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Objective: To establish cytometry profiles associated with disease stages and immunotherapy in MS., Methods: Demographic/clinical data and peripheral blood samples were collected from 227 patients with MS and 82 sex- and age-matched healthy controls (HCs) enrolled in a cross-sectional study at 4 European MS centers (Spain, Italy, Germany, and Norway). Flow cytometry of isolated peripheral blood mononuclear cells was performed in each center using specifically prepared antibody-cocktail Lyotubes; data analysis was centralized at the Genoa center. Differences in immune cell subsets were assessed between groups of untreated patients with relapsing-remitting or progressive MS (RRMS or PMS) and HCs and between groups of patients with RRMS taking 6 commonly used disease-modifying drugs., Results: In untreated patients with MS, significantly higher frequencies of Th17 cells in the RRMS population compared with HC and lower frequencies of B-memory/B-regulatory cells as well as higher percentages of B-mature cells in patients with PMS compared with HCs emerged. Overall, the greatest deviation in immunophenotype in MS was observed by treatment rather than disease course, with the strongest impact found in fingolimod-treated patients. Fingolimod induced a decrease in total CD4 + T cells and in B-mature and B-memory cells and increases in CD4 + and CD8 + T-regulatory and B-regulatory cells., Conclusions: Our highly standardized, multisite cytomics data provide further understanding of treatment impact on MS immunophenotype and could pave the way toward monitoring immune cells to help clinical management of MS individuals., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: Determining the clinical course of multiple sclerosis (MS) and prediction of long-term disability can be a big challenge. To determine early clinical features of MS, their influence on long-term disability progression, and time to transition from relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS), a cohort of Polish patients was studied. Materials and Methods: We retrospectively evaluated 375 Polish MS patients based on data from available medical records. We assessed early clinical MS features and the relationship between demographics and time from disease onset to attainment of 4 and 6 points on the Expanded Disability Status Scale (EDSS), as well as time to conversion from RRMS to SPMS. Results: The differences between initial MS variants were significantly associated with gender, age at disease onset, number and type of the first symptoms, and rate of the disability accrual. Mean times from disease onset to attainment of EDSS 4 and 6 were significantly influenced by the disease variant, age at onset, gender, degree of recovery from the initial symptoms, and first inter-bouts interval. The mean time to secondary progression was significantly influenced by the number and type of the first symptoms of RRMS. Conclusions: Early clinical features of MS are important in determining the disease variant, the time to transition from RRMS to SPMS, as well as predicting the disability accumulation of patients. Despite the small differences regarding the first MS symptoms, the disability outcomes in the cohort of Polish patients are similar to other regions of the world.

Multiple sclerosis is a major cause of neurological disability, which accrues predominantly during progressive forms of the disease. Although development of multifocal inflammatory lesions is the underlying pathological process in relapsing-remitting multiple sclerosis, the gradual accumulation of disability that characterises progressive multiple sclerosis seems to result more from diffuse immune mechanisms and neurodegeneration. As a result, the 14 anti-inflammatory drugs that have regulatory approval for treatment of relapsing-remitting multiple sclerosis have little or no efficacy in progressive multiple sclerosis without inflammatory lesion activity. Effective therapies for progressive multiple sclerosis that prevent worsening, reverse damage, and restore function are a major unmet need. In this Series paper we summarise the current status of therapy for progressive multiple sclerosis and outline prospects for the future., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Multiple sclerosis (MS) is a CNS disorder characterized by inflammation, demyelination and neurodegeneration, and is the most common cause of acquired nontraumatic neurological disability in young adults. The course of the disease varies between individuals: some patients accumulate minimal disability over their lives, whereas others experience a rapidly disabling disease course. This latter subset of patients, whose MS is marked by the rampant progression of disability over a short time period, is often referred to as having 'aggressive' MS. Treatment of patients with aggressive MS is challenging, and optimal strategies have yet to be defined. It is important to identify patients who are at risk of aggressive MS as early as possible and implement an effective treatment strategy. Early intervention might protect patients from irreversible damage and disability, and prevent the development of a secondary progressive course, which thus far lacks effective therapy.

Multiple sclerosis (MS), is a chronic disease of the central nervous system (CNS) characterized by loss of motor and sensory function, that results from immune-mediated inflammation, demyelination and subsequent axonal damage. MS is one of the most common causes of neurological disability in young adults. Several variants of MS (and CNS demyelinating syndromes in general) have been nowadays defined in an effort to increase the diagnostic accuracy, to identify the unique immunopathogenic profile and to tailor treatment in each individual patient. These include the initial events of demyelination defined as clinically or radiologically isolated syndromes (CIS and RIS respectively), acute disseminated encephalomyelitis (ADEM) and its variants (acute hemorrhagic leukoencephalitis-AHL, Marburg variant, and Balo's concentric sclerosis), Schilder's sclerosis, transverse myelitis, neuromyelitis optica (NMO and NMO spectrum of diseases), recurrent isolated optic neuritis and tumefactive demyelination. The differentiation between them is not only a terminological matter but has important implications on their management. For instance, certain patients with MS and prominent immunopathogenetic involvement of B cells and autoantibodies, or with the neuromyelitic variants of demyelination, may not only not respond well but even deteriorate under some of the first-line treatments for MS. The unique clinical and neuroradiological features, along with the immunological biomarkers help to distinguish these cases from classical MS. The use of such immunological and imaging biomarkers, will not only improve the accuracy of diagnosis but also contribute to the identification of the patients with CIS or RIS who, are at greater risk for disability progression (worse prognosis) or, on the contrary, will have a more benign course. This review summarizes in a critical way, the diagnostic criteria (historical and updated) and the definitions/characteristics of MS of the various variants/subtypes of CNS demyelinating syndromes., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To study the relationships between 1-2 year changes in well-known physician-rated measurements (Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT)) and the long-term (≥ 5 years) outcome in patient-reported outcome (PRO) measures (Multiple Sclerosis Impact Scale (MSIS-29), Multiple Sclerosis Walking Scale (MSWS-12)) that reflect the patient-perceived impact of disease, in progressive MS., Methods: We selected all progressive patients having at least two complete visits within 1-2 years, from a larger cohort of prospectively-followed MS patients. These were invited for another visit, at least 5 years later, consisting of another series of similar examinations, plus 2 PRO scales: the MSIS-29 and MSWS-12. We explored associations between early changes in physician-rated measurements and the long-term outcome as per the PRO measures., Results: In this study,134 patients fulfilled the selection criteria. We found that early change in T25FW was the only physician-rated change that was significantly related to long-term physical impact experienced by the patient, as was assessed by MSIS-29 (Kruskal-Wallis test: χ(2)=7.8, p=0.020). Early T25FW change, and to a lesser degree early 9HPT change, were significantly related to the reported long-term walking limitations, as assessed by MSWS-12 (Kruskal-Wallis test: χ(2)=13.8 and p=0.001 for T25FW, χ(2)=6.5 and p=0.038 for 9HPT). None of the early physician-rated changes were related to the long-term psychological impact experienced by the patient., Conclusion: Early changes on physician-rated scales do have long-term impact in terms of potentially predictive value of outcomes for groups of patients in progressive MS, regarding walking limitations and more global physical impact. Surprisingly, early change in T25FW, rather than early change in EDSS, was significantly associated with longer-term patient-reported disease impact. Our study data support the value of using early physician-rated examinations in clinical trials in progressive MS.

Background: Benign multiple sclerosis (BMS) is typically defined using the Expanded Disability Status Scale (EDSS), which relies heavily on ambulation. We set out to examine important psychosocial and cognitive outcomes in patients with longstanding BMS compared with patients who had recently progressed to 'no longer benign' (NLB)., Methods: A previously reported cohort of BMS (EDSS ≤3 at 20 years disease duration) were re-assessed 25-30 years post-onset. Patients remaining benign (EDSS ≤3 at re-assessment) were compared with those NLB for: depression (Beck Depression Inventory), fatigue (Modified Fatigue Impact Scale), health-related quality of life (MSQoL-54), cognition (Rao's Neuropsychological Screening Battery), and employment status., Results: A total of 75% (66/88) of the original cohort were located. A total of 61 patients were re-assessed. Twenty-five patients (41%) had progressed in EDSS and were NLB. Compared with benign patients, those NLB were more likely to have: significant fatigue (15/36 [42%] vs. 18/25 [72%], p = 0.019); poorer physical functioning (mean MSQoL-54 = 67.30 vs. 50.89, p = 0.002); an MS-related negative change in employment status (13/36 [36%] vs. 21/25 [84%], p < 0.0001) and cognitive impairment (3/28 [11%] vs. 5/19 [26%]; trend only, p = 0.317). Depression and mental health quality if life differed little between the benign and NLB patients (p > 0.6)., Conclusions: Despite remaining benign for 20 years, a significant proportion of patients progressed with further follow up. While neither depression nor patient-reported mental health quality of life was associated with EDSS progression, patients with longstanding 'benign' MS (EDSS ≤3 for 25+ years) had less fatigue, better physical quality of life and employment outcomes and infrequent cognitive impairment. Remaining benign over the long term, as defined by the EDSS, carried some advantages beyond ambulation.

Background and Purpose: Recent postmortem studies in MS brain suggest that the severity of changes in DAWM can be measured by using quantitative MR imaging. This study aimed to characterize DAWM in vivo by using 4 quantitative MR imaging measures and to explore differences between MS disease types., Materials and Methods: In 17 patients with chronic MS (7 PP, 10 SP), quantitative MR imaging was performed at 1.5T, yielding whole-brain voxelwise maps of T1, MTR, ADC, and FA. ROIs were placed to obtain values for DAWM, NAWM, and WM lesions. A general linear mixed-model analysis was used to compare T1, MTR, ADC, and FA between tissue types and disease types., Results: Values of T1, MTR, ADC, and FA for DAWM were intermediate to those observed in NAWM and WM lesions. In patients with SPMS, DAWM was significantly different from both WM lesions and NAWM regarding all 4 measures, while in patients with PPMS, DAWM differed significantly from NAWM regarding T1, MTR, and FA and from lesions only regarding FA. Most interesting, DAWM differed between disease types: DAWM in patients with SPMS exhibited significantly higher T1 and lower MTR than did DAWM in patients with PPMS., Conclusions: In vivo T1, MTR, ADC, and FA reflect the variable severity of pathologic changes in DAWM in MS. Moreover, these quantitative MR imaging measures suggest that DAWM may differ between PPMS and SPMS.

Background: Gray matter lesions are known to be common in multiple sclerosis (MS) and are suspected to play an important role in disease progression and clinical disability. A combination of magnetic resonance imaging (MRI) techniques, double-inversion recovery (DIR), and phase-sensitive inversion recovery (PSIR), has been used for detection and classification of cortical lesions. This study shows that high-resolution three-dimensional (3D) magnetization-prepared rapid acquisition with gradient echo (MPRAGE) improves the classification of cortical lesions by allowing more accurate anatomic localization of lesion morphology., Methods: 11 patients with MS with previously identified cortical lesions were scanned using DIR, PSIR, and 3D MPRAGE. Lesions were identified on DIR and PSIR and classified as purely intracortical or mixed. MPRAGE images were then examined, and lesions were re-classified based on the new information., Results: The high signal-to-noise ratio, fine anatomic detail, and clear gray-white matter tissue contrast seen in the MPRAGE images provided superior delineation of lesion borders and surrounding gray-white matter junction, improving classification accuracy. 119 lesions were identified as either intracortical or mixed on DIR/PSIR. In 89 cases, MPRAGE confirmed the classification by DIR/PSIR. In 30 cases, MPRAGE overturned the original classification., Conclusion: Improved classification of cortical lesions was realized by inclusion of high-spatial resolution 3D MPRAGE. This sequence provides unique detail on lesion morphology that is necessary for accurate classification.

We studied the clinical and evolution characteristics of multiple sclerosis (MS) patients followed since the onset of HUCFF/UFRJ in 1978. The diagnosis of MS was based on Poser's et al. and MC Donald's et al. criteria. From 188 patients, 122 were included. Eighty-five were females. The mean age onset was 32.2 years-old (range 6.0 to 61.0+/-10.3), mainly Caucasians (82/67%). The relapsing-remitting course (MSRR) was more frequent (106/86.8%). Monosymptomatic onset was significantly more frequent in Caucasians than in Afro-Brazilians (p<0.05). Seventeen patients had benign form of MS and these patients presented association with MSRR when compared with severe form (p=0.01). The mortality rate was 2.12% (4 patients died). This study was similar to other Brazilian series with regard to sex and age, and lack of correlation between EDSS and number of relapses; it confirmed south-southeast African-descendants gradient distribution and association between first mono-symptomatic relapses and Caucasian; we found lower frequency of benign forms.

Unlabelled: Three different diagnostic criteria for primary progressive MS were recently proposed for Caucasian population of Western European region., Objective: The objective of the study was to apply these criteria to a series of Brazilian patients with high ethnic diversity background to evaluate reproducibility and reliability., Methods: 52 patients classified as form of the disease that is progressive from onset and followed between 2000 and 2006 were included. Thompson, McDonald and Polman criteria were applied based in clinical date and complementary exams., Results: 72% fulfilled all three criteria with moderate agreement (p<0.001). Ten patients fulfilled at least one criterion and four failed to fulfill any of the three criteria. Strong agreement was found between Thompson and McDonald criteria (p<0.001), agreement was moderate between Thompson and Polman criteria (p<0.001) and weak agreement occurred between McDonald and Polman criteria (p=0.042)., Conclusion: The main difference between these criteria is the change in the role of CSF, previously a prerequisite for diagnosis. Rigid diagnostic criteria as Thompson have higher specificity, should be used in clinical research protocols, while more flexible criteria as Polman facilitate the diagnosis of PPMS in neurological practice, particularly in initial stages of the disease, because of their potentially higher sensitivity.

We assessed the different sets of diagnostic criteria for primary progressive multiple sclerosis (PPMS), in order to determine their sensitivity when applied to a cohort of 261 PPMS patients. According to the Thompson criteria, 168 patients (64.4%) had definite PPMS, 84 patients (32.2%) had probable PPMS, and nine patients (3.4%) had possible PPMS; according to the McDonald criteria, 180 patients (69%) had PPMS; according to the revised McDonald criteria, 194 patients (74.3%) had PPMS. Our findings indicate that the revised McDonald criteria are more sensitive than the original McDonald criteria, but less sensitive than the Thompson criteria.

In 2001, an international panel suggested new diagnostic criteria for multiple sclerosis (MS). These criteria integrate clinical, imaging (MRI), and paraclinical results in order to facilitate diagnosis. Since then, these so-called McDonald criteria have been broadly accepted and widely propagated. In the meantime a number of publications have dealt with the sensitivity and specificity for MS diagnosis and with implementing these new criteria in clinical practice. Based on these empirical values and newer data on MS, an international expert group recently proposed a revision of the criteria. Substantial changes affect (1) MRI criteria for the dissemination of lesions over time, (2) the role of spinal cord lesions in the MRI and (3) diagnosis of primary progressive MS. In this article we present recent experiences with the McDonald and revised criteria.

There are no generally effective disease-modifying drugs for progressive forms of multiple sclerosis (MS). Some MS centres use cyclophosphamide (CYC) in secondary progressive (SP) forms of MS, especially after interferon beta-1b (INFbeta-1b) treatment failure. Moreover, there are currently no approved drugs for primary progressive (PP) MS. Using the collected data of patients with progressive MS, we studied clinical patterns that predicted a good response to CYC treatment. Secondly, we compared the therapeutic response of SPMS and PPMS patients to the treatment. Data from 490 MS patients were collected. All patients presented an SP (n = 362) or PP (n = 128) form of the disease and 476 had been treated for at least one year with a monthly pulse of CYC associated with methylprednisolone (MP). CYC treatment was justified because of at least a 1-point worsening on the Expanded Disability Status Scale (EDSS) during the previous year. The EDSS score was assessed at baseline and after 6 months (M6) and 12 months (M12) of treatment. After 12 months of CYC treatment, 78.6% of SPMS and 73.5% of PPMS patients had stabilised or had an improved EDSS score. Response to CYC was not significantly different in the two progressive forms of MS. Twenty-two patients presented noticeable drug side effects, one of whom withdrew from the treatment due to intolerance. Patients with an improved EDSS at M12 had a shorter mean progressive time course (5.1 years) than patients who stabilised or worsened (7.1 years) (p = 0.02). We also observed that poor responders at M6 were also poor responders at M12 (p < 0.001). This large cohort study showed that CYC treatment was well tolerated and suggested that a better response occurred in cases with a short progressive time course. We did not find any difference in treatment response between the two progressive forms of MS. To date, no treatment is approved for PPMS and we therefore propose a trial to test the use of CYC treatment early in the course of the disease in PPMS patients with disability progression.

Background and Purpose: Persistently hypointense lesions on T1-weighted MR images have been shown to correlate with the amount of axonal damage and clinical disability in multiple sclerosis (MS) patients. The purpose of this study was to investigate whether diffusion coefficient D(av) and fractional anisotropy (FA) are able to detect quantifiable differences among three groups of focal nonactive multiple sclerosis (MS) lesions that appear qualitatively different on T1-weighted images., Methods: Conventional and diffusion tensor MR images of the brain were obtained in 18 patients with relapsing remitting (n = 10) or secondary progressive (n=8) MS and in 18 healthy volunteers. Focal nonactive MS lesions were classified as T1 isointense, T1 mildly hypointense, and T1 severely hypointense on unenhanced T1-weighted images. Differences among groups were assessed with one-way analysis of variance using the T1 lesion appearance as the grouping factor and either FA or coefficient D(av) as the dependent measure., Results: FA was lowest and coefficient D(av) was highest in T1 severely hypointense lesions, and then, in ascending and descending order, respectively, T1 mildly hypointense lesions and T1 isointense lesions. A significant difference in the values of FA was detected only between T1 isointense lesions and T1 severely hypointense lesions (P <.01), whereas no difference was found between T1 mildly hypointense lesions and either one of these two groups. A significant difference was found in the values of coefficient D(av) among all investigated lesion groups. Coefficient D(av) was found to correlate inversely with the T1-weighted contrast ratio (r=-0.58, P <.0001), whereas FA and deltaFA (percentage of FA variation in the lesion, a relative FA measure that minimizes the effect of FA spatial dependence) were not., Conclusion: Coefficient D(av) is more sensitive than FA to variations in the degree of T1 hypointensity and, thus, in the amount of the permanent brain tissue damage in patients with MS.

This paper presents a new approach to characterize subtle diffuse changes in multiple sclerosis (MS) using histograms derived from magnetization transfer ratio (MTR) images. Two major parts dominate our histogram analysis; 1) Classification of MTR histograms into control and MS subgroups; 2) Correlation with current disability, as measured by the EDSS scale (a measure of disease severity). Two data reduction schemes are used to reduce the complexity of the analysis: linear discriminant analysis (LDA) and principal component analysis (PCA). LDA is better for the classification of MTR histograms as it takes into account the between-class variation. By using LDA, the space of MTR histograms is transformed to the optimal discriminant space for a nearest mean classifier. In contrast, PCA is useful for correlation with current disability as it takes into account the variation within each subgroup in its process. A multiple regression analysis is used to evaluate the multiple correlation of those principal components with the degree of disability in MS. This is the first application of such classification and correlation techniques to magnetic resonance imaging histogram data. Our MTR histogram analysis approach give improved classification success and improved correlation compared with methods that use traditional histogram features such as peak height and peak location.

Objectives: To assess differences in magnetisation transfer ratio (MTR) analysis of normal appearing white matter (NAWM) in patients with familial multiple sclerosis (MS) and those with sporadic MS., Methods: 10 patients with familial MS, 10 patients with sporadic MS, and 10 healthy subjects were included in the study. Groups were matched according to the sex, age, disease duration, type of disease, EDSS, and MRI T1 and T2 lesion load. Magnetisation transfer imaging (MTI) with and without saturation pulse were performed. On the MTR map 16 different regions of interest of normal appearing white matter were analyzed., Results: The mean MTR value of normal appearing white matter was significantly lower both in familial patients and those with sporadic MS compared with healthy subjects (33.8% v 46.4%; 38.6% v 46.4% respectively, p< 0.05). Additionally, patients with familial MS showed significantly lower mean MTR value than patients with sporadic MS (33.8% v 38.6%, p<0.05). There was also significant regional variation of MTR values between these two groups of patients., Conclusions: Lower and more widespread MTR abnormalities in patients with familial MS might indicate differences in the extent and nature of white matter pathology between familial and sporadic MS.

Objectives: To assess the potential contribution of genetic factors to clinical phenotype in multiple sclerosis., Methods: Using a cohort of 262 pairs of coaffected siblings from 250 families with multiple sclerosis, intersibling concordance analysis was used to explore underlying genetic mechanisms in disease pathogenesis by assessing parameters of disease course, clinical presentation, age and year of onset, and measures of disability and handicap., Results: Adjusted intraclass correlation coefficients were not significant for either age of onset or for year of first symptom. One third of sibling pairs were concordant for presenting symptom (81/262), a result that was non-significant. However, course type was identical in 50% of the sibling pairs (kappa=0.17 (95% confidence interval (95% CI) 0.08 to 0.26)) indicating a significant result. Severity of the disease at assessment, using the Kurtzke and CAMBS scales, demonstrated that whereas there was no agreement for relapse rate in the previous year within the sibship, there was significant concordance for measures of disability (kappa=0.11 (95% CI 0.04 to 0.19)), progression (kappa=0.09 (95% CI 0.01 to 0.18)) and handicap (kappa=0.08 (95% CI 0.02 to 0.14))., Conclusions: Within a sibship, the clinical presentation tends to be different. However, once established, concordance is more likely to be seen for the ultimate course, leading in the end to similar disability and handicap scores. These results are consistent with the hypothesis that genes influence both disease susceptibility and evolution in multiple sclerosis.

Background: The influence of the patterns of onset of multiple sclerosis and relapses of the disease on the time course of irreversible disability is controversial., Methods: In 1844 patients with multiple sclerosis who were followed for a mean (+/- SD) of 11 +/- 10 years, we determined the time of the clinical onset of the disease, the initial course (relapsing-remitting or progressive) and the subsequent course (relapsing-remitting, secondary progressive, or primary progressive), the times of relapses, the time to the onset of irreversible disability, and the time course of progressive, irreversible disability. We used three scores on the Kurtzke Disability Status Scale (range, 0 to 10, with higher scores indicating more severe disability) as measures of the severity and progression of disability: a score of 4 (limited walking ability but able to walk for more than 500 m without aid or rest), a score of 6 (ability to walk with unilateral support no more than 100 m without rest), and a score of 7 (ability to walk no more than 10 m without rest while leaning against a wall or holding onto furniture for support). We used Kaplan-Meier analyses to determine the influence of relapses on the time to the onset of irreversible disability., Results: The median times from the onset of multiple sclerosis to the assignment of a score of 4, a score of 6, and a score of 7 on the disability scale were longer among the 1562 patients with a relapsing-remitting onset of disease (11.4, 23.1, and 33.1 years, respectively) than among the 282 patients who had progressive disease from the onset (0.0, 7.1, and 13.4 years, respectively; P<0.001 for all comparisons). In contrast, the times from the assignment of a score of 4 to a score of 6 were similar in the two groups (5.7 and 5.4 years, P=0.74). The time course of progressive, irreversible disease among patients with the primary progressive type of multiple sclerosis was not affected by the presence or absence of superimposed relapses., Conclusions: Among patients with multiple sclerosis, relapses do not significantly influence the progression of irreversible disability.

Classifications of multiple sclerosis subtypes have been largely based on clinical phenomenology. Nevertheless, definitions of relapse, remission and progression have been imprecise. Recently an international consensus group, as part of a reclassification of disease subtypes, recommended dropping the term 'relapsing-progressive' (RP) and retaining the term 'progressive-relapsing' (PR) multiple sclerosis. The term 'RP' multiple sclerosis had been applied when the early course combined both relapses and progression and was believed to identify some patients with a worse than average outcome. The PR group consisted of patients with primary progressive disease who later in their course developed relapses. Since the terminology has been largely arbitrary, we have evaluated the validity of the terms 'RP' and 'PR' multiple sclerosis in the context of long-term outcome within a large population-based cohort of progressive multiple sclerosis patients seen at the London Multiple Sclerosis Clinic (Canada) between 1972 and 1984. Mean follow-up of the entire cohort was 25 years. Designation of RP multiple sclerosis did identify a more rapidly progressive subgroup. To realign these natural history data with consensus recommendations, these patients were reassigned to secondary progressive (SP) or to primary progressive (PP) multiple sclerosis, with progression defined as at least 1 year of progressive deterioration. PP multiple sclerosis patients with relapses after a year were designated as having PR multiple sclerosis. Relapses in primary progressive multiple sclerosis occurred in 27.8% of patients at some point even two to three decades after onset. In general these relapses were mild and remitting, but served to blur the distinction between progressive and relapsing-remitting disease. The long-term outcomes of time to Kurtzke disability scores (DSS) of 3, 6, 8 and 10 were compared among the progressive subtypes. Times to these disability end-points and to death were not different between PR and PP multiple sclerosis. Survival curves for progressive patients have been amended to incorporate the reassignment of PR multiple sclerosis patients into the PP group and the RP multiple sclerosis patients into the PP and SP subgroups. The time to reach DDS 3, 6, 8 and 10 for a population-based cohort of primary and secondary progressive patients resulting from the elimination of the categories of RP multiple sclerosis and PR multiple sclerosis has been established. These results provide justification for retaining only PP and SP multiple sclerosis as the subgroups of progressive disease.