American ginseng does not improve fatigue in multiple sclerosis: a single center randomized double-blind placebo-controlled crossover pilot study.

This study examined the safety and efficacy of an escalating dose (100 mg, 200 mg, 400 mg/day) of American ginseng over 6 weeks in a single-center, randomized, double-blind, placebo-controlled, crossover trial with 56 subjects with multiple sclerosis and fatigue. There were no serious adverse events but fatigue on ginseng, as assessed by the Fatigue Severity Scale, was not significantly different from fatigue on placebo.

Change in quality of life in patients with relapsing-remitting multiple sclerosis over 2 years in relation to other clinical parameters: results from a trial of intramuscular interferon {beta}-1a.

BACKGROUND: A randomized, placebo-controlled, multicenter study of weekly intramuscular injections of interferon beta-1a (IFNß-1a) in relapsing-remitting multiple sclerosis included the Sickness Impact Profile (SIP), a validated measure of patient-reported quality of life (QoL). OBJECTIVE: To demonstrate the impact of moderate to severe SIP disability at baseline and change in QoL as measured by SIP over 2 years in relation to other study parameters. METHODS: In 158 patients, SIP scores were determined at baseline and 2 years. Scores were correlated with disease progression and treatment. RESULTS: Patients who experienced disability progression, as defined by Expanded Disability Status Scale (EDSS) and annualized relapse rate, during the study demonstrated significant worsening in Physical SIP scores compared with patients who did not progress (p=0.031). In patients with low SIP scores, indicating moderate or severe disability at baseline, treatment with IFNß-1a significantly improved Physical SIP subscores. CONCLUSIONS: Patients with disability progression defined using EDSS, the physician-derived primary outcome measure, had Physical SIP scores indicating worsening disability, validating the physician-derived primary outcome measure using patient self-report. Treatment with IFNß-1a had beneficial effects on QoL in patients with worse SIP scores at baseline.

Selective depletion of myelin-reactive T cells with the anti-OX-40 antibody ameliorates autoimmune encephalomyelitis.

The OX-40 protein was selectively upregulated on encephalitogenic myelin basic protein (MBP)-specific T cells at the site of inflammation during the onset of experimental autoimmune encephalomyelitis (EAE). An OX-40 immunotoxin was used to target and eliminate MBP-specific T cells within the central nervous system without affecting peripheral T cells. When injected in vivo, the OX-40 immunotoxin bound exclusively to myelin-reactive T cells isolated from the CNS, which resulted in amelioration of EAE. Expression of the human OX-40 antigen was also found in peripheral blood of patients with acute graft-versus-host disease and the synovia of patients with rheumatoid arthritis during active disease. The unique expression of the OX-40 molecule may provide a novel therapeutic strategy for eliminating autoreactive CD4+T cells that does not require prior knowledge of the pathogenic autoantigen.

Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE.

We have previously demonstrated that thyromimetics stimulate oligodendrocyte precursor cell differentiation and promote remyelination in murine demyelination models. We investigated whether a thyroid receptor-beta selective thyromimetic, sobetirome (Sob), and its CNS-targeted prodrug, Sob-AM2, could prevent myelin and axonal degeneration in experimental autoimmune encephalomyelitis (EAE). Compared to controls, EAE mice receiving triiodothyronine (T3, 0.4 mg/kg), Sob (5 mg/kg) or Sob-AM2 (5 mg/kg) had reduced clinical disease and, within the spinal cord, less tissue damage, more normally myelinated axons, fewer degenerating axons and more oligodendrocytes. T3 and Sob also protected cultured oligodendrocytes against cell death. Thyromimetics thus might protect against oligodendrocyte death, demyelination and axonal degeneration as well as stimulate remyelination in multiple sclerosis.

Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study.

Disease-modifying drugs are initiated early and continued for years in patients with multiple sclerosis. Long-term tolerability and impact are not known. The objective of this study was to evaluate long-term tolerability of intramuscular interferon beta-1a and effects on disability and quality of life. Patients were evaluated an average of 15 years after randomization into a placebo-controlled, double-blind trial of intramuscular interferon beta-1a for relapsing multiple sclerosis. Patient-reported Expanded Disability Status Scale, the Short Form-36, a visual analog scale of self-care independence, and a living situation questionnaire were administered. Status was ascertained in 79% (136/172) of eligible patients. Analysis focused on 122 living patients. Despite open-label, non-standardized treatment after the 2-year clinical trial, 46% (n= 56) of the patients remained on intramuscular interferon beta-1a. Expanded Disability Status Scale scores were correlated highly with Short Form-36 subcategories and visual analog scale scores. Patients currently using intramuscular interferon beta-1a had a significantly lower mean Expanded Disability Status Scale score (p= 0.011), less progression to Expanded Disability Status Scale milestones, significantly better scores on the physical component of the Short Form-36 (p< 0.0001), and reported better general health and greater independence. We conclude that patients continuing to use intramuscular interferon beta-1a had less disability and better quality of life compared with patients not currently using intramuscular interferon beta-1a 15 years after randomization into a clinical trial.

Clinical trial of a formal group fatigue program in multiple sclerosis.

Fatigue: Take Control is a novel program to teach fatigue management to people with multiple sclerosis (MS) following recommendations in the Fatigue and Multiple Sclerosis guideline. Fatigue: Take Control includes six 2-hour group sessions with DVD viewing, discussion and homework and accompanying participant and leader workbooks. While many people have participated in Fatigue: Take Control programs, its efficacy has not been determined. The objective of this study was to determine whether participation in Fatigue: Take Control reduces fatigue and increases self-efficacy in people with MS. Thirty participants were randomly assigned to a group who immediately participated in the program (FTC) or a wait-list group (WL). The primary outcome was the Modified Fatigue Impact Scale (MFIS) and secondary outcomes were the Multiple Sclerosis Self-Efficacy Scale (MSSE) and the Fatigue Severity Scale (FSS). The MFIS was administered on 10 occasions. Other measures were administered on four occasions. A mixed model tested the effects using all observations. Compared with the WL, the FTC group had significantly more improvement on the MFIS [F(1, 269) = 7.079, p = 0.008] and the MSSE [F(1, 111) = 5.636, p = 0.019]. No significant effect was found for the FSS. Across all visits, fatigue was significantly lower and self-efficacy was significantly higher for the FTC group compared with the WL group. This pilot study demonstrated significant effects in fatigue and self-efficacy among subjects taking the Fatigue: Take Control program, suggesting that this comprehensive program based on the Fatigue and Multiple Sclerosis guideline may be beneficial in MS.

Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial.

BACKGROUND: Memantine, an NMDA antagonist, is effective for moderate to severe Alzheimer's disease. OBJECTIVE: Determine whether memantine improves cognitive performance (CP) among subjects with multiple sclerosis (MS) and cognitive impairment (CI). METHODS: This double-blind, randomized, placebo-controlled trial (Clinicaltrials.gov NCT00300716) compared memantine 10 mg twice a day (4 week titration followed by 12 weeks on the highest tolerated dose) with placebo. The primary outcome was the change from baseline to exit on the Paced Auditory Serial Addition Test (PASAT) and the California Verbal Learning Test-II (CVLT-II) Long Delay Free Recall (LDFR). Secondary outcomes included additional neuropsychological tests; self-report measures of quality of life, fatigue, and depression; and family/caregiver reports of subjects' CI and neuropsychiatric symptoms. RESULTS: The differences between the groups on the change on the PASAT (placebo-memantine = 0.0 correct responses, 95% CI 3.4, 3.4; p = 0.9) and on CVLT-II LDFR (placebo-memantine =-0.6 words, 95% CI -2.1, 0.8; p = 0.4) as well as on the other cognitive tests were not significant. Subjects on memantine had no serious adverse events (AEs) but had more fatigue and neurological AEs as well as, per family members' reports, less cognitive improvement and greater neuropsychiatric symptoms than subjects on placebo. CONCLUSION: Memantine 10 mg twice a day does not improve CP in subjects with MS, ages 18-65, without major depression, who have subjective cognitive complaints and perform worse than one SD below the mean on the PASAT or on the California Verbal Learning Test-II (total recall or delayed free recall).

Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis.

OBJECTIVES: The primary objective was to evaluate the effect of omega-3 fatty acids (omega-3 FA) on matrix metalloproteinase-9 (MMP-9) production by immune cells in multiple sclerosis (MS). Quality of life, fatty acid levels, and safety were also evaluated. MATERIALS AND METHODS: Ten participants with relapsing-remitting MS (RRMS) received omega-3 FA supplementation (9.6g/day fish oil) in an open-label study. Participants were evaluated at four time points, baseline, after 1 month of omega-3 FA supplementation, after 3 months of omega-3 FA supplementation, and after a 3-month wash out. RESULTS: Immune cell secretion of MMP-9 decreased by 58% after 3 months of omega-3 FA supplementation when compared with baseline levels (p<0.01). This effect was coupled with a significant increase in omega-3 FA levels in red blood cell membranes. CONCLUSIONS: Omega-3 FA significantly decreased MMP-9 levels in RRMS and may act as an immune-modulator that has potential therapeutic benefit in MS patients.

The perceived benefit and satisfaction from conventional and complementary and alternative medicine (CAM) in people with multiple sclerosis.

OBJECTIVE: To describe the perceived benefit and satisfaction from complementary and alternative medicine (CAM) and conventional therapies and providers in MS. DESIGN: Cross-sectional mailed survey. SETTING: One thousand nine hundred and thirteen respondents who were members of the Oregon Chapter of the National MS Society. RESULTS: The benefit rating of both conventional therapies and providers was significantly higher than for CAM therapies and providers (p < 0.001 and < 0.001). When stratifying satisfaction rating by MS disease severity, significant differences were found between CAM providers and neurologists, favoring CAM providers in those with moderate disease severity (p = 0.014) and favoring neurologists in those with severe disease severity (p = 0.032). CAM providers were rated significantly higher than MDs on the following: listening skills (p < 0.001), care and concern (p < 0.001), and patient empowerment (p < 0.001). CONCLUSIONS: Although MS patients report significant benefit from conventional therapies and providers; they may seek CAM providers for emotional support. The impact of emotional support gained from providers on quality of life in MS warrant further investigation.

Infiltrative orbitopathy, optic disk edema, and POEMS.

The polyneuropathy, organomegaly, edema, monoclonal protein, and skin changes (POEMS) syndrome is a multisystem disorder of unknown etiology. Neurologic manifestations include polyneuropathy, optic disk edema, and intracranial hypertension. We studied a patient with POEMS syndrome who had an infiltrative orbitopathy.

Hypertrophic neuropathy and multiple sclerosis.

In a 62-year-old man with multiple sclerosis, postmortem examination disclosed clinically unsuspected findings of hypertrophic neuropathy. The brain and spinal cord contained many typical plaques of multiple sclerosis. Most spinal roots were thickened, and microscopic examination showed onion-bulb changes characteristic of hypertrophic neuropathy. This is the eleventh reported case of a sporadic hypertrophic neuropathy in a patient with multiple sclerosis.

Herpes zoster ophthalmicus and delayed ipsilateral cerebral infarction.

We studied five patients who had acute cerebral infarctions 5 weeks to 6 months after herpes zoster ophthalmicus (HZO). All had infarcts of the cerebral hemisphere ipsilateral to the HZO, and one also had a cerebellar infarct. Cerebral arteriography in one patient disclosed narrowing of the middle cerebral artery, occlusion of the anterior cerebral artery ipsilateral to the HZO and narrowing of the opposite anterior cerebral artery. In another case, arteriography revealed occlusion of the distal internal carotid artery on the side of the HZO.

Inter- and intrarater scoring agreement using grades 1.0 to 3.5 of the Kurtzke Expanded Disability Status Scale (EDSS). Multiple Sclerosis Collaborative Research Group.

We determined inter- and intrarater Kurtzke Expanded Disability Status Scale (EDSS) scoring agreement for four trained examining physicians who evaluated 10 clinically stable multiple sclerosis patients. These patients had previously been determined to have EDSS scores of 1.0 to 3.5 and were scheduled to participate in a funded clinical trial of intramuscular recombinant interferon-beta. Intrarater reliability was greater than interrater reliability for scoring the EDSS and all of its component functional systems scores (FSS). Specifically, individual examiners were able to reproduce three serial examination scores on the same patient on the same day (intrarater agreement) within 1.0 EDSS or 2.0 individual FSS points. Reproducible scoring across examiners (interrater agreement), however, could only be accomplished within 1.5 EDSS or 3.0 individual FSS points. Additionally, the interrater scoring variability in our patients is greater than that previously reported for patients with higher EDSS scores. We conclude that clinical trials that employ the EDSS as an outcome measure of treatment efficacy should include inter- and intrarater agreement data for all examining physicians. Most importantly, studies using a single examining physician to evaluate individual patients throughout the course of a clinical trial will require less change in the EDSS to reliably measure disease activity than will studies using more than one examining physician to evaluate individual patients throughout the trial.

Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).

BACKGROUND AND OBJECTIVE: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-1a (IFN beta-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as > or = 1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance. METHODS: Post hoc analyses related to disability outcomes using data collected during the double-blind, placebo-controlled phase III clinical trial. RESULTS: (1) Clinical efficacy related to disability did not depend on the definition of disability progression. A significant benefit in favor of IFN beta-1a was observed when > or = 2.0 point worsening from baseline EDSS was required or when worsening was required to persist for > or = 1.0 year. (2) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFN beta-1a recipients who reached the primary study outcome. (3) Significantly fewer IFN beta-1a recipients progressed to EDSS milestones of 4.0 (relatively severe impairment) or 6.0 (unilateral assistance needed to walk). (4) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFN beta-1a treatment. CONCLUSIONS: The primary clinical outcome for the IFN beta-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFN beta-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.

Monitoring relapsing remitting MS patients.

The availability of safe and partially effective disease modifying therapies necessitates changes in how neurologists monitor patients with relapsing remitting multiple sclerosis (RRMS). Neurologists need to make the diagnosis of MS as soon as possible to be able to initiate therapy early in the course of disease. In deciding whom to treat, neurologists should consider information on disease activity and burden acquired from the neurologic history and examination and magnetic resonance imaging (MRI). Patients not on a disease modifying therapy should undergo yearly clinical assessments and periodic cerebral MRI to monitor for changes in disease activity. Patients on disease modifying therapy should undergo regular clinical assessments to monitor for side-effects and disease activity. Cerebral MRI scanning may also be useful in assessing patients on therapy, particularly when considering changes in therapy.

Evidence for genetic contamination of inbred buffalo rats (RT-1b) obtained from a commercial vendor.

Inbred Buffalo rats (RT-1b) have been used in studies of experimental autoimmune encephalomyelitis and autoimmune thyroiditis. Since our studies, and those of others, have relied on the genetic purity of inbred Buffalo rats, we chose to test these animals for expression of strain-dependent, allotype-specific variants of CD45 (leukocyte common antigen, LCA) using the monoclonal antibodies RT7.1 and RT7.2. The goal of this study was to confirm the genetic purity and to verify the inbred status of Buffalo rats obtained from a commercial source.

Myelin basic protein-specific T lymphocytes induce chronic relapsing experimental autoimmune encephalomyelitis in lymphocyte-deficient (SCID) mice.

Myelin basic protein (BP)-specific T lymphocyte cell lines were selected from the lymph nodes (LN) of BP-immunized, H-2d, CXJ-1 mice prior to the onset of clinical disease. These CD4+ T cells induced severe acute experimental autoimmune encephalomyelitis (EAE) in MHC-compatible (H-2d), lymphocyte-deficient (SCID) mice (C.B-17scid/scid). The incidence of disease was much higher in immunodeficient SCID mice (71%) than in syngeneic immunocompetent CXJ-1 mice (5%). SCID mice with EAE had an acute progressive paralytic disease with inflammation and myelin loss detected in the spinal cord. Eighty-six percent (12/14) of mice followed for more than 2 weeks had 1 or more relapses of EAE. These results demonstrate that clinical remission and relapse of EAE can be induced by the single adoptive transfer of a LN-derived BP-specific T cell line in the absence of host-derived effector and regulatory lymphocytes. Furthermore, the data demonstrate that the pathogenic potential of BP-specific T cells is greater in lymphocyte-deficient SCID mice compared with immunocompetent mice, suggesting that autoreactive T cells are controlled by potent inhibitory mechanisms associated with regulatory lymphocytes. These results are relevant to mechanisms of disease remission and relapse mediated by lymphocytes involved in paralytic inflammatory diseases such as multiple sclerosis (MS).

Serum anti-myelin antibodies in chronic relapsing experimental allergic encephalomyelitis.

To investigate the role of anti-myelin antibodies in chronic relapsing experimental allergic encephalomyelitis (CR-EAE), sera from SJL/J mice with CR-EAE actively induced by inoculation with spinal cord homogenate in complete Freund's adjuvant (CFA) were compared with sera from mice to whom CR-EAE was passively transferred by lymph node cells (LNC) stimulated with myelin basic protein (BP). Sera were obtained serially from mice during both remissions and relapses of disease and were evaluated for the presence of anti-myelin antibodies using an avidin-biotin-immunoperoxidase technique. Four of six mice with CR-EAE induced with cord-CFA were positive for anti-myelin antibodies 15-124 days after inoculation, with 16 of 18 sera positive in these four mice. Two mice inoculated with cord-CFA did not have detectable serum anti-myelin antibodies, despite a clinical and histopathological picture indistinguishable from the antibody-positive mice. None of seven mice with CR-EAE passively transferred by BP-stimulated LNC had detectable anti-myelin antibodies in 30 sera obtained 7-141 days after cell transfer. We conclude that serum anti-myelin antibodies probably do not play a significant role in the pathogenesis of CR-EAE in SJL/J mice.

Characterization of basic protein-specific T cell lines selected from Lewis rats with relapsing experimental autoimmune encephalomyelitis.

Relapsing experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by intraperitoneal immunization with guinea pig whole central nervous system tissue. Basic protein (BP)-specific T cell lines selected from rats with relapsing EAE proliferated in response to BP, the 44-89 peptidase fragment of BP and the synthetic peptide, S72-89, as did lines selected from rats with non-relapsing EAE induced by immunization with guinea pig BP. BP-specific T cell lines selected from rats with relapsing EAE transferred acute but not relapsing EAE. BP-specific T cell lines selected from Lewis rats with relapsing EAE appear not to differ from those selected from rats with non-relapsing EAE.

Myelin basic protein-specific T cells induce demyelinating experimental autoimmune encephalomyelitis in Buffalo rats.

This is the first description of acute demyelinating experimental autoimmune encephalomyelitis (EAE) induced in rats by myelin basic protein (BP)-specific T lymphocytes without the administration of demyelinating antibodies. BP-specific T cell lines were selected from inbred Buffalo-strain rats (Rt-1b) following techniques used to develop similar lines from Lewis rats (Rt-1l). Unlike those of Lewis rats, the spinal cords of Buffalo rats with T cell line-mediated EAE had prominent perivascular demyelination associated with mononuclear inflammation. Like Lewis rat lines. Buffalo rat BP-specific T cell lines transferred acute, non-relapsing EAE into syngeneic recipients, demonstrating that demyelination in passive acute EAE can occur without subsequent clinical relapses.