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PubMed2004

Review of mitoxantrone in the treatment of multiple sclerosis.

Mitoxantrone is a synthetic anthracenedione recently approved by the FDA for the treatment of worsening relapsing-remitting (RR), secondary progressive (SP), and progressive relapsing (PR) multiple sclerosis (MS). In experimental allergic encephalomyelitis (EAE), mitoxantrone prevented the development of the signs and decreased the frequency of relapses in relapsing EAE. Early pilot trials using mitoxantrone were carried out using vastly different dosage regimens and patient populations, which may have resulted in conflicting results. Subsequent trials of mitroxantrone in patients with active inflammatory forms of MS suggested a profound effect in decreasing relapse rates, enhancing lesion frequency, and progression of disability. These results were later confirmed in a large, randomized, double-blind trial in patients with either worsening RRMS or SPMS. Treatment with mitoxantrone brought about statistically significant decreases in relapse rates, progression of disability, gadolinium-enhancing, and new lesions on T2-weighted MRI. Although mitoxantrone is generally well tolerated, it is associated with a variety of potential toxicities. Therefore, its use should probably be restricted to those patients with a suboptimal response to high-dose interferon therapy or those with rapidly progressive disease from onset.

Animals↗
PubMed2006

Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis.

The pathological hallmarks of secondary progressive (SP) multiple sclerosis (MS) include slowly expanding demyelination and axonal damage with less inflammation. To elucidate the pathomechanisms of secondary progressive (SP) multiple sclerosis (MS), we have investigated the expression of chemokines, chemokine receptors, matrix metalloproteinase-9 (MMP-9) and immunoglobulins in the demyelinating plaques. Immunohistochemical analysis revealed that numerous hypertrophic astrocytes were observed at the rim, but not in the center, of the chronic active lesions. Microglia/macrophages phagocytosing myelin debris were also found at the lesion border. In contrast, T cell infiltration was minimal in these plaques. Characteristically, at the rim of the lesions, there were abundant immunoreactivities for monocyte chemoattractant protein-1 (MCP-1)/CCL2 and interferon-gamma inducible protein-10 (IP-10)/CXCL10 and their receptors, CCR2 and CXCR3, while these immunoreactivities were weak in the center, thus forming a chemokine gradient. Double immunofluorescense staining demonstrated that cellular sources of MCP-1/CCL2 and IP-10/CXCL10 were hypertrophic astrocytes and that both astrocytes and microglia/macrophages expressed CCR2 and CXCR3. MMP-9 was also present at the rim of the lesions. These results suggest that MCP-1/CCL2 and IP-10/CXCL10 produced by astrocytes may activate astrocytes in an autocrine or paracrine manner and direct reactive gliosis followed by migration and activation of microglia/macrophages as effector cells in demyelinating lesions. Targeting chemokines in SPMS may therefore be a powerful therapeutic approach to inhibit lesional expansion.

Adult↗
PubMed2002

Combination therapy with interferon beta-1b and azathioprine in secondary progressive multiple sclerosis. A two-year pilot study.

Combination therapy may benefit the subgroup of patients with secondary progressive multiple sclerosis (SPMS) who do not respond to interferon beta (IFNB). We performed a two-year study of azathioprine (AZA) combined with IFNB-1b in SPMS patients who had not responded well to IFNB-1b alone. Patients with SPMS were eligible for this non-controlled prospective study if they had two or more relapses requiring corticosteroid treatment or deteriorated by at least 0.5 points on the Expanded Disability Status Scale (EDSS) while on IFNB-1b in the year preceeding the study. Patients were to continue treatment with IFNB-1b (8 MIU qod, subcutaneous) and received AZA (50 mg tid, oral). Safety was assessed in terms of adverse reactions and laboratory measures graded according to the WHO toxicity scale. Efficacy was explored by changes in relapse rate, EDSS, 9-hole peg test (9-HPT), neuropsychological scores, and magnetic resonance imaging (MRI) results. Neutralizing antibodies (NAB) were measured. Ten SPMS patients (6 females) with a median EDSS score of 4.5 were enrolled. One patient withdrew because of gastrointestinal complaints, one was withdrawn owing to poor compliance, and 8 patients completed therapy. The only frequent side effect was lymphopenia, reported at least once in all patients. Annual relapse rate was reduced by approximately 50 % in the second year. There was a significant trend for EDSS increase. Total lesion load measured by MRI decreased at 12 and 24 months; only one patient had active lesions. No changes were seen in the 9-HPT. There was a significant improvement in neuropsychological tests after 24 months ( p = 0.045). One patient tested positive for NAB throughout the study, and transient NAB were detected in 4 patients. In conclusion, combination therapy with IFNB-1b and AZA was safe and generally well tolerated in patients with SPMS. Strict clinical and laboratory monitoring is recommended during this combination therapy.

Adjuvants, Immunologic↗
PubMed2003

Clinical and laboratory characteristics of secondary progressive MS.

Secondary progressive (SP) MS follows on from but is distinct in its clinical picture from relapsing remitting (RR) MS. Diagnosis is usually straightforward except during the transitional stage when the two phenotypes merge. It is clear that most patients that start with relapsing remitting MS will develop SP disease, although the underlying pathogenesis that causes this change is subject to much debate. Clinical features such as pattern and site of symptoms, and age of onset, in the relapsing remitting stage versus progressive disease, suggests a difference in the pathophysiology. Laboratory markers may give insight into the disease mechanisms. Measures of urinary and CSF myelin basic protein-like material (MBPLM) indicate demyelination and subsequent oligodendrocyte and axonal loss. Tertiary neutralising antibodies to MBP antibodies could attenuate remission and lead to continuous progression, and neuronal antibodies found in SP disease may contribute to the axonal loss. In addition, differences in nitric oxide and other inflammatory cytokine patterns might either be secondary to or causative of the pathological mechanisms.Greater understanding of progressive MS is a priority considering permanent disability results almost entirely from this stage of the disease.

Biomarkers↗
PubMed2006

Grey matter damage predicts the evolution of primary progressive multiple sclerosis at 5 years.

Reliable prognostic markers of primary progressive (PP) multiple sclerosis evolution are still needed. Diffusion tensor (DT) MRI can quantify normal-appearing white matter (NAWM) and grey matter (GM) damage in multiple sclerosis patients. We investigated whether conventional and DT-MRI-derived measures can predict the long-term clinical evolution of PP multiple sclerosis. In 54 PP multiple sclerosis patients, conventional and DT-MRI scans of the brain and T1-weighted scans of the cervical cord were acquired at baseline and after a median follow-up of 15 months. Another clinical evaluation was performed, 56 months after baseline, in 52 patients. Measures of lesion load, brain and cord atrophy were obtained. Histograms of the mean diffusivity (MD) and fractional anisotropy (FA) values from the NAWM and GM were analysed. At follow-up, 35 patients (65%) experienced a confirmed disability progression. Baseline expanded disability status scale score and average GM MD were independent predictors of subsequent clinical deterioration in a multivariable model (Nagelkerke R2: 0.44; discriminating ability: 81%). A lower level of disability and a more severe GM damage identify PP multiple sclerosis patients with an increased risk of disease progression over the subsequent 5 years. These data may be relevant to select patients for future exploratory phase II trials.

Adult↗
PubMed2000

The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. European Study Group on Interferon beta-1b in secondary progressive multiple sclerosis.

The recently completed European trial of interferon beta-1b (IFNbeta-1b) in patients with secondary progressive multiple sclerosis (SP multiple sclerosis) has given an opportunity to assess the impact of treatment on cerebral atrophy using serial MRI. Unenhanced T(1)-weighted brain imaging was acquired in a subgroup of 95 patients from five of the European centres; imaging was performed at 6-month intervals from month 0 to month 36. A blinded observer measured cerebral volume on four contiguous 5 mm cerebral hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation. There was a significant and progressive reduction in cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P = 0.34 between groups). Exploratory subgroup analyses indicated that patients without gadolinium (Gd) enhancement at the baseline had a greater reduction of cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFNbeta-1b 1.8%, P < 0.05) whereas those with Gd-enhancing lesions showed a trend to greater reduction of cerebral volume if the patient was on IFNbeta-1b (placebo 2.6%, IFNbeta-1b 3.7%; P > 0.05). These results are consistent with ongoing tissue loss in both arms of this study of secondary progressive multiple sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFNbeta. The different pattern seen in patients with and without baseline gadolinium enhancement suggests that part of the cerebral volume reduction observed in IFNbeta-treated patients may be due to the anti-inflammatory/antioedematous effect of the drug. Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on cerebral atrophy in this population of patients with advanced disease.

Adult↗
PubMed2003

MRI metrics as surrogate endpoints for EDSS progression in SPMS patients treated with IFN beta-1b.

BACKGROUND: Although metrics derived from conventional MRI (cMRI) are widely used as outcome measures in clinical trials of MS, no formal study has been performed to validate cMRI metrics as surrogate endpoints for disability progression in MS. METHODS: A validation procedure was applied to the clinical and MRI data collected in the context of the European randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNbeta-1b) in patients with secondary progressive MS. The Prentice operational criteria were used to assess surrogacy for the number of active lesions seen on the first year T2-weighted MRI scans and the percentage T2 lesion volume change between the baseline and the first year MRI scans. The primary clinical outcome was disability at study exit (3 years), adjusted for the baseline disability. RESULTS: The number of active T2 lesions and the T2 lesion volume percentage change over the first year of the study accounted for 57% of the treatment effect on disability progression over the entire study duration. On the contrary, the same cMRI metrics accounted for 79% of the treatment effect on the relapse rate. CONCLUSIONS: This study shows that the beneficial effect of IFNbeta-1b on disability accumulation in patients with secondary progressive MS is, to a large extent, independent of the changes detected using cMRI. As a consequence, cMRI metrics should not be used as a stand-alone measure of outcome in phase III trials of IFNbeta in secondary progressive MS.

Biomarkers↗
PubMed2004

Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials.

BACKGROUND: A European (EU) and a North American (NA) placebo-controlled study with interferon beta-1b (IFNB-1b) in secondary progressive multiple sclerosis (SPMS) showed divergent results with regard to their primary outcome of sustained Expanded Disability Status Scale (EDSS) progression, while effects were similar on relapse and MRI-related endpoints. Reasons for this discrepancy were explored in the combined dataset. METHODS: Baseline characteristics and variability in EDSS assessments were compared. Retrospective combined analyses for time to confirmed progression were performed to assess treatment effects overall and in subgroups defined by pre-study disease activity criteria and other key baseline variables. RESULTS: The variance of EDSS measurements was 6.5% higher in the NA-SPMS study. The EU study included patients in an earlier phase of SPMS and with more active disease both pre-study (relapses, MRI) as well as on study (EDSS, relapses, and MRI variables as assessed in the placebo groups). The pooled analysis showed an overall risk reduction by about 20% in patients treated with 8 MIU (250 mcg) IFNB-1b for EDSS progression confirmed at 6 months (p = 0.008). Risk reduction by 30% to 40% was found for patients with at least one relapse or change in EDSS by >1 in the 2 years prior to study entry. No other consistent across-studies relation of clinical and MRI variables at baseline to potential treatment response was found. CONCLUSIONS: Although post hoc, this combined analysis of the two large studies with IFNB-1b in secondary progressive multiple sclerosis suggests that both pronounced disability progression and continuing relapse activity might help in identifying those patients in the secondary progressive phase of the disease who are more likely to benefit from treatment.

Adult↗
PubMed1986

Granulocyte function in patients with multiple sclerosis.

Peripheral blood granulocytes and sera from patients with relapsing/remittent (group I) and chronic progressive (group II) multiple sclerosis (MS) did not differ from control cells and sera with regard to the proportion of cells bearing receptors for Fc gamma and C3b; random or directed (chemotactic) motility of granulocytes; activation as measured by chemiluminescence; opsonic activity of sera. The results of this study suggest that granulocyte function in MS is normal.

Cell Movement↗
PubMed1993

Multiple sclerosis: the relationship among self-esteem, social support, and coping behavior.

This study examines the relationship of self-esteem and social support to problem-focused coping behavior of 101 individuals with multiple sclerosis, a chronic progressive disease. Results included a significant relationship between self-esteem and problem-focused coping; a nonsignificant relationship between social support and problem-focused coping; and that self-esteem and social support taken together did not contribute significantly to problem-focused coping. Although the most frequently used coping strategies employed were problem focused, subjects did use combinations of problem- and emotion-focused strategies to deal with stressful encounters. The findings highlight the importance of assessing self-esteem, social support, and coping behavior of persons afflicted with multiple sclerosis and thus with the ever present potential for physical deterioration.

Activities of Daily Living↗
PubMed2002

[Possibilities of magnetic resonance visualization in the diagnosis of multiple sclerosis].

Magnetic-resonance imaging (MRI) is considered to be the most informative non-invasive method in diagnosis, differential diagnosis and estimation of activity of multiple sclerosis (MS). MRI data of 270 patients with clinically and laboratory definite MS were analyzed to assess diagnostic MRI-criteria for MS, MRI presentations at the time of first clinical manifestation of the disease, neuroimaging patterns in children and elderly persons with MS. The MRI variants of MS are substantiated. Neuroimaging data of cervical spinal cord in 28 patients with MS are presented in parallel with corresponding clinical data. The most typical patterns are singled out. The data of brain 1H-magnetic-resonance spectroscopy (MRS) in 20 patients with MS and 8 patients with inflammatory and vascular disorders were analyzed to reveal biochemical distinction between MS and non-MS lesions as well as changes in normal appearing white matter in MS. The differential-diagnostic value of MRS is limited although decreased N-acetyl-aspartate peak is characteristic for MS lesions and in some cases in normal appearing white matter in primary-progressive MS.

Brain↗
PubMed2004

Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study.

OBJECTIVE: To evaluate the efficacy and safety of interferon beta-1b (IFNbeta-1b) in subjects with secondary progressive multiple sclerosis (SPMS). METHODS: This 3-year, multicenter, double-blind, placebo-controlled, randomized trial of IFNbeta-1b included 939 subjects from the United States and Canada with SPMS and Expanded Disability Status Scale (EDSS) scores ranging from 3.0 to 6.5. Subjects were randomly assigned to receive either placebo or IFNbeta-1b (250 microg or 160 microg/m2 body surface area), administered subcutaneously every other day. The primary outcome was time to progression by > or =1.0 EDSS point (0.5 point if EDSS score was 6.0 to 6.5 at entry) confirmed at 6 months. Secondary outcomes included mean change in EDSS score from baseline, relapse-related measures, MRI activity, and a standardized neuropsychological function test. RESULTS: There was no significant difference in time to confirmed progression of EDSS scores between placebo-treated patients and either of the IFNbeta-1b treatment groups. However, IFNbeta-1b treatment resulted in improvement on secondary outcome measures involving clinical relapses, newly active MRI lesions, and accumulated burden of disease on T2-weighted MRI. Effects were similar for both IFNbeta-1b treatment groups. Neutralizing antibodies to IFNbeta-1b were detected in 23% of 250-microg and 32% of 160-microg/m2 recipients, but their presence did not consistently affect clinical or MRI outcomes. IFNbeta-1b was also well tolerated at both doses. CONCLUSIONS: Although no treatment benefit was seen on the time to confirmed progression of disability, relapse- and MRI-related outcomes showed significant benefit with both dosing regimens tested, a result consistent with the outcomes of earlier clinical trials.

Brain↗
PubMedDate not supplied

[Cerebral atrophy in multiple sclerosis patients treated periodically with boluses of methylprednisolone].

INTRODUCTION: In the last years advances in the treatment of the remittant and secondary progressive forms of the multiple sclerosis (MS) have taken place. In the primary progressive forms (PP) the side effects of potentially useful drugs prevent their use; in some studies an improvement of the evolution with the intravenous administration of periodic pulses of methylprednisolone (MP) has been observed. OBJECTIVE: To evaluate if periodic pulses of intravenous MP injected every 4-6 weeks increase the degree of cerebral atrophy of the patients with PP MS. PATIENTS AND METHODS: We studied 11 patients with PP MS treated during 33 months with periodic pulses of intravenous MP. The degree of cerebral atrophy was evaluated in axial cuts of 10 mm of studies of magnetic resonance with the indices of Evans, bicaudate, bifrontal, frontal spears and bithalamic. The statistical evaluation of the results was made applying the test of Wilcoxon-Mann-Whitney. RESULTS: There are not statistically significant differences in the degree of cerebral atrophy with any of the used indices. CONCLUSIONS: Periodic pulses of intravenous MP do not accelerate the cerebral atrophy in patients with progressive forms of multiple sclerosis.

Adult↗
PubMed2005

Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation.

We report a 49-year-old woman with a history of progressive gait disturbance, white matter disease, and cerebrospinal fluid immunoglobulin abnormalities who met criteria for primary progressive multiple sclerosis and whose son died at age 10 years of an unknown congenital neurodevelopmental disorder. Sequencing of the proteolipid protein 1 gene showed a novel mutation, Leu30Arg (c.89TG), in the mother and son. Pelizaeus-Merzbacher disease is the cause of death in the son and explains the mother's adult-onset neurological disorder. This case goes against dogma that mothers of severely affected sons are asymptomatic as adults and expands the differential diagnosis of primary progressive multiple sclerosis to include proteolipid protein 1 gene mutations.

Arginine↗
PubMed2001

The effect of IFNbeta-1b on the evolution of enhancing lesions in secondary progressive MS.

BACKGROUND: After the resolution of contrast enhancement, the majority of new MS lesions become isointense with surrounding white matter on T1-weighted MRI. Less commonly, a hypointense T1 lesion develops, representing the development of more severe focal tissue damage. Interferon beta (IFNbeta) reduces both the number of new enhancing lesions and the duration of contrast enhancement. OBJECTIVE: To determine if IFNbeta affects the degree of tissue damage within new lesions and if its effects are related to lesion size. METHODS: One hundred twenty-five patients with secondary progressive MS from seven European sites were randomized to receive either IFNbeta-1b or placebo. Monthly, contrast-enhanced T1-weighted MR images were acquired at baseline, at months 1 to 6, and at months 19 to 24. The size of all new enhancing lesions developing between months 1 and 6 was recorded and their appearance at follow-up documented. RESULTS: In the first 6 months, fewer new enhancing lesions occurred in the IFNbeta-1b arm. This difference was greater for small (70% decrease) than for large (46% decrease) lesions. Hypointense T1 lesions were more likely to form from large (25%) than from small (9%) enhancing lesions in both treatment arms. Patients taking IFNbeta-1b developed fewer hypointense T1 lesions; however, the proportion of enhancing lesions developing into hypointense T1 lesions was similar in both arms. CONCLUSION: IFNbeta-1b reduced the number of new enhancing lesions, with a greater effect on small lesions. However, when a new enhancing lesion did become established, treatment with IFNbeta-1b did not alter its subsequent course.

Adult↗