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1.
The progressive phase of multiple sclerosis (MS) is the one most often associated with irreversible accumulation of disability. An important question remains about the place of primary progressive MS (PP-MS): does it form an integral part of the disease spectrum, or is it maybe a distinct entity? This question could apparently be very theoretical, but it is not, as patients with PP-MS remain orphans when regarding disease-modifying treatments. Thus, they are usually excluded from therapeutic trials. A clue to this question could be the comparison between the different MS subtypes with a progressive phase. We discuss here the clinical similarities and differences between secondary and primary progressive MS. 相似文献
2.
Río J Tintoré M Nos C Téllez N Galán I Pelayo R Montalban X 《Journal of neurology》2007,254(7):849-853
Abstract
Background and
objective
Observational studies
may provide additional information
about the behaviour of different
drugs in the post-marketing
period. We present the data from a
cohort of secondary progressive
multiple sclerosis (SPMS) patients
treated with interferon beta (IFNβ-1b) at our MS clinic.
Methods
This was an independent,
open-label, non-randomised,
observational study. Within the
period 1998 to 2005, all patients
with SPMS who started therapy
with IFNβ-1b at our centre were
studied. Each patient was included
in a follow-up protocol collecting
demographic and baseline clinical
data.
Results
We studied 146
SPMS patients with a median
follow-up of 60 months. Over the
total study period, 62.2% of patients
had confirmed progression.
The analysis of the time to con-
firmed progression showed that
patients with two or more relapses
in the 2 years before IFNβ initiation,
had a higher risk of disability
increase than those patients with
less than two relapses (p = 0.002).
Multiple regression analysis
showed disease activity in terms of
relapses as the only factor to
predict increase of disability during
the follow-up period. A significant
proportion of patients
(36%) stopped treatment during
the follow-up period. IFNβ was
safe, although some unexpected
adverse events were observed.
Conclusions
A higher disease
activity before the beginning of
treatment with IFNβ in SPMS
patients with a given EDSS rank
could identify those with faster
disability progression after treatment
initiation. 相似文献
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Correale J Lund B McMillan M Ko DY McCarthy K Weiner LP 《Journal of neuroimmunology》2000,107(2):130-139
Four secondary progressive MS patients were vaccinated with bovine myelin-reactive irradiated T cell lines from their peripheral blood. Patients were followed for 30-39 months, and monitored for immunological responses toward the vaccine, and for their clinical characteristics. Two patients showed stable EDSS score over time, one patient showed improvement by one EDSS step, and in the remaining patient her EDSS advanced over time. After the second inoculation there was a progressive decline of circulating whole myelin-reactive T cells, MBP143-168, PLP104-117, and MOG43-55-peptide-reactive T cells. In contrast the frequency of tetanus toxoid-reactive T cells remained unchanged. T cell vaccination (TCV) was also associated with a decline of myelin-specific IL-2- and IFN-gamma-secreting T cells. Twelve T cell lines (TCL) that recognize the inoculates were isolated from the peripheral blood of two patients. Ten of these TCL were CD8(+) and lysed the inoculates in a MHC Class I restricted manner. The remaining two TCL were CD4(+), and lysed the inoculates by MHC Class II restricted cytolytic activity. All T cell lines lysed not only myelin-reactive T cells, but also TCL specific for MBP143-168, PLP104-117 and MOG43-55 peptides. Control TCL specific for tetanus toxoid were not lysed. Neutralizing anti-Fas mAb did not influence the killing. Moreover, culture supernatants from two TCL which produce IL-10, were able to block the proliferation of myelin protein-specific TCL. This effect was abrogated using mAbs specific for IL-10. The data obtained indicated that TCV using autologous irradiated bovine myelin-reactive T cells promotes an effective depletion of T cells reactive against different myelin antigens. 相似文献
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10.
Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis 总被引:2,自引:0,他引:2
Avasarala JR Cross AH Clifford DB Singer BA Siegel BA Abbey EE 《Multiple sclerosis (Houndmills, Basingstoke, England)》2003,9(1):59-62
Mitoxantrone is a recently approved drug for patients with secondary progressive multiple sclerosis (SPMS). However, cardiac side effects limit Mitoxantrone use in SPMS and its lifetime cumulative dose should not exceed 140 mg/m2. Additionally, Mitoxantrone is contraindicated for use in SPMS patients with a baseline left ventricular ejection fraction (LVEF) of < or = 50%. The goal of this study was to monitor LVEF more frequently than ordinarily recommended since experience with Mitoxantrone use in SPMS patients is limited. An unexpected decline in LVEF in one of the SPMS patients being treated with Mitoxantrone prompted further investigation into this finding. In our clinic, 47 patients on Mitoxantrone were followed prospectively; 28 of 47 patients had received a minimum of three doses and underwent a repeat LVEF evaluation prior to their fourth dose of Mitoxantrone. Of these 28 patients, five of 28 (17.8%) had a significant decline in LVEF from baseline. It is suggested that more stringent cardiac monitoring guidelines than current Food and Drug Administration (FDA) recommendations be used to avert potential cardiac complications in SPMS patients on Mitoxantrone. 相似文献
11.
Wachowius U Talley M Silver N Heinze HJ Sailer M 《Journal of clinical and experimental neuropsychology》2005,27(1):65-77
The aim of this study was to use neuropsychological data to characterize two subtypes of multiple sclerosis (MS) patients in a large patient sample. We studied patients with primary-progressive MS (PPMS) and secondary-progressive MS (SPMS). A group of 121 MS patients (36 PPS, 85 SPMS) and 40 healthy controls were administered a brief battery of cognitive tests. Executive functioning, memory and attention were studied. Results demonstrate that PPMS patients exhibited slightly more impairment than patients with SPMS, although this difference is not significant (50% vs 37%). However, PPMS patients revealed a significantly poorer performance in verbal learning (p < 0.05) and in verbal fluency (p < 0.05). Whereas PPMS patients had significantly shorter disease durations (p < 0.05), there was no statistical difference in disability between both groups. We conclude from our study that cognitive deficits in progressive MS are frequent. Patients with PPMS tend to be more frequently and severely affected than SPMS patients. Our findings of high prevalence of cognitive involvement in PPMS have not been reported previously 相似文献
12.
Beiske AG Naess H Aarseth JH Andersen O Elovaara I Farkkila M Hansen HJ Mellgren SI Sandberg-Wollheim M Sorensen PS Myhr KM;Nordic SPMS study group 《Multiple sclerosis (Houndmills, Basingstoke, England)》2007,13(3):386-392
Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-beta1a (IFN-beta1a), 22 mug subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-beta1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS. 相似文献
13.
OBJECTIVE: Two recent randomized double-blind placebo controlled clinical trials of interferon beta-1a in multiple sclerosis have obtained hopelessness ratings using the Beck Hopelessness Scale (BHS). One of these studies, the PRISMS trial, evaluated interferon beta-1a in relapsing remitting multiple sclerosis (RRMS). Another, the SPECTRIMS trial, evaluated the same medication in secondary progressive (SP) MS. The objective of this analysis was to compare levels of hopelessness in persons with RRMS and SPMS, and to describe changes over time in the clinical trial participants. METHOD: Raw data from each clinical trial was obtained from the sponsor of the trials (Serono). Median BHS ratings, and the proportions at or above the BHS cut-point of 10 were calculated over a two (PRISMS) or three (SPECTRIMS) year period. RESULTS: The analysis included n = 532 clinical trial participants. Ratings of hopelessness were higher in SPMS clinical trial participants (SPECTRIMS) than in the RRMS group (PRISMS) at baseline (Fisher's exact test, p = 0.0035). Furthermore, ratings of hopelessness were higher during follow-up than at baseline, in the SPMS group (McNemar's exact probability,p = 0.0015), but not in the RRMS group (McNemar's exact probability,p = 0.65). Depression was strongly associated with hopelessness in both RRMS (z = 4.13, p < 0.001) and SPMS (z = 5.24, p < 0.001). CONCLUSIONS: Hopelessness is associated with SPMS, and may increase over time in this group. Hopelessness may influence suicide risk in people with MS and may potentially have an impact on coping and quality of life. Additional research is necessary to define the clinical implications of hopelessness in persons with this condition. 相似文献
14.
The design of a double-blind, placebo-controlled, European-Canadian Study on IVIG treatment in multiple sclerosis-ESIMS- is described. Three hundred and eighteen multiple sclerosis patients with a secondary progressive course, are treated with monthly infusions of immunoglobulin 10% 1 g/kg bodyweight or with 0.1 g albumin/vial for 27 months. The primary efficacy parameter is the percentage of patients with a confirmed treatment failure in the EDSS scale and/or the Nine Hole Peg Test Secondary outcome measures are MRI T2 lesion load, Magnetization Transfer Imaging, and MRI brainatrophy measures. Documentation of health resource utilisation and ability to work will cover socio-economic aspects. Recruitment of patients was completed in October 1998. The clinical part of the trial will be completed in April 2001. 相似文献
15.
Bennett JL 《Neurological research》2006,28(3):291-298
Natalizumab, a humanized monoclonal antibody against alpha4beta1 integrin, was shown in clinical trials to dramatically reduce the relapse rate, development of new magnetic resonance imaging (MRI) lesions and progression of disability in patients with relapsing multiple sclerosis. Following its expedited approval, sales of the drug were discontinued owing to the emergence of two cases of progressive multifocal leukoencephalopathy (PML), a rare but deadly viral infection of the central nervous system (CNS) associated with immunosuppression. Owing to the effect of natalizumab on central nervous system leukocyte recruitment, the emergence of PML has been attributed to diminished immunosurveillance. The lack of additional opportunistic or CNS infections among natalizumab-treated patients, however, suggests that alternate mechanisms may contribute to the infectious risk. This review examines how the inhibition of alpha4beta1-mediated adhesion might establish a unique milieu for the development of PML and how future approaches to selective adhesion molecule therapy in multiple sclerosis might avoid a similar fate. 相似文献
16.
Hayton T Furby J Smith KJ Altmann DR Brenner R Chataway J Hunter K Tozer DJ Miller DH Kapoor R 《Journal of neurology》2012,259(2):237-245
The association of pathology and neurological deficit with quality of life (QoL) in multiple sclerosis (MS) is not fully understood.
In this study, magnetic resonance imaging (MRI) measures of pathology—T1 and T2 lesion volume and ratio; active T2 lesion
number; global and regional brain volume and atrophy; magnetization transfer ratio (MTR) for lesions, normal appearing grey
and white matter (NAGM, NAWM); and spinal cord cross-sectional area—and measures of neurological disability (expanded disability
status scale, EDSS), deficit (MS functional composite, MSFC) and inflammatory activity (relapse rate) were compared with the
MS impact scale (MSIS-29), in participants in a trial of lamotrigine in secondary progressive MS. Data were collected from
118 people (85 female:33 male) aged 30–61 years (mean 50.6 years)—median EDSS 6.0 (range 4.0–7.5); mean disease duration 20.1 years
(range 3–41)—at baseline and 2 years. Regression analysis was used to identify independently significant cross-sectional and
longitudinal correlates of the physical (MSIS-phys) and psychological (MSIS-psych) components of the MSIS-29; longitudinal
analysis using the 57 people in the placebo arm. The only independently significant correlate of MSIS-phys was 1/timed walk
(TW) (p < 0.0001, R
2 = 0.13; p = 0.047, R
2 = 0.09); cross-sectionally the best model for MSIS-psych was the paced auditory serial addition test (PASAT-3) (p = 0.041) and T1-to-T2 lesion volume ratio (p = 0.009) (R
2 = 0.13); longitudinally it was change in 1/TW (p = 0.007), mean NAWM MTR (p = 0.003) and NAGM peak height (p = 0.048) (R
2 = 0.32). These data show that MRI measures and clinical measures do impact on quality of life, but the association is limited. 相似文献
17.
Wiendl H Kieseier BC Weissert R Mylius HA Pichlmeier U Hartung HP Melms A Kuker W Weller M 《Journal of neurology》2007,254(7):884-889
Abstract
Objective
To study
the safety and efficacy of treosulfan,
a cytotoxic alkylating
agent, in patients with active
secondary progressive multiple
sclerosis.
Background
Treosulfan
(L-threitol-1,4-bis(methanesulfonate))
is a bifunctional alkylating
agent with a favorable profile of
side effects, approved for the
treatment of ovarian cancer.
Treosulfan has previously been
shown to reduce the severity of
experimental allergic encephalomyelitis
under pre-therapeutic
and therapeutic conditions. In
human peripheral blood mononuclear
cells, treosulfan reduces
proliferative capacity and increases
apoptosis.
Study design
This is a nonrandomized, open
label study conducted in two
centers. Eleven patients with
active secondary progressive MS
that failed to or did not qualify
for approved disease modifying
drugs were treated with treosulfan
for 1 year. Patients received
intravenous infusions of 7 g/m2
every 4 weeks for 3 months (cycles
1–4, induction phase) with a
predefined one-step dose escalation,
thereafter every 3 months
for the following 9 months (cyles
5–7, maintainance phase). Cranial
MRI was performed every
3 months, EDSS and MSFC as
well as physical examination
were assessed at each clinical
visit.
Results
Treatment with
treosulfan was safe and well
tolerated. Nine of 11 patients
remained on study drug over the
complete treatment period and
showed clinical stabilisation or
improvement as determined by
EDSS and MSFC. Two patients
discontinued study drug because
of leukocytopenia and withdrawal
of consent, respectively. No clinical
relapses were observed during
the treatment period. Thus,
the median number of relapses
per year was reduced signifi-
cantly by 1.5 (range –3 to 0),
p < 0.016, compared to prestudy.
Therapy with treosulfan
lead to a clear reduction of MRI
activity as revealed by a reduced
number of Gd + enhancing lesions
on T1 weighted images.
The mean number and volume of
T2 lesions remained unchanged
over 1 year. Four out of 9 patients
under treosulfan showed
no detectable disease activity (no
Gd enhancing lesions, no new or
newly enlarging T2 lesions).
Conclusions
Application of treosulfan
in MS was safe and well
tolerated. Further studies are
warranted to evaluate the efficacy
of this treatment in secondary
progressive MS. 相似文献
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19.
Hughes RA 《Journal of the neurological sciences》2003,206(2):199-202
This non-systematic review identified four randomised trials that have tested the efficacy of interferon beta in secondary progressive multiple sclerosis (SPMS). Two were trials of interferon beta 1a (IFNb1a) and two of interferon beta 1b (IFNb1b). All have shown significant reductions in relapse rates and accumulation of new magnetic resonance imaging (MRI) lesions, but only one trial (of IFNb1b) showed significant slowing of disability progression. Post hoc analyses of these trials suggest that the differences in outcomes might be partly explained by the differences between the trials in the proportions of patients with relapsing disease. In one of the trials of IFNb1a (the SPECTRIMS trial), the hazard ratio for progression in the treated relapsing patients with relapses in the two pre-study years was 0.74 compared to placebo patients with pre-study relapses and 1.01 in the treated patients compared to the placebo patients without pre-study relapses. In the same trial, the treatment effects on MRI parameters were more marked in the patients who had recent pre-study relapses compared with those who had not. These observations have led to the recommendation in national guidelines that prescribing of IFNb in SPMS be limited to those patients who have had disabling relapses in the last 2 years. These conclusions should be reviewed when the full results of all four trials have been published. 相似文献
20.
Myers LW 《Current neurology and neuroscience reports》2001,1(3):286-293
Multiple sclerosis (MS) is generally considered an immunemediated demyelinating disease, and treatments designed to modify
the course of MS are immunosuppressive or immunomodulatory. Although most people with MS have a relapsing-remitting course
initially, the majority will eventually experience a more gradual decline in neurologic function, termed secondary progressive
MS. Some patients have gradual worsening from the beginning, termed primary progressive MS. Recent pathologic studies have
revealed that axonal injury and neuronal degeneration are much more prominent in MS than previously recognized, and may be
the explanation for the gradual decline in neurologic function that characterizes progressive MS. The results of several clinical
trials in MS indicate that suppression of the immune-mediated inflammation may decrease the relapse rate in MS, but not stop
the progressive loss of neurologic function. There are many promising approaches to this clinical dilemma, but none has been
proven to be effective in stopping or retarding progressive MS. More well-designed, controlled, blinded, randomized clinical
trials are needed to test these putative therapies. In the mean time, we should avoid subjecting patients to potentially dangerous
and unproven regimens. 相似文献