Secondary progressive multiple sclerosis - clinical course and potential predictive factors

BACKGROUND AND PURPOSE: To characterize the course of secondary progressive multiple sclerosis (SPMS), with an attempt to assess the predictive value of early clinical variables. MATERIAL AND METHODS: Medical records of 100 patients with SPMS (40 men, 60 women, aged 34-73) were analyzed retrospectively. Age at onset of MS, first symptoms, annual exacerbation rate (AER), time to progressive phase (TTP), degree of disability at its beginning (Expanded Disability Status Scale; EDSS SP), and annual progression in disability in relapsing-remitting and progressive phases (APD RR and APD SP) were compared for the gender subgroups, and the relationships between them were analyzed. RESULTS: Time to progressive phase range was 2-29 years (mean 11.51) and EDSS SP 2-7.5 (mean 5.55). Time to progressive phase in women was longer and EDSS SP was lower than in men. Age at onset of MS, AER and ADP RR correlated positively with TTP. Optic neuritis was the most common first symptom (49%; motor deficit and cerebellar/brainstem involvement 26% and 21%, respectively). Time to progressive phase in the former subgroup was shorter than in the latter, but no differences in ADP SP were found. Annual progression in disability in relapsing-remitting was higher than APD SP. Degree of disability at its beginning (EDSS SP) correlated negatively with ADP SP. CONCLUSIONS: Older age at onset, male gender, frequent relapses and fast increase in disability in the relapsing-remitting phase are risk factors for conversion to SPMS. Increase in disability during the progressive phase is slower than in the relapsing-remitting phase and depends mainly on initial EDSS. Individual variability of the course of MS has to be considered.     

Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events.

The clinical data of 309 patients with definite multiple sclerosis were recorded in the European data base for multiple sclerosis (EDMUS) to determine the prognostic significance of several demographic and clinical variables. An interview with closed questions structured according to standardised criteria of disease phases and courses was used to assess the clinical course. The reliability was evaluated by four trained neurologists in a sample of 33 patients with multiple sclerosis. Both the within and between rater agreement on data collection was fair to high for the historical variables (K = 0.33-1). Between rater agreement was more variable for the evaluation of 12 different EDMUS event categories (K = 0.3-0.95). The predictive model for the time to reach a secondary progression showed that an age at onset older than 25 (p = 0.006) and an event at onset followed by disability > or = 3 on the Kurtzke expanded disability status scale (EDSS; p = 0.004) were the most unfavourable clinical variables in 249 patients with relapsing remitting (180) or relapsing progressive (69) courses. In the 69 patients with relapsing progressive disease, the time to reach severe disability (EDSS > or = 6) was negatively influenced by a first interval between attacks shorter than one year, a number of bouts with EDSS > 2 in the first two years of the disease, and involvement of the pyramidal system at onset (p < 0.05). In 60 patients with chronic progressive disease this outcome was negatively influenced by pyramidal, brainstem, and sensory involvement at onset (p < 0.01).     

Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis

Predicting clinical outcome is one of the major and most interesting issues in MS patients. If the global evolution of disability (usually chosen levels on the Kurtzke's Disability Status Scale) has been widely studied, much less is known about the progression of disability during the secondary progressive phase of the disease. It is usually said that there is a poorer prognosis once patients enter a progressive phase, whether from onset (like in primary progressive MS) or after an initial relapsing-remitting phase. The secondary progressive phase of multiple sclerosis (MS) is the one most often associated with the development of severe and irreversible disability. Despite this fact, there is a lot of information about the initial relapsing-remitting phase in the literature, but much less about the secondary progressive one. We review here information available from the literature and from the Lyon MS database about this secondary progressive phase.     

吸烟对多发性硬化病人病情进展影响

目的探讨吸烟对多发性硬化(MS)病人病情进展的影响。方法从2005-01～2010-12,随访三所医院364例临床诊断为MS的病人,分为吸烟组、戒烟组和非吸烟组,根据临床和磁共振成像(MRI)特点,比较各组转化为继发进展型MS的比例、脑实质分数(BPF)和T2高密度病灶体积变化。结果吸烟组与非吸烟组相比,扩展残疾状态量表评分(EDSS)和多发性硬化严重程度评分(MSSS)增加,从复发缓解型MS(RRMS)向继发进展型MS(SPMS)的转化较快,T2加权病灶体积增加,BPF减少。结论研究提示吸烟对MS进展有不利影响,吸烟可加速RRMS向SPMS的转化。     

The prevalence of multiple sclerosis, distribution of clinical forms of the disease and functional status of patients in Csongrád County, Hungary.

OBJECTIVE: The aim of this study was to determine the prevalence of multiple sclerosis (MS) in the population of Csongrád County, Hungary (400,128 inhabitants) and to determine the functional status (based on the Expanded Disability Status Scale; EDSS) of the patients according to the clinical forms of the disease. METHODS: The diagnosis was established with the aid of the Poser diagnostic criteria, and the degree of physical disability was determined using the Kurtzke EDSS. RESULTS: In Csongrád County, the prevalence of MS is 62/100,000. The distribution of patients according to the clinical forms of MS was as follows: 15% had the benign form, 54% had relapsing-remitting MS, 20% had secondary chronic progressive MS and 11% had the primary chronic progressive form of MS. Sixty percent of relapsing-remitting MS patients had an EDSS score of 0-4 points and 33% had an EDSS score of 4.5-6.5 points. CONCLUSION: The distribution of patients according to the clinical forms of the disease in this representative population is comparable to results in other regions of the world.     

Correlation between brain MRI lesion volume and disability in patients with multiple sclerosis

In this study we evaluated the relationships between clinical variables and lesion volumes measured from magnetic resonance imaging (MRI) scans in a large cohort of multiple sclerosis (MS) patients. One hundred and thirty patients with MS entered the study: 36 patients had relapsing-remitting (RR), 39 benign (B), 42 secondary progressive (SP) and 13 primary progressive (PP) courses. There was a significant correlation (r=0.3; p=0.0006) between the total lesion load and the EDSS score when the whole cohort of patients was considered. This correlation increased (r=0.5) when only patients with RRMS and SPMS were considered. Our data indicate that a correlation between disability and MRI lesion volume in MS exists, but its strength is moderate.     

The pathogenesis of primary progressive multiple sclerosis: antibody-mediated attack and no repair?

Primary progressive multiple sclerosis (MS) differs from the more common form of MS which has an initial relapsing-remitting course in a number of ways, including pathological features, clinical course, differential diagnosis and response to treatment. The lesions in primary progressive MS tend to be more diffuse, less inflammatory and less likely to remyelinate than those occurring in relapsing-remitting MS and secondary progressive MS; there are also fewer focal lesions in the brain in primary progressive MS. Recent evidence suggests that antibodies to central nervous system (CNS) antigens have an important role in disease progression. Such antibodies could cause demyelination, inhibit remyelination and cause axonal destruction. Ongoing immune attack by autoantibody and lack of CNS repair could be responsible for the gradually increasing disability in primary progressive MS. Further research on the B-cell and autoantibody response in primary progressive MS might lead to advances in diagnosis and treatment. Inhibition of autoantibody production by inducing B-cell apoptosis with rituximab is a potential new therapy for primary progressive MS.     

Deep gray matter perfusion in multiple sclerosis: dynamic susceptibility contrast perfusion magnetic resonance imaging at 3 T

OBJECTIVES: To assess the presence of perfusion abnormalities in the deep gray matter of patients with relapsing-remitting and primary progressive multiple sclerosis (MS) in comparison with healthy controls and to investigate the impact of perfusion impairment on clinical disability and fatigue. DESIGN: Survey. SETTING: Research-oriented hospital. Patients Twenty-two patients with MS and 11 age- and sex-matched healthy volunteers. Intervention Absolute cerebral blood flow, cerebral blood volume, and mean transit time were measured in the thalamus, putamen, and caudate nuclei. MAIN OUTCOME MEASURES: Decrease of cerebral blood flow in the deep gray matter of patients with MS and correlation between perfusion impairment and the severity of fatigue. RESULTS: The cerebral blood flow value averaged over the thalamus, putamen, and caudate nuclei was significantly lower in patients with primary progressive MS (P<.001) and in patients with relapsing-remitting MS (P = .01) compared with controls, and there was a trend for patients with primary progressive MS to have lower average cerebral blood flow than patients with relapsing-remitting MS (P = .06). With respect to cerebral blood volume, there was a significant difference between patients with primary progressive MS and controls (P<.001) and between the 2 groups of patients (P = .03) but not between patients with relapsing-remitting MS and controls (P>.30). The fatigue score was significantly correlated with cerebral blood flow (r = 0.4; P<.001) and cerebral blood volume (r = 0.5; P = .004). CONCLUSION: The decrease of tissue perfusion in the deep gray matter of patients with MS is associated with the severity of fatigue.     

Investigation of cytokine (tumor necrosis factor-alpha, interleukin-6, interleukin-10) concentrations in the cerebrospinal fluid of female patients with multiple sclerosis and systemic lupus erythematosus.

Humoral immune response seems to play a role in the pathogenesis of multiple sclerosis (MS) and in the central nervous system (CNS) complications of systemic lupus erythematosus (SLE). The aim of the present study was to compare the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10 in the cerebrospinal fluid of female patients with several forms of MS (50 patients), and in female patients with several types of CNS complications in SLE (50 patients). Samples were investigated using an enzyme-linked immunosorbent assay technique. Involvement of CNS in SLE patients seems to be characterized with elevated concentrations of all three cytokines in CNS and intrathecal synthesis of IL-6. In MS patients, an intrathecal synthesis of TNF-alpha (relapsing-remitting form) and IL-6 (primary progressive form) were observed. Clinical forms of MS seem to be immunologically heterogeneous. The activation of cytokine network was observed in SLE patients with CNS complications, independent of the pathological process. Similarities between SLE and MS patients with the primary progressive form of the disease were demonstrated concerning the intrathecal synthesis of IL-6. Only MS patients with the relapsing-remitting clinical form showed intrathecal TNF-alpha synthesis.     

Recent progress in the diagnosis and treatment of multiple sclerosis

Magnetic resonance imaging (MRI) now provides valuable diagnostic and prognostic information for the management of multiple sclerosis (MS) but the diagnosis still largely rests on the clinical features of central nervous system (CNS) lesions disseminated in time and place. Recent histological and MRI studies indicate that extensive axonal damage can occur in MS, even early in the disease course, and is likely to be an important cause of accumulating disability. Several immunomodulating agents have now been shown to have beneficial effects in MS. High dose intravenous or high dose oral methylprednisolone therapy accelerates recovery from attacks of relapsing-remitting MS, but at present there is no convincing evidence that standard dose (intermediate dose) oral corticosteroid therapy is beneficial for such attacks. Interferon beta, copolymer 1 (glatiramer acetate) and i.v. immunoglobulin therapy each significantly reduce the frequency of attacks of relapsing-remitting MS. Interferon beta also inhibits the progression of disability in relapsing-remitting MS and secondary progressive MS, but its effect on primary progressive MS is unknown. Oral low dose methotrexate therapy slows the progression of disability in secondary progressive MS and possibly in primary progressive MS, but it is likely that the currently used dosage (7.5 mg weekly) is suboptimal. Further research is needed to determine the optimal doses and combinations of the above therapies in MS and to develop better therapies, particularly for primary progressive MS.     

Multiple sclerosis in Pakistan

We describe retrospective data from the largest series of patients (n=142) with multiple sclerosis (MS) from Pakistan. Mean age at onset was 27 years, with a female to male ratio of 1.45:1. The disease onset was polysymptomatic in 75% patients. Motor weakness was the most common onset symptom (70%), followed by sensory symptoms (45%). Optico-spinal type of MS was seen in only 3% of patients The course was relapsing-remitting (RR) in 81%, primary progressive (PP) in 21%, and secondary progressive (SP) in 4% of patients. Almost three-fourths of the patients were moderately (45%) or severely (31%) disabled at the time of evaluation. Two-thirds of patients with severe disability had a mean disease duration of only 5.2 years. In conclusion, MS is not uncommon in Pakistan, and many patients were found to have severe disability despite short disease duration.     

Diffusion tensor magnetic resonance imaging in multiple sclerosis

OBJECTIVES: To quantify, using diffusion tensor imaging (DTI), the tissue damage in lesions and normal-appearing white matter (NAWM) from a large cohort of patients with MS and to investigate the magnitude of the correlation between DTI-derived metrics and clinical disability. METHODS: Dual-echo and DTI scans were obtained from 78 patients with relapsing-remitting, secondary progressive, or primary progressive MS and from 20 normal control participants. Post-contrast T1-weighted images were also obtained from the patients. After creating mean diffusivity (D) and fractional anisotropy (FA) images and image coregistration, D and FA values were measured for 4846 lesions (3207 nonenhancing T1-isointense, 1511 nonenhancing T1-hypointense, and 128 enhancing), 497 NAWM areas from patients, and 160 white matter areas from the controls. RESULTS: The average lesion D was higher and the average lesion FA was lower than the corresponding quantities of the NAWM (p < 0.001). The values of enhancing and nonenhancing lesions were not different, whereas enhancing lesions had lower FA (p < 0.001). T1-hypointense lesions had higher D and lower FA than T1-isointense lesions (p < 0.001). NAWM of patients had higher and lower FA than white matter of controls (p = 0.01). Significant correlations were found between T1 and T2 lesion volume and and FA of lesions and NAWM. In the overall patient sample, a moderate correlation was also found between lesion D and the Expanded Disability Status Scale score (r = 0.28, p = 0.01). However, the r value of this correlation was 0.48 in patients with secondary progressive MS, whose disability was also correlated with average lesion FA (r = -0.50). CONCLUSIONS: The results of this study show that DTI is able to identify MS lesions with severe tissue damage and to detect changes in the NAWM. They also indicate that DTI-derived measures are correlated with clinical disability, especially in patients with secondary progressive MS, thus suggesting a role for DTI in monitoring advanced phases of the disease.     

Natural history of primary progressive multiple sclerosis

The relationship of primary progressive multiple sclerosis (PPMS) to relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) remains unclear. Natural history data from a population-based cohort of patients with PPMS followed for approximately 25 years demonstrate remarkable similarities in the progressive phases of PPMS and SPMS. Immunogenetic and magnetic resonance imaging studies in large numbers of patients also fail to differentiate between the two MS categories. PPMS thus resembles SPMS without the relapses, although the two forms do differ with respect to sex ratio. An unfavourable outcome in PPMS in predicted by rapid early progression of disability and involvement of three or more systems. Natural history studies provide information on likely long-term outcomes and can be used in the design and interpretation of clinical trials in PPMS. The evidence that PPMS is distinct remains weak.     

Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis

CONTEXT: Hypointense lesions on T1-weighted spin-echo magnetic resonance images (T1 lesions) represent destructive multiple sclerosis (MS) lesions, consisting of axonal loss and matrix destruction. These lesions are being used as a secondary outcome measure in phase III clinical trials. Clinical determinants of T1 lesions may differ between subgroups of patients with MS and subsequently may have implications for the selection of patients for clinical trials. OBJECTIVE: To determine if clinical characteristics of patients with MS are related to T1 lesion volume. DESIGN: A survey of 138 patients with MS (52 with relapsing-remitting MS, 44 with secondary progressive MS, and 42 with primary progressive MS). SETTING: The Magnetic Resonance Center for Multiple Sclerosis Research, University Hospital "Vrije Universiteit," Amsterdam, the Netherlands. MAIN OUTCOME MEASURES: Type of MS, Expanded Disability Status Scale (EDSS) score, sex, age at first symptoms, and T1 lesion volume. RESULTS: Patients with secondary progressive MS have the highest T1 lesion volume. Patients with relapsing-remitting MS have a lower T1/T2 ratio than patients with secondary progressive MS and patients with primary progressive MS. In patients with relapsing-remitting MS and secondary progressive MS, T1 lesion volume relates to disease duration and EDSS score, while in patients with primary progressive MS sex is important. A trend toward higher T1 lesion volume was shown for male patients with primary progressive MS when compared with female patients with primary progressive MS (1.0 cm(3) vs 0.3 cm(3), P=.03); a trend toward higher T1 lesion volume was found with age at onset in patients with relapsing-remitting MS and in patients with primary progressive MS. CONCLUSIONS: In patients with MS different clinical characteristics associate with T1 lesion volume, suggesting a more destructive type of lesions in certain subgroups. A possible sex difference in (destructive) lesion development on magnetic resonance imaging should be evaluated in more detail, preferably in a cohort.     

Magnetisation transfer ratio histogram analysis of primary progressive and other multiple sclerosis subgroups

INTRODUCTION: Global magnetisation transfer ration (MTR) histogram analysis in the brain offers a method for evaluating pathological change both as a result of lesions and microscopic changes in normal appearing tissues. METHODS: 39 controls and 83 MS patients (46 primary progressive, 11 benign, 10 relapsing-remitting, 16 secondary progressive) were studied to explore the relationship of six conventional MTR histogram parameters with MS clinical subgroups and disability. Principal component (PC) analysis, which makes use of all the histogram data, was also used to examine the relationship between the MTR histogram and disability. RESULTS: When primary progressive patients were compared to controls, there were abnormalities of average MTR, and MTR at the 25th, 50th and 75th percentile. Disabled relapsing onset patients exhibited abnormalities in the same four parameters. Benign and nondisabled relapsing onset patients exhibited no significant abnormalities. Modest correlations were observed between disability and individual MTR parameters in relapse onset but not primary progressive patients--PC analysis revealed stronger and significant associations with disability in both subgroups. (r=0.40 for primary progressive and r=0.51 for relapsing onset). CONCLUSION: A number of MTR parameters are abnormal in primary progressive MS. MTR abnormalities are seen in disabled patients, whether of relapsing or primary progressive onset. The improved correlation with disability obtained by PC analysis suggests a useful role of this method for following clinically relevant pathological changes depicted in the MTR histogram.     

A conventional and magnetization transfer MRI study of the cervical cord in patients with MS

OBJECTIVE: To evaluate the contribution made by cervical cord damage, assessed using a fast short-tau inversion recovery (fast-STIR) sequence and magnetization transfer ratio (MTR) histogram analysis to the clinical manifestations of MS. BACKGROUND: Previous studies have failed to show significant correlations between the number and extent of T2 spinal cord lesions and the clinical status of patients with MS. Fast-STIR is more sensitive than T2-weighted imaging for detecting cervical cord MS lesions. MTR histogram analysis provides estimates of the overall disease burden in the cervical cord with higher pathologic specificity to the more destructive aspects of MS than T2-weighted scans. METHODS: We obtained fast-STIR and magnetization transfer (MT) scans from 96 patients with MS (52 with relapsing-remitting [RRMS], 33 with secondary progressive [SPMS], and 11 with primary progressive [PPMS] MS) and 21 control subjects. Dual-echo scans of the brain were also obtained and lesion load measured. Results: Eighty-one of the patients with MS had an abnormal cervical cord scan. Patients with SPMS had more cervical cord lesions and more images with visible cervical cord damage than did patients with RRMS or PPMS (p = 0.04). The entire cohort of patients with MS had lower average MTR of the cervical cord (p = 0.006) than control subjects. Compared to control subjects, patients with RRMS had similar cervical cord MTR histogram-derived measures, whereas those with PPMS had lower average MTR (p = 0.01) and peak height (p = 0.02). Patients with SPMS had lower histogram peak height than did those with RRMS (p = 0.03). The peak position and height of the cervical cord MTR histogram were independent predictors of the probability of having locomotor disability. We found no correlation between brain T2 lesion load and any of the cervical cord MTR histogram metrics. CONCLUSIONS: This study shows that the amount and severity of MS pathology in the cervical cord are greater in the progressive forms of the disease. An accurate assessment of cervical cord damage in MS gives information that can be used in part to explain the clinical manifestations of the disease.     

Interferon-beta1b in multiple sclerosis: effect on progression of disability and clinical markers of treatment response

There is limited long-term data on the effect of interferon-beta1b (IFN-beta1b) on disability progression in patients with multiple sclerosis (MS). There is also no reliable way of predicting individual responses to IFN-beta1b treatment. This prospective study investigated early clinical prognostic markers of disease activity and progression in 115 patients with relapsing-remitting MS (RRMS) treated with IFN-beta1b for almost 5 years. The study also compared progression of disability in IFN-beta1b-treated patients with a historic untreated cohort of MS patients (n = 44). The number of relapses in the first 2 years of MS and in the 2 years before treatment predicted an early relapse after IFN-beta1b treatment. The IFN-beta1b-treated group experienced a slower progression of disability than the untreated cohort, suggesting that IFN-beta1b treatment delays progression of disability in RRMS.     

Opticospinal multiple sclerosis in Iran

Clinical course, magnetic resonance imaging (MRI) findings and cerebrospinal fluid data (CSF) on 20 patients among 520 with clinically definite multiple sclerosis (MS) according to the criteria of Poser et al., with opticospinal clinical presentation above 5 years and mean disease duration of 8+/-4.4 years were reviewed. The prevalence rate was 3.8%. The clinical course was relapsing-remitting (RR) for all patients. The mean age of onset was 24+/-8.2 years. The gender ratio was 2.3:1 female:male. First clinical presentation was spinal signs in 12 (60%), optic neuritis in 7 (35%) and simultaneous involvement of both eyes in 1 (5%) patient. No transverse myelitis (TM), sustained severe optic neuritis (SSON) or minor brain stem signs were recorded. No conversion to conventional MS (CMS) or secondary progressive MS (SPMS) was identified during the study period and no case had positive family history for the disease. The yearly number of attacks was 0.66+/-0.84, with mean Kurtzke expanded disability status scale (EDSS) of 2.5+/-1.2. All patients had 1 to 5 hemispheral T2 lesions in brain MRI, non-fulfilled Barkhof criteria for brain lesions. All had preventricular and 14 (70%) had juxtacortical lesions. None had gadolinium T1 enhanced lesions. No involvement of the brainstem or cerebellar structures was detected. Fifteen had 1 cervical lesion, five had 2 and four had 1 concomitant thoracic cord signal, all extending below three vertebral segments in sagittal planes with peripheral white matter location on the axial planes. Spinal fluid contained normal cell and protein with negative oligoclonal bands (OB).     

Multiple sclerosis: disability and mortality in a cohort of clinically diagnosed patients

A sample of hospitalized MS patients was selected according to clinical and demographic criteria with the aim of establishing prognostic factors. The sample included 52 patients with first hospitalization from 1 January, 1975, to 31 December, 1976. At follow-up after 12 years a malignant course was observed in 33 patients (death in 13, severe disability in 20 patients). The malignant course was related to age at onset (greater than or equal to 35 years) and higher disability, progressive course and cerebellar symptoms at onset. One half of patients with a relapsing-remitting course entered into a progressive phase of the disease after a mean duration of 7.3 years.