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Primary/Progressive Multiple Sclerosis 2

  1. Increased AntiGanglioside AntiBodies in Primary and Secondary/Progressive Multiple Sclerosis
    Ann Neurol, 1998 Dec, 44:6, 980-3

  2. Increased Spasticity in Primary/Progressive MS with Interferon-ß-1b
    Neurology, 1998 Dec, 51:6, 1720-3

  3. Interferon-ß-1b in Secondary/Progressive Multiple Sclerosis
    Lancet, 1998 Nov, 352:9139, 1491-7

  4. Co-registration of PET and MRI in different courses of MS using Cobalt-55 as a Calcium-tracer
    Acta Neurol Belg, 1997 Sep, 97:3, 178-82

  5. Association of Interleukin-1ß and InterLeukin-1 Receptor antagonist Genes with disease severity in MS
    Neurology, 1999 Feb, 52:3, 595-9

  6. Phase II Study of I.V. MethylPrednisolone in Secondary/Progressive Multiple Sclerosis
    Neurology, 1998 Jul, 51:1, 239-45

  7. The Mayo Clinic-Canadian Cooperative Trial of Sulfasalazine in active Multiple Sclerosis
    Neurology, 1998 Nov, 51:5, 1342-52

  8. Modified Total Lymphoid Irradiation and Low Dose CorticoSteroids In Progressive Multiple Sclerosis
    J Neurol Sci, 1997 Nov, 152:2, 172-81

  9. Major Histocompatibility Complex Class II Alleles and the course and outcome of MS
    Neurology, 1998 Sep, 51:3, 742-7

  10. Interferon-beta-1a in Primary/Progressive MS: an exploratory, randomized, controlled trial
    Neurology 2003 Jan 14;60(1):44-51




#1

Increased AntiGanglioside AntiBodies In Primary And Secondary/Progressive MS

Sadatipour BT; Greer JM; Pender MP
Ann Neurol, 1998 Dec, 44:6, 980-3
Univ of Queensland, Dept of Medicine, Brisbane, Australia
PMID# 9851447; UI# 99066772
Abstract

Plasma samples from 70 patients with Multiple Sclerosis (MS), 41 patients with Other Neurological Diseases (OND), and 38 healthy subjects were examined for AntiBodies against Gangliosides GM1, GM3, GD1a, GD1b, and GD3 using enzyme-linked Immunosorbent assays.

The percentages of subjects with increased anti-GM3 responses were significantly higher in the Progressive MS (56.3%) and Secondary/Progressive MS (42.9%) groups than in the Relapsing/Remitting MS (2.9%), healthy subject (2.6%), and OND (14.6%) groups.

Elevated AntiGanglioside AntiBodies may be secondary to Axonal damage or may be a cause of Axonal damage and accumulating Disability in Progressive MS. In either case, they may serve as a marker of Axonal damage in MS.



#2

Increased Spasticity In Primary/Progressive Multiple Sclerosis With Interferon-ß-1b

Bramanti P; Sessa E; Rifici C; DAleo G; Floridia D; Di Bella P; Lublin F
Neurology, 1998 Dec, 51:6, 1720-3
Univ of Messina, Cattedra di Neurofisiopatologia, Centro per lo Studio ed il Trattamento dei Neurolesi Lungodegenti, Italy
PMID# 9855531; UI# 99071173
Abstract

Spasticity is a disabling symptom of MS that is enhanced during Interferon-ß-lb (IFN-ß-1b) treatment.

Nineteen patients with Primary/Progressive MS were treated with IFN-ß-1b; an additional 19 patients did not receive this treatment.

Thirteen of the 19 patients treated with IFN-ß-1b had increased Spasticity requiring increased AntiSpasticity drug administration.

This observation suggests that further studies are needed before Interferons can be so widely used in Primary/Progressive MS patients.



#3

Placebo-Controlled Multicenter Randomized Trial Of Interferon-ß-1b In S/P Multiple Sclerosis

European Study Group on Interferon-ß-1b in Secondary/Progressive MS
A placebo-controlled multicenter randomized trial

Lancet, 1998 Nov, 352:9139, 1491-7
PMID# 9820296; UI# 99036182
Abstract

Background
The beneficial effects of Interferon-ß have only been shown for patients in the Relapsing/Remitting phase of Multiple Sclerosis (MS).

The role of Interferon-ß in the treatment of patients who are in the Secondary/Progressive phase of the disease (SP-MS), and for whom no effective drug treatment is available, has not been assessed.

Methods
In this multicenter, double-masked, randomized, placebo-controlled trial, outpatients with SP-MS having scores of 3.0-6.5 on the Expanded Disability Status Scale (EDSS) received either 8 million IU Interferon-ß-1b every other day subcutaneously, or placebo, for up to 3 years.

The primary outcome was the time to confirmed progression in disability as measured by a 1.0 point increase on the EDSS, sustained for at least 3 months, or a 0.5 point increase if the baseline EDSS was 6.0 or 6.5.

A prospectively planned interim analysis of safety and efficacy of the intention-to-treat population was done after all patients had been in the study for at least 2 years.

Findings
358 patients with SP-MS were allocated placebo and 360 were allocated Interferon bß-1b; 57 patients (31 placebo, 26 Interferon beta-1b) were lost to follow-up.

There was a highly significant difference in time to confirmed progression of Disability in favor of Interferon-ß-1b (p=0.0008).

Interferon-ß-1b delayed progression for 9-12 months in a study period of 2-3 years. The odds ratio for confirmed progression was 0.65 (95% CI 0.52-0.83).

This beneficial effect was seen in patients with superimposed relapses and in patients who had only progressive deterioration without relapses.

Positive results were also obtained regarding time to becoming wheelchair-bound, relapse rate and severity, number of Steroid treatments and hospital admissions, as well as on Magnetic Resonance Imaging variables.

The drug was safe and side effects were in line with previous experience with Interferon-ß-1b. The study was stopped after the interim results gave clear evidence of efficacy.

Interpretation
Treatment with Interferon-ß-1b delays sustained Neurological deterioration in patients with SP-MS.

Interferon-ß-1b is the first treatment to show a therapeutic effect in patients with SP-MS.



#4

Co-Registration Of PET And MRI In Different Courses Of MS Using Cobalt-55 As A Calcium-tracer

Jansen HM; Decoo D; Minderhoud JM
Acta Neurol Belg, 1997 Sep, 97:3, 178-82
Univ of Gent, Dept of Neurology, Belgium
PMID# 9345589; UI# 98005457
Abstract

MRI) is the most accurate paraclinical test in MS to monitor disease activity, although poorly correlated with clinical impairment.

PET using Co-55 as a Ca-tracer may visualize Co-transport across the Neuronal membrane, Ca-mediated inflammatory processes and passive leakage through a breach in the Blood-Brain Barrier.

Co-registration of MRI and Co-PET may actually allow identification of clinically active lesions. MRI and Co-PET were performed as described elsewhere.

Based on a statistic parametric mapping (SPM-96)-software package, MRI and Co-PET were superimposed. A semi-automated technique was used to count the MS-Lesions.

We included four groups of eight MS-patients with Relapsing/Remitting (RR), Primary/Progressive (PP), Progressive/Relapsing (PR) and Secondary/Progressive (SP) courses and eight healthy volunteers.

MS was assessed in terms of impairment using Kurtzke's Expanded Disability Status Scale (EDSS) and Scripps Neurological Rating Scale (NRS). Co-PET displayed focal uptake throughout the MS Brain, both in the Gray and White Matter.

All four patients groups (as compared to controls) demonstrated a more InHomogeneous distribution of Co-spots with a tendency to show clustering, most evident in RR-MS.

SPM-analysis revealed an essentially different distribution pattern of MS spots on MRI and Co-PET.

(Merging of) Co-PET and MRI may eventually form complementary tools for identifying clinically relevant lesions, thus providing a more reliable secondary outcome measure in MS.



#5

Association Of InterLeukin-1ß And InterLeukin-1 Receptor Antagonist Genes With Disease Severity In MS

Schrijver HM; Crusius JB; Uitdehaag BM; García González MA; Kostense PJ; Polman CH; Peña AS
Neurology, 1999 Feb, 52:3, 595-9
Univ Hospital Vrije Universiteit, Dept of Neurology, Amsterdam, The Netherlands
PMID# 10025794; UI# 99148661
Abstract

Objective
To investigate whether PolyMorphisms in the InterLeukin-1ß (IL-1ß) and IL-1 Receptor antagonist (IL-1RA) Genes are associated with both susceptibility to and clinical characteristics of MS.

Background
Genetic susceptibility to MS is determined by many partially identified Genes. The Genes encoding various Cytokines are logical candidates for MS susceptibility and phenotype.

Methods
Genotypes were determined from 148 patients with Clinically Definite MS and 98 healthy controls. All the patients were unrelated, Dutch, and white.

Patient files were reviewed for disease type, initial symptoms, age at onset of disease, and rate of disease progression.

Results
No significant differences in Genotypes, allele frequencies, or carrier frequencies were found between MS patients and healthy controls.

Stratification for disease type (Relapsing/Remitting, Primary/Progressive, or Secondary/Progressive) did not provide significant differences between patients and controls.

However, a specific IL-1RA/IL-1ß combination was associated with disease severity.

MS patients with the IL-1RA allele 2+/IL-1ß allele 2- combination had a higher rate of progression on the Expanded Disability Status Scale when compared with the other possible combinations (p = 0.007).

Conclusions
IL-1RA and IL-1ß are disease severity Genes rather than disease susceptibility Genes.

Furthermore, these Gene PolyMorphisms may define subgroups of patients with a worse prognosis.



#6

Phase II Study Of I.V. MethylPrednisolone In Secondary/Progressive Multiple Sclerosis

Goodkin; Kinkel; Weinstock; VanderBrug; Secic; Gogol; Perryman; Uccelli; Neilley
Neurology, 1998 Jul, 51:1, 239-45
UCSF/Mt. Zion Multiple Sclerosis Center, San Francisco, CA 94115, USA
PMID# 9674809; UI# 98337566
Abstract

Objective
To compare the tolerability and efficacy of two doses of I.V. MethylPrednisolone in patients with Secondary/Progressive MS.

Methods
I.V. MethylPrednisolone administered in high or low dose every other month for up to 2 years to 108 patients with Secondary/Progressive MS.

Results
No significant difference in efficacy with the primary outcome, a comparison of the proportions of patients in each treatment group who experienced sustained progression of Disability.

A relative treatment effect was detected with the high-dose regimen as measured by the preplanned secondary analysis, a comparison of time to onset of sustained progression of disability.

Drug-related adverse events were observed more frequently in high-dose recipients but serious drug-related adverse events were uncommon, and cessation of study drug was only required in one patient.

Conclusion
The results of the secondary analysis of this study suggest that a phase III trial of CorticoSteroids for Secondary/Progressive MS is warranted.



#7

The Mayo Clinic-Canadian Cooperative Trial Of Sulfasalazine In Active Multiple Sclerosis

Noseworthy JH; OBrien P; Erickson BJ; Lee D; Sneve D; Ebers GC; Rice GP; Auty A; Hader WJ; Kirk A; Duquette P; Carter J; Francis G; Metz L; Shuster E
Neurology, 1998 Nov, 51:5, 1342-52
Mayo Clinic/Mayo Foundation, Rochester, MN 55905, USA
PMID# 9818858; UI# 9818858
Abstract

Objective
To determine whether Sulfasalazine is better than placebo in slowing Disability progression in MS.

Methods
In this randomized, double-blind, placebo-controlled phase III trial, 199 patients with active Relapsing/Remitting (n = 151) or Progressive (n = 48) MS were evaluated at 3-month intervals for a minimum of 3 years (94% completed 3 years of follow-up; mean follow-up, 3.7 years).

MRI studies were performed at 6-month intervals on a subset of 89 patients.

Results
Sulfasalazine failed to slow or prevent disability progression as measured by the primary outcome (confirmed worsening of the Expanded Disability Status Scale [EDSS] score by at least 1.0 point on two consecutive 3-month visits).

Sulfasalazine influenced favorably a number of secondary outcomes during the first 18 months of the trial (e.g., annualized relapse rate, proportion of relapse-free patients; Progressive subgroup only: rate of EDSS progression at 1 and 2 years, median time to EDSS progression) but these positive findings were not sustained into the second half of the trial.

Conclusions
Sulfasalazine does not prevent EDSS score progression in the subset of MS patients studied by this protocol.

Treatments may improve relapse-related outcomes in MS, at least temporarily, without providing sustained slowing of EDSS progression. Phase III MS trials should be of sufficient length to determine a meaningful impact on disease course.



#8

Modified Total Lymphoid Irradiation And Low Dose CorticoSteroids In Progressive Multiple Sclerosis

Cook SD; Devereux C; Troiano R; Wolansky L; Guarnaccia J; Haffty B; Bansil S; Goldstein J; Sheffet A; Zito G; Jotkowitz A; Boos J; Dowling P; Rohowsky Kochan C; Volmer T
J Neurol Sci, 1997 Nov, 152:2, 172-81
Univ of Medicine and Dentistry of New Jersey, New Jersey Medical School, Dept of NeuroSciences, Newark 07103, USA
PMID# 9415539; UI# 98076021
Abstract

In a double-blind prospective randomized trial, we assessed the efficacy and safety of modified Total Lymphoid Irradiation (TLI) plus Low Dose Prednisone (TLI-LDP) as compared to sham TLI plus Identical Prednisone therapy (sham TLI-LDP) in 46 patients with Progressive forms of Multiple Sclerosis (MS).

No significant difference existed between groups at study entry in patient age, sex, duration of MS, or disability status.

However, following treatment, significantly fewer TLI patients showed a sustained one point decline in the Expanded Disability Status Scale, the primary study endpoint, as compared to the sham TLI group using the Kaplan-Meier Product-limit survival analysis, (P<0.005).

Risk for relapse requiring treatment with IntraVenous MethylPrednisolone was reduced by 54% in the TLI-treated group (P<0.05).

Significantly fewer TLI-LDP patients had Gadolinium enhancing plus new T2-weighted lesions (P=0.018) when compared to the sham group post-treatment.

There was also a substantial and significant decrease in blood Lymphocytes in the TLI-LDP group when compared to either pretreatment values or to sham TLI-LDP through at least 12 months post-therapy.

Side effects secondary to TLI were generally mild and well-tolerated. These results further support the hypothesis that TLI and systemic ImmunoSuppression have a beneficial effect in Progressive forms of MS.



#9

Major Histocompatibility Complex Class II Alleles And The Course And Outcome Of MS

A population-based study

Weinshenker BG; Santrach P; Bissonet AS; McDonnell SK; Schaid D; Moore SB; Rodriguez M
Neurology, 1998 Sep, 51:3, 742-7
Mayo Clinic and Mayo Foundation, Dept of Neurology, Rochester, MN 55905, USA
PMID# 9748020; UI# 98418816
Abstract

Background
The Major Histocompatibility Complex (MHC) has been consistently associated with susceptibility to MS and the course of several other human AutoImmune Diseases.

A putative association between the course and severity of MS and the MHC remains controversial.

Methods
DR and DQ Genotyping by either restriction fragment length PolyMorphism or sequence-specific PCR-based typing in 119 patients representing 73.4% of the population with MS evaluated in a cross-sectional Disability survey and 100 healthy controls from Olmsted County, Minnesota.

Results
We found a positive association between MS susceptibility and the DR15-DQ6 and DR13-DQ7 haplotypes, and we found a negative association with the DR1-DQ5 haplotype.

We found a trend to a positive association of Primary/Progressive MS with DR4-DQ8 and DR1-DQ5 and an association of "bout onset" MS with DR17-DQ2. We did not find an association with disease severity, as defined by EDSS/duration.

Conclusion
Lack of consistency between different studies may be due to regional variation in MS and limitations of power but likely indicate a minor effect of MHC Class II Genes on the course and severity of MS.



#10

Interferon-beta-1a In Primary/Progressive MS: An Exploratory, Randomized, Controlled Trial

Leary SM, Miller DH, Stevenson VL, Brex PA, Chard DT, Thompson AJ
Neurology 2003 Jan 14;60(1):44-51
Institute of Neurology, University College London, NMR Research Unit, UK
PMID# 12525716
Abstract

Background
Patients with Primary/Progressive MS have atypical clinical and MRI characteristics and have been excluded from most therapeutic trials. The authors report a randomized, controlled trial restricted to Primary/Progressive MS.

Methods
Fifty subjects were randomized to weekly IM Interferon-ß-1a 30 microg, 60 microg, or placebo for 2 years. The primary endpoint was time to sustained progression in disability.

Secondary outcomes included the Timed 10-Meter Walk, Nine-Hole Peg Test, and on MRI, T2 and T1 Brain lesion loads and Brain and Spinal Cord Atrophy.

Results
The 30- microg dose of Interferon-ß-1a was well tolerated, but the 60- microg dose caused severe Flulike reactions and raised Liver Enzymes. No treatment effect was seen on the primary endpoint.

Subjects on Interferon-ß-1a 30 microg had a lower rate of accumulation of T2 lesion load than controls (p = 0.025); subjects on 60 microg had a greater rate of Ventricular enlargement than controls (p = 0.025).

Conclusions
This study has demonstrated that Interferon-ß-1a 30 microg was well tolerated, identified useful outcome measures, but showed no efficacy on the primary outcome measure or on most of the secondary outcome measures.



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