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Results for “Multiple Sclerosis, Chronic Progressive”

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PubMed1988

The short-term effect of an immunosuppressive treatment on CSF myelin basic protein in chronic progressive multiple sclerosis.

CSF levels of myelin basic protein (MBP) and intrathecally produced CSF IgG (de novo IgG) were measured in 11 chronic progressive multiple sclerosis patients with a deteriorating course of the disease for at least 6 months preceding observation and a reference group of 17 neurological patients suffering from disc herniation. In the multiple sclerosis patients, CSF levels were determined just before and once in the period 3 to 10 weeks after the start of an immunosuppressive treatment with cyclophosphamide and prednisone. For multiple sclerosis patients the CSF MBP levels before treatment were significantly higher than for controls. The CSF MBP levels after the treatment were nearly all within the control range. The abnormal high concentration of intrathecally produced CSF IgG (de novo IgG) in multiple sclerosis patients was reduced after treatment. A correlation between CSF MBP and CSF de novo IgG in multiple sclerosis patients could not be demonstrated. If CSF MBP is an indicator of the (activity of) myelin breakdown in the brain, it can be concluded that an intensive immunosuppressive treatment in combination with prednisone has, at least, a short-term, beneficial effect on the amount of demyelinisation and possibly on the disease activity.

Adult↗

PubMed1992

Low-dose (7.5 mg) oral methotrexate for chronic progressive multiple sclerosis. Design of a randomized, placebo-controlled trial with sample size benefits from a composite outcome variable including preliminary data on toxicity.

OBJECTIVE: To present a detailed description of (1) the study design of this ongoing trial, (2) advantages of using a composite outcome variable instead of multiple individual outcome measures, (3) treatment group characteristics at baseline, and (4) observed short-term methotrexate (MTX) toxicity. DESIGN: Randomized, double-masked, placebo-controlled intervention study. SETTING: Referral-based outpatient multidisciplinary multiple sclerosis (MS) clinic. PATIENTS: Participation offered to all clinically definite chronic progressive multiple sclerosis (CPMS) patients attending clinic ages 21 to 60, disease duration > 1 year, Expanded Disability Status Scale (EDSS) score 3.0 to 6.5 (ambulatory with moderate disability). Patients first stratified by EDSS 3.0 to 5.5 and 6.0 to 6.5, then randomized to MTX or placebo treatment. INTERVENTION: Weekly oral low-dose (7.5 mg) MTX or identical-appearing placebo for 2 years followed by a 1-year observation period. MAIN OUTCOME MEASURES: Sample size calculations undertaken prior to enrolling patients based upon a composite outcome variable consisting of designated change in any of the following functional measures: (1) EDSS, (2) Ambulation Index (AI), (3) Box and Block Test (BBT), and (4) 9-Hole Peg Test (9HPT). RESULTS: (1) Treatment group characteristics were comparable at baseline, (2) no patient has been withdrawn for adverse effects or lost to follow-up, (3) no significant short-term MTX toxicity has been observed. CONCLUSIONS: (1) The use of a composite outcome measure in the design of MS clinical trials is a promising alternative to multiple individual outcome measures that are relatively insensitive to detecting clinical change, (2) low-dose oral weekly MTX does not appear to be associated with significant short-term toxicity in CPMS. Conclusions regarding therapeutic efficacy of MTX in MS must await completion of this clinical trial.

Adult↗

PubMed1988

T cell subsets and disease progression after total lymphoid irradiation in chronic progressive multiple sclerosis.

T lymphocyte subset percentages were determined in 16 total lymphoid irradiation (TLI) treated and 18 sham treated control patients with chronic progressive multiple sclerosis. During the first year after treatment, the ratio of T helper/inducer to T suppressor/cytotoxic cells (Th/Ts ratio) was significantly higher in sham treated multiple sclerosis patients who worsened clinically compared with TLI treated and sham treated multiple sclerosis patients who remained clinically stable. TLI caused a fall in the percentage of T helper cells in treated patients, while the percentage of T suppressor cells remained stable during the first year after treatment. In contrast, the percentage of T suppressor cells fell in sham treated multiple sclerosis patients who worsened clinically.

Follow-Up Studies↗

PubMed1995

Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis.

A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic. Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients' Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity. We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.

Administration, Oral↗

PubMed1984

Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.

We studied a large kindred with a chronic progressive neurologic disorder affecting at least 10 men and 11 women in four generations in a pattern compatible with autosomal dominant inheritance. In 20 of the affected subjects, evaluated before the availability of computerized tomography and without regard to family history, the diagnosis was multiple sclerosis. Symptoms of the neurologic disorder begin in the fourth and fifth decades and include cerebellar, pyramidal, and autonomic abnormalities. The autonomic symptoms, which involve bowel and bladder regulation and orthostatic hypotension, may be the earliest changes but are frequently disregarded. Survival for 20 years after onset is common. The CT scan is striking and shows a symmetrical decrease in white-matter density, beginning in the frontal lobes but extending to all of the centrum ovale and the cerebellar white matter. Limited pathological observation reveals gross white-matter degeneration with microscopic vacuolation, preservation of U fibers and cortical structures, and no inflammatory changes or reactive gliosis. Because of its hereditary basis, the disorder should be susceptible to genetic definition and ultimately to treatment or prevention.

Adult↗

PubMed1990

Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. I. Clinical and MRI evaluation.

A randomized, double-blind, placebo-controlled, noncrossover trial determined the efficacy of lymphoblastoid interferon (IFN) in chronic progressive multiple sclerosis (CP MS). Fifty patients received 5 X 10(6) IU IFN subcutaneously daily for 6 months while 50 received placebo. After 2 years, there were no significant differences between the 2 groups based on clinical evaluations and quantitative MRI analysis of the brain, although a trend was observed in the IFN group. Clinically, the IFN group was worse at 1 and 3 months and improved at 6 to 18 months, when compared with the placebo group. Results of MRI evaluations of the brain at 6 months support this trend. This trend likely resulted from a subpopulation of 10 IFN-treated patients, characterized by a higher women:men ratio and a lower EDSS score at entry into the trial. We cannot recommend lymphoblastoid IFN as treatment for CP MS at this time.

Adult↗

PubMedDate not supplied

Effect of immunosuppressive cladribine treatment on serum leucocytes system in two-year clinical trial in patients with chronic progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis is presumably cell-mediated autoimmune disorder with immune abnormalities as presence of activated T-cells and increase interleukin 2 (IL-2) and soluble IL-2 receptor (sIL-2R) levels in central nervous system and peripheral blood of patients. The aim of immunosuppressive treatment is to diminish such activation. The aim of this study was to evaluate the influence of immunosuppressive cladribine treatment with total dose of 2.1 mg/kg b.w. administered in 7 cycles for 12 months, on serum leucocytes in 34 chronic progressive multiple sclerosis (CPMS) patients observed for 2 years as well as IL-2 and sIL-2R serum levels assessed before and right after the treatment. MATERIAL AND METHODS: The study was designed as a randomised, placebo-controlled, double-blind trial. The patients were divided in two groups: group I, cladribine-treated, n = 34; group II, placebo-treated, n = 35. Group III were healthy controls, n = 20. Leucocyte levels were determined with flow-cytometry. IL-2 and sIL-2R levels were assessed with enzyme-linked immunosorbent assay. RESULTS: Statistically significant gradual decrease of lymphocyte level was observed from 7th week to 12th month after the beginning of treatment. During the following 12 months, lymphocyte levels remained decreased in comparison to baseline. Mean values of IL-2 and sIL-2R levels measured 12 months after the treatment were found to be lowered by 20% (p. = 0.01) and by 24% (p. = 0.0005), respectively. CONCLUSION: The results obtained indicate fast and long-lasting decrease of serum leucocyte level and suppressive influence of cladribine treatment on immune processes in multiple sclerosis patients.

Adult↗

PubMed2003

Central motor conduction differs between acute relapsing-remitting and chronic progressive multiple sclerosis.

OBJECTIVE: To characterize central motor conduction in relation to the clinical deficits and to the disease duration in 90 patients with acute relapsing-remitting MS (RR-MS) and in 51 patients with chronic primary or secondary progressive MS (P-MS). METHODS: The triple stimulation technique (TST) was used to quantify the central motor conduction failure (expressed by the TST amplitude ratio) and conventional motor evoked potentials (MEPs) were used to measure the central motor conduction time (CMCT). RESULTS: The TST amplitude ratio was reduced in presence of a clinical motor deficit (p=0.02 for RR-MS, p<0.01 for P-MS), but did not significantly differ in RR-MS and P-MS (p>0.05) when patients with similar clinical motor deficit were compared. The CMCT was not related to the clinical motor deficit in both RR-MS and P-MS. However, the CMCT was markedly prolonged in P-MS, when patients with similar clinical motor deficit and with similar disease duration were compared (p<0.01). The differences were not attributable to differential involvement of the spinal cord, which was similar in RR-MS and P-MS. CONCLUSIONS: Our results disclose differences between the central motor conduction in RR-MS and P-MS that are not related to disease severity, spinal cord involvement or disease duration.

Acute Disease↗

PubMed1995

A longitudinal study of the T cell activation marker CD26 in chronic progressive multiple sclerosis.

Activated T cells are implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Serial measurements of T cell activation molecules and T cell subpopulations were performed over 12 months in patients with chronic progressive multiple sclerosis and healthy controls, and correlated with clinical indices of disease progression measured by standardized disability scores. Of the markers studied, the activation molecule CD26 appeared to exhibit a more consistent pattern and to be elevated in MS patients; therefore we concentrated our attention on this marker, especially in view of recent evidence of its role in T cell activation. In this small patient group, the elevation of CD26 in the MS patients did not reach statistical significance, when compared to the level in the controls. Interestingly, the percentage of CD26 but not CD25 or HLA-DR correlated with the MS patients' disability scores. However, the clinical significance of this observation as an indication of disease activity in chronic progressive MS remains to be demonstrated in studies of larger patient populations.

Adult↗

PubMed1997

Treatment with electromagnetic fields reverses the long-term clinical course of a patient with chronic progressive multiple sclerosis.

It is estimated that 10-20% of patients with multiple sclerosis (MS) have a chronic progressive (CP) course characterized by an insidious onset of neurological deficits followed by steady progression of disability in the absence of symptomatic remission. To date no therapeutic modality has proven effective in reversing the clinical course of CP MS although there are indications that prolonged treatment with picotesla electromagnetic fields (EMFs) alters the clinical course of patients with CP MS. A 40 year-old woman presented in December of 1992 with CP MS with symptoms of spastic paraplegia, loss of trunk control, marked weakness of the upper limbs with loss of fine and gross motor hand functions, severe fatigue, cognitive deficits, mental depression, and autonomic dysfunction with neurogenic bladder and bowel incontinence. Her symptoms began at the age of 18 with weakness of the right leg and fatigue with long distance walking and over the ensuing years she experienced steady deterioration of functions. In 1985 she became wheelchair dependent and it was anticipated that within 1-2 years she would become functionally quadriplegic. In December of 1992 she began experimental treatment with EMFs. While receiving regularly weekly transcortical treatments with AC pulsed EMFs in the picotesla range intensity she experienced during the first year improvement in mental functions, return of strength in the upper extremities, and recovery of trunk control. During the second year she experienced the return of more hip functions and recovery of motor functions began in her legs. For the first time in years she can now initiate dorsiflexion of her ankles and actively extend her knees voluntarily. Over the past year she started to show signs of redevelopment of reciprocal gait. Presently, with enough function restored in her legs, she is learning to walk with a walker and is able to stand unassisted and maintain her balance for a few minutes. She also regained about 80% of functions in the upper limbs and hands. Most remarkably, there was no further progression of the disease during the 4 years course of magnetic therapy. This patient's clinical recovery cannot be explained on the basis of a spontaneous remission. It is suggested that pulsed applications of picotesla EMFs affect the neurobiological and immunological mechanisms underlying the pathogenesis of CP MS.

Adult↗

PubMed1995

Meta-analysis of clinical studies of the efficacy of plasma exchange in the treatment of chronic progressive multiple sclerosis.

OBJECTIVE: To examine the hypothesis that addition of therapeutic plasma exchange (TPEX) to an immunosuppressive drug regimen increases that regimen's efficacy to halt the progression of chronic progressive multiple sclerosis (CPMS). METHODS: The literature was searched for prospective controlled clinical trials evaluating the efficacy of TPEX in CPMS. Six studies were eligible for meta-analysis. Their results were combined, using Cochran's and Peto's methods. Three outcome measures were studied: 1) the change in Kurtzke's disability status scale (DSS) scores, 2) the relative odds of neurologic decline by 1 or more DSS grades, and 3) the relative odds of neurologic improvement by 1 or more DSS grades, in the treatment versus the comparison group of patients. Reported results of neurologic evaluations at 6, 12, 24, and 36 months of follow-up were analyzed separately. RESULTS: TPEX significantly (P < .05) reduced the proportion of patients who experienced neurologic decline (by 1 or more DSS grades) at 12 months of follow-up (relative odds of decline = 0.441, 95% confidence interval = 0.210-0.929). CONCLUSIONS: There is a need for further clinical research into the possibility of a beneficial effect of TPEX in patients with CPMS likely to experience neurologic decline over the ensuring 12 months. Targeting treatment to a particular subgroup of CPMS patients may be necessary for TPEX to prove effective.

Chronic Disease↗

PubMed1990

Decrease of CD4+CD45+ T-cells in chronic-progressive multiple sclerosis.

Circulating lymphocyte subpopulations defined by anti-CD45 and other more common T-cell-specific monoclonal antibodies were analysed in 77 patients with multiple sclerosis and 38 healthy controls. A selective decrease of CD4+CD45+ cell percentages and absolute numbers in chronic-progressive patients was found; in 13 out of 26 patients this subpopulation was less than 11% CD4+CD45+ cells. Similarly, the whole CD45+ cell subset, as well as CD45+ cells expressed as percentages of CD4+ cells, were significantly reduced in chronic-progressive multiple sclerosis. CD4+CD45+ cells, commonly termed "inducer of suppression" T-lymphocytes, did not correlate with percentages or numbers of CD8+ cells. It is concluded that suppressor inducer T-cells act on the CD8+ subset function rather than reducing CD8+ cell numbers. Since CD4+CD45+ cells represent an early stage of lymphocyte maturation (naive T-cells), an under-representation of this subpopulation in active multiple sclerosis might reflect an increased conversion of naive cells into memory cells. This concept may be relevant for a better understanding of the disease pathogenesis.

Adult↗

PubMed1996

Treatment with electromagnetic field alters the clinical course of chronic progressive multiple sclerosis--a case report.

It is estimated that 10-20% of patients with multiple sclerosis (MS) have a chronic progressive (CP) course characterized by an insidious of neurological deficits followed by steady progression of disability in the absence of symptomatic remission. No therapeutic modality has shown specific efficacy in the treatment of patients with CP MS and there are no data to indicate that any pharmacologic or other modality alters the clinical course of CP MS. Treatment with picotesla electromagnetic fields (EMFs) is a highly effective modality for the symptomatic management of MS including the chronic progressive form. In addition, this treatment also appears to alter the natural course of the disease in CP patients. A 36 year-old man experienced, at the age of 31, insidious weakness in the legs and several months later developed difficulties with balance with ataxia of gait. His gait abnormality progressed slowly over the following years and at the age of 35 he was severely disabled with spastic paraparesis and ataxia using a rolling walker for ambulation and a scooter for longer distances. In particular, his disability had progressed rapidly over the six months preceding the initiation of treatment with EMFs. He as classified have CP MS and his prognosis was considered extremely unfavorable due to the degree of cerebellar and pyramidal tract involvement and the rapid course of deterioration. In July 1995 the patient began experimental treatment with EMFs. While receiving three treatment sessions a week over 12 months he experienced improvement in cerebellar functions such as gait, balance and tremor as well as bowel and bladder functions, mood, sleep and cognitive function and resolution of diplopia, blurring of vision, dysarthria, paresthesias in the hands, and fatigue. Most remarkably, there was no further progression of the disease during the course of magnetic therapy. This case illustrated that treatment with EMFs, in addition to producing symptomatic improvement, also reverses the clinical course of CP MS.

Adult↗

PubMed2000

Treatment of chronic progressive multiple sclerosis with intravenous immunoglobulins--interim results on drug safety of an ongoing study. IVIG study group.

In a blinded administrative look we analyzed the safety profile of intravenous immunoglobulin (IVIG) treatment in an ongoing randomized, placebo controlled double blind study on the treatment of multiple sclerosis (MS) patients with primary or secondary chronic progressive MS. Up to October 1999 131 patients were included in the study. Collectively, these patients received approximately 1,200 infusions either with IVIG (400 mg/kg bodyweight every 4 weeks) or with placebo; approximately 600 IVIG infusions were administered. All reported serious adverse events (SAE), including reports on adverse events submitted directly to the drug safety department of the sponsor, were closely analyzed A total of 25 SAE's (in 25 patients) have been reported up until 15th October 1999, whereby the main criterion for 'serious' in all of these cases was hospitalization. None of these 25 SAE were regarded as drug related. No side effects relating to liver functions, kidney functions or rheological problems have been reported. Since the mean score on the EDSS-scale of the patients at the point of inclusion in the study was 5.6 (median EDSS: 6.0) we conclude that IVIG treatment, at a dose of 400 mg/kg bodyweight every 4 weeks, is a relatively safe therapy even for severely disabled multiple sclerosis patients.

Adult↗

PubMed1997

Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85 VVHFFKNIVTP96 in chronic progressive multiple sclerosis.

Peptide-based tolerance induction may be useful for antigen-specific immunotherapy of human autoimmune diseases. Induction of tolerance to myelin basic protein (MBP) was examined in a Phase I clinical trial in multiple sclerosis (MS) patients with chronic progressive disease using a peptide that is immunodominant for MBP specific T cells and B cells. Tolerance induction was monitored by quantification of MBP specific autoantibodies in cerebrospinal fluid (CSF). The route of peptide administration was important since only intravenous but not intrathecal or subcutaneous injection induced tolerance to MBP. Following a single intravenous injection of a peptide containing epitope P85VVHFFKNIVTP96, MBP autoantibodies were undetectable for three to four months. Tolerance was more prolonged following a second injection since autoantibodies were low or undetectable after one year in the majority of patients. Duration of tolerance to MBP depended on MHC class II haplotypes of patients; tolerance was long-lived in all patients with disease associated HLA-DR2. No neurological or systemic side effects were observed, regardless of the route of peptide administration. These data demonstrate that intravenous administration of a soluble peptide can result in long-lasting tolerance to an autoantigen in humans.

Autoantibodies↗

PubMed2000

Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31.

The hereditary leukodystrophies represent a group of neurological disorders, in which complete or partial dysmyelination occurs in either the central nervous system (CNS) and/or the peripheral nervous system. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, and the phenotype is similar to that of chronic progressive multiple sclerosis. We report clinical, neuroradiological and neuropathological data from the originally reported ADLD family. Furthermore, we have localized the gene that causes ADLD to a 4 cM region on chromosome 5q31. Linkage analysis of this family yielded a LOD score of 5.72 at theta = 0.0 with the microsatellite marker D5S804. Genetic localization will lead to cloning and characterization of the ADLD gene and may yield new insights into myelin biology and demyelinating diseases.

Brain↗

PubMed1989

Effective treatment of chronically progressive multiple sclerosis with low-dose cyclophosphamide with minor side-effects.

Twenty-one multiple sclerosis (MS) patients with a chronically progressive course were treated with a low dose of cyclophosphamide (CY). The control group consisted of 21 MS patients with a chronically progressive course who received the standard treatment (ACTH or cortisone). The control group consisted of patients who preferred the standard therapy because of its beneficial effects. In contrast, the patients of the CY group wanted to try a new therapy because the standard therapy was not effective. Thus before starting the study the progression of the disease was faster in the CY group than in the standard therapy group. As regards age, sex and degree of disability, the two groups were comparable. For 20 of the 21 patients in the CY group the degree of disability (Kurtzke scale) remained stable over 1 year; for 2 of the 20 stable patients there was even an improvement. In the standard therapy group, 7 out of 21 patients were stable over 1 year, while 14 showed progressive disability. A quantitative neurological score at the beginning and 1 year after the therapy showed a nearly identical difference between the CY group and the control group. The changes of the patients' abilities in daily-life activities (which were observed and recorded by the nurses) were similar to the Kurtzke scale data obtained by the physicians. The beneficial effect of CY in chronically progressive MS was thus highly significant (P less than 0.001). The side-effects of low-dose CY were fewer than those of ACTH.

Adult↗

PubMed1996

Elevated serum levels of interleukin-12 in chronic progressive multiple sclerosis.

The serum levels of the heterodimeric cytokine IL-12 were measured by solid-phase ELISA in a group of healthy subjects, multiple sclerosis (MS) patients with secondary chronic progressive course of the disease and patients suffering from other neurological diseases (OND). Serum levels of IL-12 higher than 5 pg/ml (limit of sensitivity of the assay) were only found in 2/30 (6.7%) of the healthy subjects and none of the 8 subjects with OND. In contrast, IL-12 was found in the majority of CPMS patients' sera (10/15, 66.7%) with values ranging between 5.5 and 18.6 pg/ml. These results are suggestive for an up-regulated production of IL-12 in CPMS.

Adult↗