Elsevier

The Lancet Neurology

Volume 5, Issue 4, April 2006, Pages 343-354
The Lancet Neurology

Review
Secondary progressive multiple sclerosis: current knowledge and future challenges

https://doi.org/10.1016/S1474-4422(06)70410-0Get rights and content

Summary

The secondary progressive phase of multiple sclerosis (MS), which is characterised by a steady accrual of fixed disability after an initial relapsing remitting course, is not clearly understood. Although there is no consensus on the mechanisms underlying such a transition to the progressive phase, epidemiological and neuroimaging studies indicate that it is probably driven by the high prevalence of neurodegenerative compared with inflammatory pathological changes. This notion is lent support by the limited efficacy of available immunomodulating and immunosuppressive treatment strategies, which seems to be further decreased in the late stages of secondary progressive MS. No established clinical or paraclinical predictors of the transition from relapsing remitting to secondary progressive MS have been described. However, the use of quantitative MRI-derived measures is warranted to monitor natural history studies and therapeutic trials of secondary progressive MS with increased reliability. In view of the small effects of immunomodulating and immunosuppressive treatments in preventing the transition to secondary progression, the development of treatments promoting neuroaxonal repair remains an important goal in this disease.

Introduction

During the past decade, the advent of disease-modifying treatments has substantially changed the work-up of relapsing remitting multiple sclerosis (MS). Early treatment initiation is now recommended to maximise the efficacy of currently available therapies, which are known to mainly act against the inflammatory components of MS. By contrast, understanding and treatment of the progressive phase of MS, which is characterised by the steady accumulation of fixed disability, is suboptimum. Clinical and paraclinical predictors of a transition from an initial relapsing remitting phase to a secondary progressive course have little prognostic value. Moreover, the immunological and pathological substrates of secondary progressive MS are poorly defined. With respect to neuroimaging aspects, conventional MRI seems to lose sensitivity for monitoring the secondary progressive phase of MS and more specific in-vivo markers of neurodegeneration are needed for a reliable assessment of putative new treatment options. This review aims to critically summarise and provide a background for the planning of future studies and therapeutic trials of secondary progressive MS.

Section snippets

Consensus definition of secondary MS progression

During the relapsing remitting phase of MS, neurological sequelae from relapses can persist but, by definition, they are stable—ie, do not worsen between the episodes of acute neurological dysfunction. The word progression denotes the continuous worsening of neurological impairment over at least 6 or 12 months.1, 2, 3, 4, 5 The date of onset of MS progression is difficult to define and is usually assessed retrospectively once the duration of continuous neurological worsening has been

Immunopathology

The immunopathological characteristics of the transition from relapsing remitting MS to secondary progressive MS have been poorly investigated. A debated concept is whether the progressive phase is associated with the decrease in inflammatory and demyelinating processes, which are substituted by neurodegenerative features. Few pathological studies have focused on patients with secondary progressive MS.29, 30 The most relevant finding in these reports is an unusual type of demyelination

Conventional MRI

The average burden of brain T2-hyperintense lesions tends to be higher in patients affected by secondary progressive MS than in those with relapsing remitting or primary progressive MS.39, 40, 41 The load of focal spinal cord lesions was also shown to be higher in patients with secondary progressive MS than in those with relapsing remitting or primary progressive MS in some,41, 42 but not in all studies.43 However, the correlations between locomotor disability and brain or cord T2 lesion loads

Interferon-beta

Four large-scale, double-blind, randomised, placebo-controlled studies assessing the effectiveness of interferon beta in patients with secondary progressive MS have yielded controversial results. The European multicenter trial on interferon beta-1b in SPMS (EUSPMS)118 enrolled 718 patients who were treated with either interferon beta-1b or placebo for up to 3 years. The primary outcome was the time to confirmed disability progression, as measured by an increase in EDSS23 sustained for at least

Conclusion

Although there is no consensus on the mechanisms underlying the evolution from the relapsing remitting to the secondary progressive phase of MS, epidemiological and MRI studies indicate that this transition can be mainly driven by the prevalence of neurodegenerative over inflammatory pathological features. The limited efficacy of available immunomodulating and immunosuppressive therapeutic strategies, which can strongly reduce inflammation, in prevention of accumulation of irreversible

Search strategy and selection criteria

Data for this review were identified by searches of Medline, Current Contents, and references from relevant articles. The search terms “secondary progressive MS”, “epidemiology”, “immunology”, “pathology”, “magnetic resonance imaging”, and “treatment” were used. The search strategy was carried out in December, 2005. Only papers published in English and from 1995 onwards were reviewed. The final reference list was generated on the basis of originality and relevance to the topics covered in

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