Antonio Scalfari

The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability.

The relationship of relapses to long-term disability in multiple sclerosis is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation. We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing–remitting phase. Survival was compared among groups stratified by (i) early relapses—number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing–remitting phase. Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus ≥3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10. In contrast, neither total number of relapsing–remitting phase attacks nor of relapses experienced during the relapsing–remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints. The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing–remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence—to a lesser degree—its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing–remitting patients.

Clinical prognostic factors in multiple sclerosis: a natural history review.

This Review summarizes the natural history studies on multiple sclerosis (MS) that have evaluated prognostic factors. Reassessment of prognostic factors is warranted, as our ability to offer patients a reliable prognosis is limited, yet we rely on this knowledge to appropriately design clinical trials and interpret their results. The selection criteria for studies to review included a geographical referral base, duration of at least 9 years, prospective design, and populations of at least 100 patients with MS. For all forms of MS combined, negative prognostic factors included progressive disease, and disability at 2 and 5 years. In relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS) combined, negative prognostic factors were the onset of progression, a higher relapse rate, greater disability in the first 5 years, a shorter interval to the second relapse, and the involvement of more systems. Additional negative factors include a shorter time to progression in SPMS and a faster rate of disability in the first 2 and 5 years in primary progressive MS (PPMS). Onset of progression, relapse rate and disability in the initial 5 years could be fruitful therapeutic targets; however, longer-term clinical trials will be required to justify these end points.

Onset of secondary progressive phase and long-term evolution of multiple sclerosis

Objectives To assess factors affecting the rate of conversion to secondary progressive (SP) multiple sclerosis (MS) and its subsequent evolution. Methods Among 806 patients with relapsing remitting (RR) onset MS from the London Ontario database, we used Kaplan–Meier, Cox regression and multiple logistic regression analyses to investigate the effect of baseline clinical and demographic features on (1) the probability of, and the time to, SP disease, (2) the time to bedbound status (Disability Status Scale (DSS 8)) from onset of progression. Results The risk of entering the SP phase increased proportionally with disease duration (OR=1.07 for each additional year; p<0.001). Shorter latency to SP was associated with shorter times to severe disability. The same association was found even when patients were grouped by number of total relapses before progression. However, the evolution of the SP phase was not influenced by the duration of the RR phase. Male sex (HR=1.41; p<0.001), older age at onset (age ≤20 and 21–30 vs >30 HR=0.52 (p<0.001), 0.65 (p<0.001), respectively) and high early relapse frequency (1–2 attacks vs ≥3 HR=0.63 (p<0.001), 0.75 (p=0.04), respectively) predicted significantly higher risk of SP MS and shorter latency to progression. Times to DSS 8 from onset of progression were significantly shorter among those with high early relapse frequency (≥3 attacks), and among those presenting with cerebellar and brainstem symptoms. Conclusions The onset of SP MS is the dominant determinant of long-term prognosis, and its prevention is the most important target measure for treatment. Baseline clinical features of early relapse frequency and age at onset can be used to select groups at higher risk of developing severe disability based on the probability of their disease becoming progressive within a defined time period.

Early Relapses, Onset of Progression, and Late Outcome in Multiple Sclerosis

OBJECTIVES To investigate the relationship among attacks in the first 2 years (early relapses), secondary progression (SP), and late disability in multiple sclerosis (MS). DESIGN Cohort study with follow-up of 28 years. SETTING Referral MS center. PATIENTS Patients (N=730) with relapsing-remitting MS diagnosed according to Poser criteria, from the database of the London Multiple Sclerosis Clinic, London, Ontario, Canada. MAIN OUTCOME MEASURE Long-term evolution of patients with high (≥ 3 attacks) and early (within the first 2 years of the disease) frequency of relapses. In the total SP population and in patients grouped by numbers of early relapses, we assessed the predictive effect of latency to progression (time to SP) on times to attain cane requirement (Disability Status Scale score of 6 [DSS 6]) and bedridden status (DSS 8). RESULTS Among the group with frequent early relapses (n=158), outcomes were variable. Although 103 (65.2%) experienced rapid conversion to SP MS (median duration, 5 years) and rapidly attained DSS 6 and DSS 8 scores (7 and 17 years, respectively), the remainder (n=55) did not enter the SP phase, despite adverse early relapse features. Among the total SP population, longer latency to progression was associated with lower probability of attaining DSS 6 (odds ratio, 0.76 [95% CI, 0.69-0.84] and 0.44 [95% CI, 0.37-0.52] for 5- and 15-year latency, respectively) and longer times to severe disability. The same association between time to onset of SP and late outcomes was observed even in patients matched by number of early attacks. However, duration of the relapsing-remitting phase did not influence the times from SP onset to DSS levels. CONCLUSIONS Our results indicate dissociation between early inflammatory attacks and onset of the SP phase and further question the validity of relapse frequency as a surrogate marker for late disability. Among the group with frequent early relapses, we observed a large variability of outcomes, ranging from one extreme to the opposite.

Regional distribution and evolution of gray matter damage in different populations of multiple sclerosis patients

Background Both gray-matter (GM) atrophy and lesions occur from the earliest stages of Multiple Sclerosis (MS) and are one of the major determinants of long-term clinical outcomes. Nevertheless, the relationship between focal and diffuse GM damage has not been clarified yet. Here we investigate the regional distribution and temporal evolution of cortical thinning and how it is influenced by the local appearance of new GM lesions at different stages of the disease in different populations of MS patients. Methods We studied twenty MS patients with clinically isolated syndrome (CIS), 27 with early relapsing-remitting MS (RRMS, disease duration <5 years), 29 with late RRMS (disease duration ≥ 5 years) and 20 with secondary-progressive MS (SPMS). The distribution and evolution of regional cortical thickness and GM lesions were assessed during 5-year follow-up. Results The results showed that new lesions appeared more frequently in hippocampus and parahippocampal gyri (9.1%), insula (8.9%), cingulate cortex (8.3%), superior frontal gyrus (8.1%), and cerebellum (6.5%). The aforementioned regions showed the greatest reduction in thickness/volume, although (several) differences were observed across subgroups. The correlation between the appearance of new cortical lesions and cortical thinning was stronger in CIS (r2 = 50.0, p<0.001) and in early RRMS (r2 = 52.3, p<0.001), compared to late RRMS (r2 = 25.5, p<0.001) and SPMS (r2 = 6.3, p = 0.133). Conclusions We conclude that GM atrophy and lesions appear to be different signatures of cortical disease in MS having in common overlapping spatio-temporal distribution patterns. However, the correlation between focal and diffuse damage is only moderate and more evident in the early phase of the disease.

The relationship of age with the clinical phenotype in multiple sclerosis.

Background: The multiple sclerosis (MS) clinical course and relapses frequency before progression vary widely. Objective: To investigate the influence of age on the MS phenotype. Methods: Among 751 primary progressive (PP = 217) and secondary progressive (SP = 534) MS patients from the London Ontario database, we assessed the relationship of age on the relapse frequency and on the progressive phase evolution, and the impact of relapses on the age at onset of progression. Results: Age at onset did not influence the early attacks frequency, but patients younger at onset had larger number of total attacks before progression (age = 27.4, 31.0 and 32.8 mean years; ⩾4, 2–3 and 1 relapses, respectively) and longer latency to SP. Although frequent early relapses predicted younger age at SP onset, patients with no attacks (primary progressive multiple sclerosis (PPMS)), or 1, 2–3 and ⩾4 relapses during the relapsing-remitting phase started progressing at similar age (38.6, 41.3, 41.4 and 39.2 mean years, respectively). The age at onset of progressive phase did not affect its evolution. Conclusions: Age strongly influences the phenotype before progression. Relapsing-remitting patients younger at onset are more likely to display a predominantly inflammatory course, yet relapses number does not affect the age at onset of progression.

Surrogate endpoints for EDSS worsening in multiple sclerosis: A meta-analytic approach: Measuring disability in relapsing-remitting MS

# {#article-title-2} To the Editor: Sormani et al.1 attempt to validate multiple sclerosis (MS) relapse frequencies as surrogates for estimating the prevention of disability progression expected from relapse reduction. In pooled data on relapsing-remitting MS (RRMS), a strong association ( R 2 = 0.71; p < 0.001) was observed between treatment effects on relapses and on defined Expanded Disability Status Scale (EDSS) “worsening” defined in these trials. However, neither Sormani et al. nor the editorialists2 acknowledge that the measures of disability used in these trials could not be validated themselves.3 Trial-defined worsening was no more likely than improvement, identically defined, in placebo arms. The results of Sormani et al., limited to 2-year periods, conflict with natural history analysis of times to cane, bed, and death from MS at 28 years,4 information perhaps not available then.3 Low (1–2), intermediate (3–4), and high (greater than or equal to 5) attack frequencies during RRMS did not differ in times to hard disability endpoints. Frequent relapses from year 3 after onset to conversion to secondary progressive MS (SPMS) are associated with better outcomes, invalidating these relapses as outcomes predicting late disability.3 This epoch characterizes the data in the analysis by Sormani et al. Patients in trials and ethics committees considering their appropriateness should be aware that this measure cannot be validated. Potential benefit of relapse suppression on short-term neurologic dysfunction and possibly on lower, often asymptomatic, levels of the disability scale is conceded. In an untreated natural history cohort, we cannot support conclusions recently endorsed by Rudick and Kappos.2 Clinical trials usually observed for 2 years after randomization need the context of times to hard DSS endpoints as long as 2 …

Combined MRI lesions and relapses as a surrogate for disability in MS.

Submissions to Writ e Click this week highlight a common difficulty: how to relate conclusions from research to clinical practice and vice versa. Dr. Ebers and colleagues debate with authors Sormani and De Stefano about the article “Combined MRI lesions and relapses as a surrogate for disability in MS,” with a sticking point over the difference between surrogacy and correlation. They agree in calling for another look at the outcomes used in multiple sclerosis trials. Drs. Kent and Mandava, in reference to “Predicting outcome of IV thrombolysis-treated ischemic stroke patients: The DRAGON score,” point out the …

Predicting a window of therapeutic opportunity in multiple sclerosis

ARTICLE Sir, The relationship between cumulative relapses and unremitting progressive disability is highly relevant to clinical practice and to randomized controlled trial design. Neuropathological studies unmentioned by Andersen (2010) have not been able to confirm the widespread belief that severe disability accumulates as a result of successive exacerbations. DeLuca et al. (2006), examining one of the largest reported pathological cohorts of multiple sclerosis cases, demonstrated lack of correlation between plaque load and axonal loss in the corticospinal tracts throughout the length of the spinal cord where the clinical phenomena characterizing the progressive phase typically localize. Disease progression and inflammatory attacks are probably driven by different mechanisms (Trapp and Nave, 2008). This became clear in the interferon and monoclonal antibody studies which showed no impact on disease evolution following relapse suppression, and MRI studies have provided but weak or non-existent correlations between lesion load and long-term disease evolution (Fisniku et al. , 2008). Previous natural history studies have demonstrated predictive value of early disease features, including early relapse rate (Weinshenker et al ., 1989 b ; Eriksson et al. , 2003). Nevertheless, this was no longer reported to apply once permanent disability occurs (defined as 4 on the Disability Status Scale [DSS]; Confavreux et al. , 2003). Outcome appears to be largely determined during the early stage of the disease, and once progression has begun, its rate seems independent of factors preceding it (Confavreux et al. , 2003). It is unaffected by superimposed inflammatory attacks (Kremenchutzky et al. , 1999) and it is homogeneous among progressive subtypes (Kremenchutzky et al. , 2006). Number of relapses during the first 2 (Weinshenker et al. , 1989 b ) and 5 years (Kantarci et al. , 1998; Confavreux et al. , 2003) had …

The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis

Objective To investigate the relationship among cortical radiologic changes, the number of early relapses (ERs), and the long-term course of multiple sclerosis (MS). Methods In this cohort study, we assessed the number of cortical lesions (CLs) and white matter (WM) lesions and the cortical thickness (Cth) at clinical onset and after 7.9 mean years among 219 patients with relapsing remitting (RR) MS with 1 (Low-ER), 2 (Mid-ER), and ≥3 (High-ER) ERs during the first 2 years. Kaplan-Meier and Cox regression analyses investigated early factors influencing the risk of secondary progressive (SP) MS. Results Fifty-nine patients (27%) converted to SPMS in 6.1 mean years. A larger number of CLs at onset predicted a higher risk of SPMS (hazard ratio [HR] 2.16, 4.79, and 12.3 for 2, 5, and 7 CLs, respectively, p < 0.001) and shorter latency to progression. The High-ER compared to the Low-ER and Mid-ER groups had a larger volume of WM lesions and CLs at onset, accrued more CLs, experienced more severe cortical atrophy over time, and entered the SP phase more rapidly. In the multivariate model, older age at onset (HR 1.97, p < 0.001), a larger baseline CL (HR 2.21, p = 0.005) and WM lesion (HR 1.32, p = 0.03) volume, early changes of global Cth (HR 1.36, p = 0.03), and ≥3 ERs (HR 6.08, p < 0.001) independently predicted a higher probability of SP. Conclusions Extensive cortical damage at onset is associated with florid inflammatory clinical activity and predisposes to a rapid occurrence of the progressive phase. Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy.