNP gene on chromosome 20. Affected members were 23 to 35 years old at the onset of illnesses that lasted from 4 to 13 years, yet experimental transmission of disease from the proband (11-year duration) produced a typically brief incubation period and duration of illness in each of three inoculated primates. Also, the PrP amyloid protein that accumulates in CJD brain was only barely detectable in extracted brain tissue from one case with massive spongiform change and was undetectable in another case with no spongiform change, perhaps because of epitope shielding by a configurational change in the protein induced by the mutation. Analysis of this and other families with similar inserts suggests that such mutations in the PRNP gene not only predispose to CJD, but also modify its phenotypic expression.

• Cerebral involvement in multiple sclerosis may result not only in sensory and motor symptoms but also in impaired mentation. We hypothesize that cognitive dysfunction occurs due to cortical deafferentation or disconnection arising from subcortical white-matter disease. We examined the P300 event-related potential in 31 patients with multiple sclerosis, correlating it with disease severity ratings based on magnetic resonance imaging signal intensity changes, cognitive dysfunction, and disability status. The patients with multiple sclerosis exhibited significantly prolonged P300 wave latencies compared with 32 control subjects. The P300 latency was strongly correlated with the presence of demyelinative brain lesions seen on magnetic resonance imaging scans and with cognitive impairment, but was only weakly associated with the Kurtzke disability status score, consistent with this scale primarily reflecting spinal rather than cerebral demyelination. Our study results support a relationship between subcortical white-matter lesions and cognitive impairment in multiple sclerosis.

• We present six patients with hemifacial spasm and multiple sclerosis. To our knowledge, this association has not been described previously in the North American literature. Magnetic resonance imaging was obtained in all the patients and plaques consistent with multiple sclerosis were identified. In two patients the plaques were seen in the area of the facial nucleus on the involved side. We suggest that hemifacial spasm can be a manifestation of multiple sclerosis. These cases illustrate the utility of magnetic resonance imaging in the investigation of hemifacial spasm. Our findings also support a central (nuclear) origin in multiple sclerosis associated with hemifacial spasm. ( Arch Otolaryngol Head Neck Surg . 1991;117:554-556)

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-β1a (IFN-β1a) 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.

To the Editor: Recombinant interferon beta-1b (Betaseron) was licensed in 1993 to reduce exacerbations of multiple sclerosis. Approval of the drug was greeted enthusiastically, despite a modest 30 percent reduction in relapses and side effects that include local inflammatory reactions and a flulike syndrome.1 We report the occurrence of severe necrotizing cutaneous reactions in a 38-year-old woman with an eight-year history of multiple sclerosis. She self-injected the standard dose of recombinant interferon beta-1b (9 million units) subcutaneously on alternate days. Erythematous patches appeared at the injection sites on both thighs during the third month of treatment. These areas became violaceous, . . .

INTRODUCTION. The central nervous system (CNS) has traditionally been regarded as an immunologically privileged and isolated organ. This immunoisolation is achieved through the specific structure of the blood brain barrier and CNS immunosuppressive microenvironment. 1,2 However, activated macrophage/microglia (MO) and astrocytes participate in the pathogenesis of various neurological diseases through expressing of MHC and adhesion molecules and releasing reactive oxygen intermediates, quinolinic acid, chemokines, cytokines, and other components of inflammation. The role of macroglia/macrophages and astrocytes in cellular/molecular mechanisms of pathogenesis of three common dementias; HIV-associated dementia (HAD), Alzheimer’s disease (AD), and multiple sclerosis (MS) have been studied. Each disease had its specific clinical course and symptomatology that are well known. At the cellular and molecular levels there are both common and distinct features that are under study and require further elucidation. Recently Link et al. 3 indicated support for roles of both microglia and astrocytes in regulating demyelination in MS. We have generalized this significant concept of neuropathogenesis to HAD and AD. HIV-1 infection is the original insult in Neuro-AIDS. In fact, our results indicate that there are neurovirulent strains of HIV-1 that invade the brain. Furthermore, we have published preliminary studies showing that there is brain regional heterogeneity of macrophage/microglia, virus load, and virus strains. At the cellular level, there is a greater virus load in central nervous system (CNS) macrophage/microglia than in peripheral nervous system (PNS) macrophages. In both tissues, macrophages appear to be involved in pathogenesis and produce toxic molecules including cytokines, chemokines, and nitric oxide (NO). Furthermore, we have demonstrated increased NO synthase in brain interneurons of drug abusers with AIDS associated with increased neuronal death (manuscript under review). The etiologies of AD and MS remain unknown. However, cellular/molecular mechanisms of pathogenesis are specific manifestations of these diseases. For example, it is clear that AD results from production of aberrant eta-amyloid proteins and oligopeptides. Microglia and astrocytes are activated as a result and are associated with further damage. Demyelination in MS involves lipid-laden macrophages perhaps spurred by viral and other antigens. In all three diseases cytokine/chemokine communication between microglia and astrocytes occur and apoptosis is a mechanism of neuronal death. Also, apoptosis of oligodendrocytes occurs in MS.

A phase 1, randomized, placebo-controlled, five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed. Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS. All doses were safe and well tolerated in MS. Serum concentrations of natalizumab are detectable for 3 to 8 weeks after a single 1- or 3-mg/kg IV dose and justify controlled efficacy studies.

Ten HTLV-I-associated myelopathy (HAM) patients (four men and six women aged 38 to 58 years) with Expanded Disability Status Scale (EDSS) scores ranging from 4.0 to 8.5 entered an open-label zidovudine study. A high-dosage induction (2 g/d for 4 weeks) was followed by 1 g/d for 20 weeks. Five patients were natives of the Caribbean island Hispaniola, and one each was from Colombia, Cuba, El Salvador, Jamaica, and the United States; all were positive by polymerase chain reaction, and nine had positive Western immunoblots for HTLV-I. Side effects included anxiety, insomnia, gastric upset, anorexia, and loss of taste. Preexisting leg cramps were increased in two and headaches in one. Hemoglobin decreased from a mean of 13.5 to 11.8 g/dl and the hematocrit from 40.7% to 34.9% at 8 weeks, and then stabilized. Neutropenia appeared regularly but did not necessitate drug withdrawal. Mean EDSS scores changed little for the group as a whole, but the seven ambulatory patients improved objectively, with their scores dropping from 5.5 to 4.0 and none worsening. Timed gait improved by at least 50%. Following withdrawal, four of the five who had improved regressed. Zidovudine appears to be safe in subjects with HAM who have no other major health problems and should be investigated further.

• Human T lymphotropic virus type I (HTLV-I)—associated myelopathy (HAM) (tropical spastic paraparesis/HAM) has rarely been reported in the United States. We present 10 well-documented cases with positive Western immunoblot test results and polymerase chain reactions for HTLV-I. The clinical and laboratory features of these American-born patients resemble those previously reported series of tropical spastic paraparesis and HAM from the Caribbean and japan, but important differences were observed. In our study there were equal numbers of whites and blacks and of men and women. Age at onset was younger than that reported from the Caribbean and Japan. Rate of progression to paraparesis varied but was more rapid than previously reported. Half were transfusion recipients but six had multiple sexual partners, with one regularly interacting with prostitutes and reporting a history of drug abuse. Although more rapid progression was seen in the transfusion recipients, this did not explain the earlier age of onset in this group of patients. The HTLV-I, and the associated myelopathy, are endemic in Florida, suggesting that immigration from, and proximity, to the Caribbean basin are contributing risk factors.