Secondary progressive multiple sclerosis: A national consensus paper on diagnostic criteria.

BACKGROUND: In clinical practice, the diagnosis of secondary progressive multiple sclerosis (SPMS) is often delayed, retrospective and non-reproducible, as there are no consensus criteria that define the advent of SPMS. Early identification of SPMS is essential to improve patient care. METHODS: Eight regional board meetings in France involving 56 multiple sclerosis (MS) experts (neurologists) were convened to discuss diagnostic criteria for SPMS. Subsequently, a national board meeting of 13 neurologists (with an expert representing each geographical region) was held to review points of convergence or divergence between regions and to develop a national consensus document. RESULTS: Based on the discussions from the regional boards, the MS experts at the national board retained the worsening of the EDSS score, with compatible clinical features, as the only consensus criterion for the diagnosis of SPMS in clinical practice. The patient should have experienced during at least the previous 6 months and in the absence of any relapse, a worsening in the EDSS score of +1.0 point (if the previous EDSS was≤5.0) or of +0.5 point (if the previous EDSS was≥5.5), with a pyramidal or cerebellar functional system score≥2 and without setting a minimum EDSS score; or, in case of a stable EDSS score≥4.0, a worsening of a functional score. This worsening should be confirmed within 3 to 6 months. According to the MS experts, the patient's age, duration of illness and a minimal threshold EDSS score are only risk factors for transition to SPMS. Patient reports during consultation and cognitive impairment are important warning signs, which should trigger an objective assessment with specific tests or closer monitoring. Clinical relapse and/or MRI activities are non-discriminatory for making the diagnosis of SPMS. CONCLUSIONS: The experts defined precise diagnostic criteria adapted to clinical practice for earlier identification of SPMS, paving the way for better management of this stage of the disease.

Clinical follow-up of 411 patients with relapsing and progressive multiple sclerosis 10 years after discontinuing mitoxantrone treatment: a real-life cohort study.

BACKGROUND AND PURPOSE: Mitoxantrone (MITOX) has been used to treat patients with aggressive multiple sclerosis (MS) for decades. We aimed to describe the effectiveness and adverse events over 10 years post-MITOX in patients with relapsing and progressive MS from an exhaustive real-life database. METHODS: Data from patients who received MITOX before 1 January 2006 were collected from the MS Lorraine registry. Expanded Disability Status Scale (EDSS) scores and annual relapse rates (ARRs) year by year during follow-up and the year prior to MITOX were compared. Time to the first relapse and a 1-point increase in EDSS score were used in Cox multivariate models to find associations with potential predictive factors. RESULTS: A total of 411 patients were included. The ARR for the 155 relapsing patients had decreased from 2.0 (SD 1.20) the year before treatment to 0.3 (SD 0.31) by year 10 (P < 0.0001). The EDSS score increased from 2.8 (SD 1.44) to 4.8 (SD 1.90) by year 10 (P < 0.0001). A high ARR at MITOX initiation was associated with a longer time to a 1-point increase in EDSS score (hazard ratio, 0.81; 95% confidence interval, 0.67-0.99; P = 0.04). The EDSS score in 256 progressive patients increased from 5.0 (SD 1.33) to 6.5 (SD 1.26) by year 10 (P < 0.0001). We identified four cases of acute myeloid leukemias. CONCLUSIONS: Patients with the most active forms of MS are the most likely to benefit from MITOX in the long term.

Classification and diagnostic criteria for demyelinating diseases of the central nervous system: Where do we stand today?

The diagnosis of multiple sclerosis (MS) and other demyelinating diseases of the central nervous system is challenging, and although the currently available biological and imaging tools offer considerable support to physicians, these tools often fail to provide a simple and final answer at the time of a first event. Thus, sets of diagnostic criteria have been published and tested on patient cohorts, and are now used in clinical trials and in daily clinical practice. These criteria have evolved over time to take into account physicians' and patients' needs, along with emerging paraclinical tests. The different presentations of MS have given rise to the use of a common classification system to identify patient profiles and adapt care protocols accordingly. This article reviews the various classifications of the forms and diagnostic criteria of MS and related syndromes, including neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSDs), acute disseminated (demyelinating) encephalomyelitis (ADEM) and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Also discussed is their validity in the light of the currently available literature.

[Reconsidering fatigue at the onset of multiple sclerosis]. / Reconsidérer l'apparition du handicap dès le début de la SEP : la fatigue.

Fatigue is a frequent symptom of multiple sclerosis (MS). It has been reported to varying degrees at all stages of the disease by 50 to 90% of all MS patients. Fatigue is now recognised as a disabling symptom which negatively impacts daily living. This symptom was underrated until recently but has now been included in clinical practice. Most fatigue scales have been developed in the English language and are culturally specific to their country of origin. The Fatigue Severity Scale is a one-dimensional nine-item scale which briefly assesses the impact of fatigue on the daily lives of MS patients. It has been widely used in different studies, even though it appears to be less relevant than the multi-dimensional 40-item Fatigue Impact Scale which was developed in Canada by Fisk et al (1994). The Fatigue Impact Scale is useful because it assesses different aspects of MS-related fatigue, such as the effects of fatigue on cognitive and physical activities and can include daily living. The Multiple Sclerosis Council for Clinical Practice Guidelines recommends the use of a 21-item Modified Fatigue Impact Scale which is a shortened version of the 40-item Fatigue Impact Scale. Using word-for-word translations of these scales into French would fail because the results would not be interpretable. We first translated and culturally adapted the Fatigue Impact Scale to French-speaking patients. We then evaluated the psychometric properties of this French version (EMIF-SEP). We used the EMIF-SEP scale to study fatigue in French MS patients. We found a significant correlation between higher EMIF-SEP total scores and higher EDSS scores; likewise physical dimension of the EMIF-SEP were linked to disability. But no correlations were found between the cognitive aspects of fatigue and disability. Other studies have failed to show any correlation between fatigue and disability. We suggest that this may be due to differences in sample size, or to the type of instrument used to quantify fatigue. As seen above, some tools do not allow for multi-dimensional assessment of fatigue. The EMIF-SEP scale is useful in that it allows for qualitative and quantitative assessment of fatigue.

Natural history of multiple sclerosis in a population-based cohort.

BACKGROUND AND PURPOSE: We sought to identify predictive clinical factors of disability during initial course in multiple sclerosis (MS) patients. METHODS: A total of 2871 MS patients from the LORSEP (Lorraine Multiple Sclerosis) population-based cohort were analyzed. The relationships between baseline demographic, clinical predictors and time to assignment of Expanded Disability Status Scale (EDSS) scores of 3, 4 and 6 were assessed using a Cox regression model. RESULTS: Multivariate analysis showed that, for relapsing-remitting patients, a shorter time to assignment of an EDSS score of 4 was associated with an older age of onset of MS and incomplete recovery from the first relapse. Median times were not influenced by gender or the time between the first two relapses. The results also demonstrated that MS progression is independent of the initial clinical data once an EDSS score of 4 is reached rather than a score of 3 because the time from EDSS 3 to assignment of EDSS 4 were correlated with predicting variables. The data were very different for the time between assignment of scores of 4 and 6 because the median times were not influenced by any of the predicting variables.

Multiple sclerosis with a progressive course from onset in Lorraine-Eastern France.

To investigate the patient characteristics, disease progression, and associated risk factors in patients with multiple sclerosis (MS) with a progressive onset, we conducted a longitudinal population-based study of 359 patients (252 with primary progressive MS (PPMS) and 107 with progressive relapsing MS (PRMS)) in Lorraine, France. As outcome measures, we assessed the time from MS onset to reaching disability status scale (DSS) scores of 4, 6 and 7 and the time from assignment of DSS score of 6 to assignment of DSS score of 7. We studied the influence on these outcomes of sex, age of onset and symptoms of onset. We also studied the influence of the time from MS onset to assignment of DSS 6 on the time from MS onset to assignment of DSS 7. There were no significant differences in the demographic data (gender and age at onset of MS) and clinical data (median time to DSS scores of 4, 6 and 7) between the patients with PPMS and PRMS suggesting such a distinction may be unnecessary. The male/female ratio in all 359 patients with MS with a progressive onset was 1/1.36. The median age at onset was 42.7 years (25% Q1 = 34.7; 75% Q3 = 50.0), was lower for male (40.5 years) than for female patients (44.2 years; p = 0.002). The median time to DSS scores of 4, 6 and 7 were (in years) 3.0 (95% CI = 2.8 to 3.7), 9.9 (95% CI = 9.0 to 10.6), and 17.0 (95% CI = 14.9 to 19.0). A cane was required in 25% of patients 5 years after onset and in 75% 15 years after onset. We did not find any significant unfluence of sex, age at onset, or symptoms at onset on the time from MS onset to assignment of scores 6 or 7 or on the time from the assignment of a score of 6 to the assignment of a score of 7.

Fatigue in multiple sclerosis is related to disability, depression and quality of life.

Fatigue in multiple sclerosis is a frequent and disabling symptom that can interfere in daily functioning. The aim of this study is to demonstrate the relationship between fatigue and disability, disease course, depression and quality of life. We administered French valid versions of the Fatigue Impact Scale (EMIF-SEP), the short form of the Beck depression inventory (13 items) and the SF-36 to 237 out of 312 patients with clinically definite multiple sclerosis with EDSS

Isolated tumefactive demyelinating lesions: diagnosis and long-term evolution of 16 patients in a multicentric study.

Isolated tumefactive demyelinating lesion (TDL) is a rare disease and a challenging entity especially for the differential diagnosis, biopsy indications, and therapeutic decisions. Long-term evolution is not well known. The objective of the study is to describe clinical and MRI characteristics and long-term follow-up of patients with isolated TDL. We performed a retrospective study including patients (1) with one TDL radiologically defined by a ≥20 mm FLAIR hyperintensity involving the white matter associated with T1 hypointensity that enhanced after gadolinium injection and (2) without any other MS lesion on the first MRI. Tumor, abscess, or other inflammatory diseases (ADEM, Baló's concentric sclerosis, systemic disease) were excluded. Sixteen patients (11 females/5 males) were included. The mean age of onset was 35.7 years (range 20-65). MRI disclosed supratentorial lesions with a mean size of 39.4 mm and usually mild edema/mass effect. Peripheral (mainly open-ring pattern) and central (mainly heterogeneous) enhancement were respectively seen in 9/16 and 11/16 patients. CSF study (n = 15) found oligoclonal bands (OCB) in seven. A cerebral biopsy was performed in 11 cases showing acute inflammatory demyelination. Thirteen patients were treated by pulse steroids with marked improvement in ten. At last clinical follow-up (mean 65.8 months, range 6-181), diagnosis was MS in 5 (31 %), isolated TDL in 10 (63 %) and one patient had a second TDL (6 %). Isolated tumefactive demyelinating lesions are a rare diagnostic entity. After a mean follow-up of 5 years, almost one-third became MS whereas most of the patients had no further event.

Impact of disease-modifying treatments in North African migrants with multiple sclerosis in France.

BACKGROUND: Multiple Sclerosis in North African migrants (MS-NA) is more aggressive with mostly primary progressive forms and cerebellar symptoms. Despite an earlier onset in NA patients, the disease progresses more rapidly, with a higher proportion showing incomplete recovery from the first relapse, a shorter time between the first two relapses, a higher number of relapses in the first 5 years, and a shorter time to reach an EDSS of 4.0 and 6.0. We collected data and studied the impact of disease-modifying therapies (DMT) in NA patients with MS, among the 4144 MS patients treated in our MS clinics. METHODS: We performed a descriptive population-based study of MS-NA patients. Data were crossed with expected age- and gender-matched characteristics available in our EDMUS databases for the period 1995-2007. RESULTS: A total of 133 patients, representing 66% of the MS-NA patients included in the database were identified: mean age at the first documented symptom: 29.7 years; mean time from diagnosis to the beginning of DMT: 1.2 years. 40% of MS-NA patients had an EDSS >3 at the beginning of treatment (vs. 25%; P=0.002). A majority of patients were treated initially with immunomodulatory drugs (MS-NA: 48% vs. CT: 51%, P=0.8). NA patients were treated earlier after diagnosis (1.3 years vs. 4.5 years, P=0.003), with the frequent use of immunosuppressive drugs: for remitting forms, mitoxantrone (18.5% vs. 7.8%, P=0.0001) and for progressive forms, cyclophosphamide (38% vs. 28%, P=0.003). CONCLUSIONS: Considering EDSS follow-up during DMT, MS-NA patients appear as responsive as other MS patients to treatment, despite the earlier treatment prescription and the more frequent use of immunosuppressors.

Validity of a French version of the fatigue impact scale in multiple sclerosis.

PURPOSE: Fatigue is a frequent and common symptom of multiple sclerosis (MS) that can interfere with patients' everyday activities. There is no objective scale for assessing fatigue in French MS patients. The objective of this study was to adapt an English language scale for use with French patients. METHODS: The Fatigue Impact Scale was translated and culturally adapted into French by a committee of medical and linguistic specialists. The psychometric properties of this new instrument, called EMIF-SEP were assessed. RESULTS: EMIF-SEP is composed of 40 items. Four dimensions of this scale (cognitive, physical, social role and psychological) were identified by factor analysis. Each dimension had a high internal consistency (Cronbach's alpha >0.80). The test-retest reproducibility was very satisfactory; intra-class correlation coefficients were all above 0.70. CONCLUSION: EMIF-SEP is the first scale for assessing MS-related fatigue which has been adapted to French-speaking patients. It is useful for clinical practice and MS-related research.

Clinical follow-up of 304 patients with multiple sclerosis three years after mitoxantrone treatment.

The objectives of this study were to assess the benefits of 1) mitoxantrone after three years of follow-up and 2) disease-modifying treatment (DMT) after stopping mitoxantrone. A retrospective analysis was performed on 304 patients with active relapsing-remitting (RR) or progressive multiple sclerosis (PMS) who were treated with mitoxantrone. After mitoxantrone therapy, some patients received DMT (interferon-beta or glatiramer acetate) while others did not. The disease course of the two groups was evaluated by the Expanded Disability Status Scale (EDSS) before and after mitoxantrone and then every year for three years. The mean EDSS score at starting mitoxantrone and three years after stopping mitoxantrone respectively, were: 3.3 (1.3) and 3.2 (1.7) for the RRMS patients and 5.9 (1.2) and 6.4 (1.4) for the PMS patients. Before starting mitoxantrone, demographic and clinical parameters of predictive disability were not significantly different between patients who received DMT or not. The variation of EDSS between time of stopping mitoxantrone and three years later was significantly different (+0.9 versus +0.3; P=0.03) for patients with RRMS. We found that mitoxantrone treatment induces stable disease up to two years after discontinuation of mitoxantrone therapy. In the third year, patients without DMT deteriorated.

Increasing incidence of multiple sclerosis among women in Lorraine, Eastern France.

This study aims to describe the prevalence and incidence rates of multiple sclerosis (MS) in Lorraine, France, and its secular trend from 1990 to 2002. Cases were sourced from the regional network of MS healthcare workers in the Lorraine region and include all cases with definite or probable MS according to Poser's criteria. We identified 2718 patients with MS on 31 December 2004. The prevalence rate was 120/100,000 (95% confidence interval [CI]: 119-121). Between 1990 and 2002, the average age- and sex-adjusted annual incidence rate was 5.5/100,000 (95% CI: 4.4-6.6). During this same period, there was a significant increase in overall incidence in women but not in men. The mean age at MS onset, disability score five years after onset, number of relapses during the first five years, and proportion of first attack with sequelae or polysymptomatic symptoms were not significantly different between each annual cohort during the study period. The prevalence and incidence rates of MS we found in our study were higher than in previous studies in France. The increase in incidence of MS between 1990 and 2002, mostly in women, was not related to better ascertainment of patients with mild disability.

More severe disability of North Africans vs Europeans with multiple sclerosis in France.

OBJECTIVE: To compare the clinical disease progression in European (E) and North African (NA) patients with multiple sclerosis (MS) patients in France. METHODS: We compared the clinical features of MS in 211 NA patients and 2,945 E patients in a French population-based cohort with definite MS according to McDonald's criteria. RESULTS: Among the NA patients with MS, 66.4% were women vs 72.9% of the E patients (p = 0.04), 15.6% had a primary progressive form of MS vs 11.7% of the E patients (p = 0.08), and the mean age at onset was 29.9 +/- 9.8 years in the NA patients vs 32.9 +/- 10.6 years in the E patients (p < 0.0001). In the NA patients, there was a higher proportion of patients with incomplete recovery from the first relapse (p < 0.0001), a shorter time between the first two relapses (p = 0.02), a higher number of relapses in the first 5 years (p = 0.03), and a shorter time to reach an Expanded Disability Status Scale score of 4.0 (p = 0.001) or 6.0 (p < 0.0001). The only statistical difference in these factors between NA patients born in France and those born in North Africa was the mean age at onset of symptoms: it was earlier in NA patients born in France (p < 0.0001). CONCLUSIONS: The course of multiple sclerosis is more aggressive in North African than in European patients.

Predictive parameters of mitoxantrone effectiveness in the treatment of multiple sclerosis.

INTRODUCTION: In a number of controlled trials it was established that mitoxantrone has a beneficial effect on disease progression in multiple sclerosis (MS) patients with a worsening disease course. The aim of this study was to investigate the use of mitoxantrone in clinical practice, and especially to describe predictive parameters of its effectiveness under these conditions. OBJECTIVES AND METHODS: In a retrospective, open-label mitoxantrone study we analysed 94 MS patients (49% relapsing remitting MS (RRMS), 41% secondary progressive MS and 10% primary progressive MS) who received monthly 20 mg i.v. mitoxantrone and 1 g i.v. methylprednisolone for six months, and selected as a criterion of effectiveness the percentage of patients with an Expanded Disability Status Scale (EDSS) improvement of at least one point (confirmed after one year) after stopping the treatment. A multivariate analysis was undertaken to assess the predictive value of five parameters on mitoxantrone effectiveness: (1) total number of relapses since disease onset and before treatment, (2) number of relapses within the past 24 months before treatment, (3) number of relapses in separate areas within the past 24 months before treatment, (4) active MRI scans (including Gd-enhanced lesions), and (5) clinical course of MS. RESULTS: During the observation period from 1 January 1997 to 30 May 2000 more than 44% of the patients improved by one point or more on the EDSS (confirmed after one year), 39% remained stable and 17% deteriorated. In patients with a RRMS course three or more relapses within the past 24 months preceding treatment, and at least one Gd-enhancing lesion resulted in a strong relative benefit (i.e., relative risk) of mitoxantrone effectiveness. In contrast, total number of relapses since disease onset had no impact on disease evolution and disability progression. Multivariate analysis revealed the number of relapses in separate areas within the past 24 months before treatment as the strongest predictive parameter (P < 0.001). CONCLUSION: Mitoxantrone is effective in improving and stabilizing patients with a worsening MS course in routine clinical practice. Several strong predictive parameters of mitoxantrone effectiveness were investigated among which the number of relapses in separate areas within the past 24 months before treatment was found to be the strongest parameter to predict clinical improvement.