Secondary progressive multiple sclerosis: current knowledge and future challenges

Review

Secondary progressive multiple sclerosis: current knowledge and future challenges Marco Rovaris, Christian Confavreux, Roberto Furlan, Ludwig Kappos, Giancarlo Comi, Massimo Filippi

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.

Clinical aspects 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.1–5 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 established. When the initial relapsing remitting phase is followed by a transition to the progressive phase, the disease is named secondary progressive MS. To standardise the terminology used in the description of MS clinical http://neurology.thelancet.com Vol 5 April 2006

phenotypes, an international panel of experts defined secondary progressive MS as an “initial relapsing remitting disease course followed by progression with or without occasional relapses, minor remissions, and plateaus”.6 Overall, in a representative population of patients with MS, onset of disease is of the relapsing remitting type in 85% of patients.6 In MS surveys, the higher the duration of the follow-up, the higher the proportion of cases with a relapsing remitting onset who will have converted to secondary progressive MS.

Lancet Neurol 2006; 5: 343–54 Neuroimaging Research Unit (M Rovaris MD, M Filippi MD), Department of Neurology (M Rovaris MD, R Furlan MD, G Comi MD, M Filippi MD), and Neuroimmunology Research Unit (R Furlan MD), Scientific Institute and University Ospedale San Raffaele, Milan, Italy; Department of Neurology and EDMUS Coordinating Center, Hôpital Neurologique Pierre Wertheimer, Université Claude Bernard, Lyon, France (C Confavreux MD); and Department of Neurology and Research, University Hospital, Basel, Switzerland (L Kappos MD) Correspondence to: Dr Massimo Filippi, Neuroimaging Research Unit, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy fi[email protected]

Epidemiology Thanks to the numerous available long-term natural history studies,7 knowledge of the onset of progression in MS is evidence based. McAlpine and Compston8 first showed clearly that “there is a fairly constant rate of change from a remitting to a progressive course, and that there is a gradual rise in the total percentage of progressive cases as the disease advances”. A similar progression has been proven in series in Lyon, France,9–11 and in Gothenburg, Sweden.12,13 As estimated by survival analysis, the median time to secondary progression in MS patients with a relapsing remitting onset in the Lyon series was 19·1 years, with a mean yearly rate of 2·5% of relapsing remitting patients converting to secondary progressive MS.11 In a Canadian series,14 however, 30–40% of patients with an initial relapsing remitting course developed secondary progressive MS within 10 years from disease onset, with a median time to conversion of between 10 and 15 years. For patients presenting with a distinct clinically isolated syndrome, the median time to onset of secondary progression was 19·0 years in the Gothenburg series.13 Consistent results have been reported in other Italian15 and Swedish16 series. Thus a reasonable estimate of the median time from relapsing remitting MS onset to secondary progression is about 19 years.7 Age at onset is the strongest predictor of the conversion to secondary progressive disease: the older 343

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the patient at onset, the shorter the time to onset of progression.10,11,13,17–21 Male sex has been associated with a shorter time to progression than female sex in many series,11,13,17,18,20 but not in others.8,10,15,19,21 With respect to initial symptoms, most series reported that visual or sensory and sometimes brainstem-related symptoms are associated with an increased time to secondary progression, whereas spinal-cord-related symptoms are associated with a diminished time to evolution.11,13,17–20,22 An incomplete recovery from the initial exacerbation has consistently been associated with a reduced time to secondary progression.13,15,21 A shortened time from the clinical onset of MS to the second episode was shown to be predictive in some studies,10,11,21 but not in others.13,15 The number of relapses during the first 2–5 years of disease was shown to be inversely related to the time to secondary progression in some studies,17,18 but not in others.13,15,21 A Norwegian study showed that the higher the disability score or the number of affected functional systems 5 years after the onset of MS, the shorter the time to progression.13 Among the 1844 patients of the Lyon Natural History MS cohort, 27% were classified as having secondary progressive MS at the time of the survey. To investigate the dynamics of clinical MS progression, three robust landmarks of disability were assessed: disability status scale (DSS)23 score 4 (walking without aid and a limited walking distance but exceeding 500 m without rest), score 6 (walking with unilateral support and a walking distance not exceeding 100 m without rest), and score 7 (home restriction, a few steps still being possible while holding onto a wall or furniture but not exceeding 10 m without rest). In this cohort, the median times to reach irreversible disability from MS onset, as estimated by survival analysis, were 6·1 years for DSS 4, 12·5 years for DSS 6, and 19·1 years for DSS 7. The same cohort study showed that the median times to reach these disability scores from the onset of the disease were significantly shorter in patients with primary progressive MS.24 By contrast, the time course of disability accumulation during the progressive phase of the disease was more rapid in secondary progressive MS than in primary progressive MS.25 This finding is in agreement with those from other series.26–28 In the London Ontario cohort, the median survival time from onset of progression to reach DSS 6 was 5·5 years in patients with secondary progessive MS and 9·5 years in those with primary progressive MS.27,28 However, in the Gothenburg cohort,20 the median survival time from the onset of progression to DSS 6 was about 5 years and was not significantly different between secondary progressive MS and primary progressive MS. In the Lyon MS cohort,24 the progression of irreversible disability from DSS 4 to DSS 6 was closely similar, whether relapses occurred or not. In these patients, however, the time from score 4 to score 7, as well as the time from score 6 to score 7, were longer when relapses occurred during the progression. In any case, the speed 344

of progression from DSS 4 to DSS 6 seems to have a wide interpatient variability and its predictors are still unknown.

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 characterised by slowly expanding plaques with foamy macrophages containing lipids, especially in periplaque white matter. The description of absent or modest perivascular cuffs in the lesions, but the presence of lymphocytes and plasma cells in the periplaque white matter, is consistent with reduced inflammatory activity in and around lesional areas,30 although the activity is more prominent than in primary progressive MS.29 Very scarce elements of an ongoing neurodegenerative process are available in these reports, although Wallerian degeneration and other axonal alterations are reported in the spinal cord.30 More recently, Kutzelnigg and colleagues31 did a pathological study on a series of more than 50 patients, of whom 20 had secondary progressive MS. In this study, several distinguishing characteristics of secondary progressive MS have been described. Demyelination in the cerebral cortex, diffuse injury in the form of focal axonal swelling and axonal end bulbs, and diffuse rather than focal inflammation (defined as diffuse T-lymphocyte infiltration and microglial activation) were shown to be significantly increased in primary progressive MS and secondary progressive MS compared with relapsing remitting MS. Serafini and colleagues32 reported, in a very small group of patients, that ectopic lymphoid follicle-like structures containing B cells, T cells and plasma cells, and a network of follicular dendritic cells producing CXCL13 (a finding usually associated with chronic inflammation) were present in the cerebral meninges of patients with secondary progressive MS, but not in those with relapsing remitting MS and primary progressive MS. The results of these studies seem to indicate that inflammatory characteristics remain an important aspect of pathological changes in secondary progressive MS, albeit with different patterns than in the relapsing remitting phase of the disease. Whether inflammation could completely burn out during the latest stages of secondary progressive MS, as suggested by evidence from neuroimaging studies and treatment trials, needs to be established. The underlying immunological mechanisms that parallel the evolution from relapsing remitting to secondary progressive MS are difficult to identify on the basis of these pathlogical data alone. Furthermore, http://neurology.thelancet.com Vol 5 April 2006

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available data can seem to contrast with the assumption that inflammation is decreased in secondary progressive MS. Interleukin 10 has been shown to be decreased and interleukin 12p40 to be upregulated in supernatants of peripheral blood mononuclear cells from patients with secondary progressive MS compared with those with relapsing remitting MS.33 According to the Th1/Th2 paradigm this finding is not suggestive of reduced proinflammatory activity. Other studies have described an increase in CCR2+ cells and a decrease in CCR5+ cells in patients with secondary progessive MS compared with those with relapsing remitting MS. These findings have been interpreted as a possible Th2 shift occurring in secondary progressive MS.34,35 In a study that compared the concentration of mRNA in peripheral blood mononuclear cells from a large population of patients with MS, significantly (p<0·005) increased expression of IL-1α, IL-5, IL-10, TNFβ, and CXCL10, and significantly decreased expression of CCL5, CCR3, and CXCR5 were found in samples from patients with secondary progressive MS compared with those from clinically stable patients with relapsing remitting MS.36 These results cannot be clearly explained in terms of current knowledge on inflammatory vs anti-inflammatory patterns. Adhesion molecules LFA-1 and α4-integrin have been analysed on peripheral blood mononuclear cells from patients with MS and shown to be up-regulated in patients with secondary progressive MS compared with those with relapsing remitting MS.37 These findings have been discussed by the authors in light of prominent disease activity in patients with secondary progressive MS, in parallel with the same type of rise in patients with relapsing remitting MS who are having a clinical relapse. In another study,38 proinflammatory cytokine concentrations were shown to be higher in female than in male patients with secondary progressive MS, whereas they did not differ between men and women affected by relapsing remitting MS. This finding indicates that sex differences in cytokine profiles might be another immunological hallmark of the progressive phase of MS. All these observations indicate that there is no consensus on the immunological mechanisms underlying the evolution from relapsing remitting MS to secondary progressive MS. This can be explained by the limitations of the available methods of investigation, which are inadequate in case of changes occurring in the target organ. The series of patients who are included in postmortem studies are, in fact, hardly representative of the general MS population. On the other hand, investigations on peripheral blood mononuclear cells are limited by the fact that the blood stream can represent a mere trafficking compartment in which pathogenically relevant lymphocyte subpopulations could be unevenly represented. Thus, the identification of the immunological changes associated with the shift to secondary progressive MS will have to rely on new approaches, such as gene-expression microarrays and proteomics. http://neurology.thelancet.com Vol 5 April 2006

Figure 1: An illustrative example of lesion evolution to “black hole” in a patient with secondary progressive MS An enhancing lesion (the scan on which the lesion enhances is shown on the left) appears hypointense to surrounding white matter at the first scan after the enhancement (baseline scan; middle panel). After 6 months of follow-up, the signal intensity of the lesion is still hypointense compared with surrounding white matter (right panel). Reproduced with permission of the American Academy of Neurology.56

Neuroimaging 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.39-41 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 in secondary progressive MS are generally null or weak.41,43,44 The number of gadolinium-enhancing lesions tends to decrease in patients with relapsing remitting MS as they enter the secondary progressive phase and becomes very low in advanced secondary progressive disease.45–47 However, this finding has not been confirmed in other studies.48 The number of gadolinium-enhancing lesions on a baseline scan is a significant predictor of subsequent MRI activity in both relapsing remitting and secondary progressive MS,49 but only modestly predicts the clinical evolution in the subsequent 2 years.50 On the other hand, the frequency of large51 and ring-enhancing52 lesions were shown to be correlated with subsequent expanded disability status scale (EDSS) worsening in patients with relapsing remitting MS, which suggests that specific 345

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accrual and brain atrophy.76–80 This lends support to the notion of a dissociation between the inflammatory and neurodegenerative aspects during the secondary progressive phase of MS.

Quantitative MR-based techniques

Figure 2: Colour-coded areas of brain atrophy development in secondary progressive MS overlaid on a template T1-weighted image Involvement of the bilateral anterior orbital gyrus and left mammillary body (A). Involvement of the caudate nuclei; left middle temporal gyrus; left thalamus; and frontal, parietal, temporal, and occipital region (B). Involvement of the cingulate sulcus and regions of frontal and parietal cortex (C). Reproduced with permission of the American Society of Neuroradiology.61

patterns of contrast enhancement might be predictors of an increased risk of unfavourable clinical evolution. Several findings indicating that a greater load of T1-hypointense lesions is the best discriminant between secondary progressive MS and relapsing remitting or primary progressive MS42,43,47,53–55 have not been confirmed by other studies,40,41 possibly because of the known methodological limitations of T1 lesion count and volume measurement. Interestingly, however, a recent study56 comparing the evolution of newly formed gadoliniumenhancing lesions in patients with secondary progressive MS and relapsing remitting MS has shown a four-fold higher risk of black-hole development in the secondary progressive group (figure 1). A greater severity of brain57–61 and cord42,62–66 atrophy is seen in secondary progressive MS than in benign or relapsing remitting MS, which significantly correlates with the degree of neurological disability. By contrast with this finding, the rate of brain atrophy progression over short-term periods has been shown not to differ among the various MS phenotypes.67,68 In conflict with earlier reports,43 neither the severity of brain and cord atrophy nor their short-term progression rates were shown to differ between secondary progressive and primary progressive MS in large-scale studies in which these two patient groups were matched for disease duration and disability.41,69,70 Preliminary evidence61 seems to indicate that the distribution patterns, rather than the overall rate, of brain atrophy might differ between relapsing and progressive MS, being predominant in secondary progressive MS in the cortical and deep grey matter areas (figure 2). Conventional MRI has been widely applied to monitor therapeutic trials of secondary progressive MS and proven to provide valid surrogate endpoints for disability progression (table).71 However, the consistent finding of a significant treatment effect in reducing gadoliniumenhancing lesion frequency and T2-hyperintense lesion load accumulation72–75 was not accompanied by a comparable effect on T1-hypointense lesion load 346

Quantitative MR-based techniques have the potential for increased specificity to the most destructive pathological characteristics of MS. Among these techniques, magnetisation transfer (MT) MRI,81 diffusion MRI,82 and T1 relaxation time measurements83 enable us to quantify the extent of structural changes both in T2-visible lesions and in tissue that appears normal on conventional MR images. Proton MR spectroscopy (¹H-MRS)84 can add information about the biochemical nature of such changes, with the potential to improve significantly our ability to monitor inflammatory demyelination and axonal injury. Cross-sectional MT MRI studies of patients with secondary progressive MS40,41,55,85–87 have shown that normal-appearing brain tissues are damaged, as shown by a significant decrease of the average MT ratio values when compared with those from healthy individuals and patients with less disabling disease phenotypes. The most compelling piece of evidence that a reduction of MT ratio values indicates severe tissue damage comes from post-mortem studies showing a strong correlation of MT ratio values from MS lesions and normal-appearing white matter with the percentage of residual axons and the degree of demyelination.88,89 The scarce correlations between MT MRI findings and T2-visible lesion load or brain volume indicate that damage to normal-appearing brain tissue in secondary progressive MS does not merely depend on the degeneration of fibres that pass through macroscopic lesions. Longitudinal MT MRI studies have shown that newly-enhancing lesions from patients with secondary progressive MS had lower MT ratio values at the time of their appearance and presented a more severe and significant MTR reduction during the followup than did those from patients with relapsing remitting disease.85,90 The 1-year changes of metrics derived from the histogram analysis of brain MT ratio maps were more prominent in patients with secondary progressive MS than in those with relapsing remitting disease.85 That MT MRI is sensitive to the accrual of brain pathology in secondary progressive MS accords with the results of a subcohort analysis from a clinical trial.91 MT MRI studies of the cervical cord showed that MTR abnormalities were more pronounced in secondary progressive MS than in relapsing remitting disease.92,93 Another study comparing cervical cord MT MRI findings from patients with secondary progressive MS and primary progressive MS showed no significant differences (figure 3).41 Several diffusion MRI studies94–99 have achieved conflicting results when comparing secondary progressive MS with the other disease phenotypes. Only two histogram-based studies95,98 showed that water http://neurology.thelancet.com Vol 5 April 2006

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diffusivity and anisotropy abnormalities of the whole brain were significantly more pronounced in secondary progressive MS than in relapsing remitting MS. Bozzali and colleagues,100 using diffusion MRI and brain tissue segmentation techniques, showed that grey matter changes are more pronounced in patients with secondary progressive MS than in those with relapsing remitting MS. Rovaris and colleagues69,70 also showed that the diffusion abnormalities of T2-visible lesions, normalappearing white matter, and grey matter are more severe in patients with secondary progressive MS than in those with primary progressive disease. On the other hand, a 1-year follow-up study70 has shown a significant increase of water diffusivity in lesions and grey matter of patients with secondary progressive and primary progressive MS compared with baseline. This finding suggests that progressive grey matter damage might yet be an additional factor leading to the accumulation of disability in progressive MS. Recent advances in diffusion MRI acquisition and post-processing have made the study of the cervical cord feasible. In the cervical cord of patients with secondary progressive disease, water diffusivity and tissue anisotropy are abnormal and these abnormalities tend to be of a greater magnitude than in relapsing remitting disease.66 When comparing various MRIderived metrics, cervical cord diffusion parameters showed the strongest relation with patients’ motor disability.66 In a study that used T1 relaxation time measurements,101 both normal-appearing white matter and grey matter T1 relaxation time histogram-derived parameters showed greater abnormalities in patients with secondary progressive MS than in those with relapsing remitting MS. However, grey matter T1 histogram peak location was the strongest predictor of disability in patients with secondary progressive MS together with a measure of brain atrophy. In the cervical cord of MS patients,102 T1 relaxation time was shown to be significantly prolonged compared with controls, with significantly higher values in secondary progressive MS than in relapsing remitting MS. Significant correlations between cord T1 relaxation time values, patients’disability, and cord atrophy were also shown. ¹H-MRS-measured N-acetyl aspartate (NAA) is known to be associated with neuronal and axonal viability.103 Early studies104,105 reported a marginal difference between secondary progressive and relapsing remitting MS in the NAA concentrations of normal-appearing white matter. Other cross-sectional studies106–109 noted lower NAA concentrations in secondary progressive MS than in relapsing remitting MS or benign MS and moderate correlations with the severity of neurological disability. More recently, Adalsteinsson and colleagues110 showed that in grey matter, and not normal-appearing white matter, NAA concentrations differed between secondary progressive and relapsing remitting MS. These differences among studies could be indicative of http://neurology.thelancet.com Vol 5 April 2006

Technique

Summary findings in SPMS

Interpretation

T2-weighted MRI

Greater lesion load than in RRMS and PPMS Weak correlation with disability

Reflects the accrual of pathologically heterogeneous macroscopic lesions without a phenotype-specific pattern

Gadolinium-enhanced MRI

Lesser frequency and amount of active lesions than in RRMS (controversial)

Prevalence of neurodegeneration over inflammation Persistence of “low-burning” grade, MRIundetectable inflammatory processes?

T1-weighted MRI

“Black hole” load best discriminant Suboptimum reliability of this approach between SPMS and other MS phenotypes Inability to quantify tissue damage within Improved correlation with disability macroscopic lesions and in the NABT (controversial)

Brain and cord atrophy measurement

More severe and faster rate of accumulation than in RRMS Similarity with PPMS Improved correlation with disability

Atrophy reflects the final outcome of neurodegeneration May lose sensitivity in the later stages of SPMS

Magnetisation transfer MRI

More pronounced abnormalities within lesions than in RRMS Diffuse and severe NABT damage Detectable short-term changes

NABT damage contributes to disability progression MT MRI is a potentially useful tool to monitor SPMS trial

Diffusion MRI

More pronounced GM damage than in RRMS and PPMS, with significant shortterm worsening

GM damage seems to be an important feature of progressive MS

Proton MR spectroscopy

More severe neuroaxonal dysfunction than in RRMS (controversial) Strong correlations with disability

Axonal damage underlies MS irreversible disability

Functional MRI

Activation of a widespread sensorimotor network for simple motor tasks

The failure of compensatory mechanisms may be a key aspect of MS progression

SPMS=secondary progressive MS; RRMS=relapsing remitting MS; PPMS=primary progressive MS; NABT=normal-appearing brain tissue; MT MRI=magnestisation transfer MRI; GM=grey matter.

Table: Neuroimaging features of secondary progressive MS

known variability of 1H-MRS measurements related to methodological issues. However, in a study by Vrenken and colleagues,111 only the ratio between NAA and creatine was significantly lower in the normal-appearing white matter from patients with MS than in the controls, without differences among the various MS phenotypes; whereas, the absolute concetrations of NAA were similar in patients and healthy individuals. The authors conclude that, in the normal-appearing white matter of patients with secondary progressive MS and other courses of MS, increased glial activity, as shown by increased creatine concentrations, can occur without axonal dysfunction.

Functional MRI Cortical activations during motor, sensory, or cognitive tasks can be interrogated with functional MRI (fMRI). In patients with MS112–114 a reorganisation of the motor network has been described, which could account for the small association between structural pathology and levels of disability. Such a reorganisation is especially extensive and widespread in primary progressive MS115,116 and its degree is highly correlated with the severity of damage to normal-appearing brain tissue. Only one study116 has electively investigated the fMRI pattern of cortical activations during simple motor tasks in patients with secondary progressive MS compared with healthy individuals. Similar to what was described in patients with primary progressive MS who had high levels of 347

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Healthy patients Primary progressive MS Secondary progressive MS

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physical disability,114,115 the activation of a widely distributed sensorimotor network was reported in patients with secondary progressive MS, with the recruitment of several cortical and subcortical areas, which might help to limit the functional consequences of tissue injury (figure 4). In another cross-sectional study117 that compared patients with different MS disease phenotypes by use of a simple motor task, those with secondary progressive MS showed an increased activation of several regions, mostly located in the frontal and parietal lobes, when compared with patients with relapsing remitting MS and mild disability. Thus, the failure of first-line compensatory mechanisms could, at least in part, explain the accrual of disability reported in progressive MS.

Treatment Interferon-beta Four large-scale, double-blind, randomised, placebocontrolled 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-

Figure 4: Relative cortical activations in right-handed patients with secondary progressive MS during the performance of a simple motor task with their functionally normal right hand Compared with healthy volunteers, patients showed increased recruitment of the ipsilateral inferior frontal gyrus (A), middle frontal gyrus bilaterally (B, C), and contralateral infraparietal sulcus (C). Reproduced with permission of Elsevier.116

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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 3 months. This progression was shown to be significantly delayed (p=0·007) in treated patients. The proportion of patients with either progression or relapses decreased by nearly 30% in the treated group. Subgroup analysis suggested that patients with high prestudy disease activity had a pronounced effect from treatment.118–120 Additional analyses indicated that treatment with interferon beta-1b had also a significant positive effect on patients’ healthrelated quality of life.121 MRI results from the trial showed that interferon beta-1b did not significantly prevent cerebral atrophy, but it reduced the development of T1-hypointense lesions.44,77 In the SP Efficacy Trial of Rebif (interferon beta-1a) in MS (SPECTRIMS), 618 patients received interferon beta-1a (22 µg or 44 µg) or placebo subcutaneously three times per week for 3 years.122 The primary outcome, time to confirmed progression in disability, was not significantly affected by active treatment. However, the relapse rate was significantly reduced by active treatment. Significant effects were also seen on other exacerbation-related outcomes and on a composite measure incorporating five separate clinical and MRI outcomes. The hazard ratio for time to progression for the combined interferon beta-1a groups compared with placebo was 0·74 in patients with prestudy relapses (p=0·055) and 1·01 for those without (p=0·934). Exploratory post-hoc analyses suggested greater benefit in women and in patients who had reported more than one relapse in the 2 years before the study. However, the latter effect did not achieve statistical significance. Interferon beta-1a treatment significantly reduced the median numbers of active lesions per patient per scan and the accumulation of T2 lesion load.75 In the North American Study of interferon beta-1b in secondary progressive MS (NASPMS),123 939 patients were randomly assigned placebo, an interferon beta1b dose of 8 million IU, or an interferon beta-1b dose adjusted for bodyweight and size (5 million IU/m²). Each treatment was administered every other day. The primary endpoint was time to confirmed progression of disability defined as an EDSS increase sustained for 6 months or more. This study was stopped early because of a lack of efficacy. However, the relapse rate was significantly lower for patients who received interferon beta than for those receiving placebo, and total T2 lesion volume increased by 11% in the placebo group compared with only 0·4% for the 8 million IU group and 0·8% for the 5 million IU/m² group. The number of new gadolinium-enhancing lesions was reduced by 64% and 76% in the two active treatment groups.123 The effectiveness of interferon beta-1a in the treatment of patients with secondary progressive MS has also been assessed in the International MS SP Avonex Clinical Trial (IMPACT) study.124 This trial included 436 patients, who were randomised to receive interferon beta-1a (60 µg) or http://neurology.thelancet.com Vol 5 April 2006

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Placebo Active drug Double dose

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Figure 5: Percentages of patients with secondary progressive MS who had relapses during treatment with interferon beta or placebo in EUSPMS, SPECTRIMS, NASPMS, and IMPACT trials In all these studies, treatment with interferon beta resulted in significantly lower relapse rate than did placebo.

study results showed no significant effect of treatment on time to EDSS failure, relapse rates, T2-lesion load, or MT MRI outcomes.127,128 Howewer, a significantly lower rate of brain atrophy progression was observed in patients treated with intravenous immunoglobulin than in patients in the placebo group, which could warrant further investigation.128

Immunosuppressive strategies A wide range of immunosuppressants, including methotrexate, cladribine, cyclophosphamide, methylprednisolone, azathioprine, cyclosporine, and mitoxantrone have been used in patients with secondary progressive MS.129 Goodkin and colleagues130 administered methylprednisolone every other month 12·0

10·9

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9·7 MRI T2 lesion load median change in (%)

placebo by weekly intramuscular injection for 2 years. The primary outcome measure was baseline to month 24 change in the MS functional composite (MSFC). At the end of follow-up, the change in median MSFC Z score was reduced by 40·4% in the patients who received interferon beta-1a compared with those treated with placebo (p=0·033). Active treatment had no significant effect on EDSS, but patients treated with interferon beta1a did have 33% fewer relapses (p=0·008), and there was a significant benefit of active treatment on eight of 11 MS quality-of-life inventory subscales. New or enlarging T2hyperintense lesions and gadolinium-enhancing lesions were significantly reduced at months 12 and 24 in patients who received inteferon beta-1a. Among these studies, the EUSPMS was the only trial to show a significant positive effect of treatment on the accumulation of irreversible disability as measured by EDSS. However, the results from all these studies indicated significant positive effects of treatment on relapse rate (figure 5), increase in T2-lesion load (figure 6), and MRI measures of MS activity. The differences among these studies are not readily explained by methodological considerations, but they could be due, at least in part, to the different patient populations included. This discrepancy is indicated by the fact that placebo patients in the NASPMS study progressed less than both placebo and active treatment groups in the EUSPMS study, although the inclusion criteria were nearly identical. Indeed, in the NASPMS trial, patients had to deteriorate as the result of a gradual progression and those with disability accrual after a relapse were not eligible, whereas, in the EUSPMS trial, patients could also be enrolled when the prestudy EDSS deterioration was due to incomplete recovery from a relapse. This difference could have led to the selection of different groups of patients in these two trials, with those participating into the EUSPMS who were closer to the relapsing remitting phase of MS and those enrolled into the NASPMS who were probably further on in the course of the disease. A combined analysis of EUSPMS and NASPMS showed that relapse activity and greaterthan-average EDSS progression in the 2 years preceding inclusion might be the most robust predictors of a positive response to treatment.120 However, a longitudinal study125 of 21 patients with secondary progressive MS showed that the discontinuation of interferon beta-1a treatment could be associated with an increase in neurological disability and brain MRI lesion load after a year.

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There is substantial evidence that treatment with intravenous immunoglobulins has positive effects in a wide range of diseases, and a meta-analysis lends support to its efficacy in the treatment of relapsing remitting MS.126 The efficacy of intravenous immunoglobulin (1 g/kg administered every 4 weeks for 26 months) was assessed in 318 patients with clinically active secondary progressive MS during the preceeding 2 years.127 The

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Figure 6: Percent changes in T2 lesion load in patients treated with interferon beta or placebo in EUSPMS, SPECTRIMS, and NASPMS trials Lesion burden remained stable or decreased in patients who received interferon beta and increased by about 10% in those treated with placebo (PL).

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for up to 2 years to 108 patients with secondary progressive MS. The study results indicated that treatment with high-dose methylprednisolone might have a modest benefit in delaying time to onset of sustained progression of disability. Methotrexate and cyclophosphamide have also been reported to be effective in stabilising disease in some studies, including patients with chronic progressive MS, but this effect has not been confirmed in other studies.130–135 The results of recent controlled and uncontrolled trials of cyclophosphamide136–138 have, however, reported a strong effect in patients with secondary progressive MS with poor response to other disease-modifying treatments. Cladribine, an antineoplastic drug approved for the treatment of hairy-cell leukemia, did not show any clinical benefit in a phase III trial of progressive MS.74 In this cohort, cladribine had a significant effect in reducing MRI activity and T2-lesion volume increase, but not in preventing brain atrophy progression and T1-hypointense lesion load increase.78 Mitoxantrone is a synthetic anthracenedione chemotherapeutic agent with broad immunosuppressive and cytotoxic activity. The Mitoxantrone in MS Study (MIMS) included 194 patients with worsening relapsing remitting or secondary progressive MS.139 These patients were assigned treatment with placebo or mitoxantrone (5 mg/m² or 12 mg/m²), given every 3 months for 2 years. The primary endpoint was a composite of five clinical measures: changes from baseline in EDSS, ambulation index, and standard neurological status; number of relapses treated with corticosteroids; and time to first treated relapse. At 24 months, patients treated with mitoxantrone had significant benefit over the placebo group for the primary outcome, but this effect was reported in the total group and not specifically in those patients with secondary progressive MS. However, in the same trial, mitoxantrone treatment did not show significant efficacy on the primary MRI outcome measure—ie, the frequency of active MRI scans at 12 and 24 month assessments.140 Major toxic effects could significantly restrict the use of non-selective immunosuppression to treat patients with secondary progressive MS. Toxic effects of long-term, low-dose methotrexate treatment include interstitial pulmonary fibrosis, hepatotoxicity, bone marrow suppression, spontaneous abortions, and teratogenesis.129 The modest clinical benefits achieved with cyclophosphamide must be weighed against sideeffects, such as haemorrhagic cystitis, nausea, vomiting, alopecia, and infertility.129 The use of cyclophosphamide has also been associated with the development of secondary malignancies.129 Although the results of MIMS indicated good tolerability for mitoxantrone, safety data from other studies suggest that use of the drug could result in bone-marrow suppression, doserelated cardiotoxicity indicated by reduced left ventricular ejection fraction, and irreversible congestive heart failure. 350

Because of this potential cardiotoxicity, treatment with mitoxantrone has to be restricted to a cumulative lifetime dose of 140 mg/m².129 A humanised antileucocyte monoclonal antibody, alemtuzumab, which causes prolonged T-lymphocyte depletion, has also been used as immunosuppressive treatment in secondary progressive MS.141–143 Treatmentrelated adverse events included an acute cytokine release syndrome, associated with the transient exacerbation of neurological symptoms, and, in about 30% of patients, the occurrence of Graves disease. After a single course of alemtuzumab 100 mg given intravenously, a significant reduction of the relapse rate and a suppression of conventional MRI activity were noted in 36 patients with secondary progressive MS who were followed-up for more than 8 years. Unfortunately, these patients continued to show a sustained accumulation of disability due to uncontrolled progression, marked by unrelenting cerebral atrophy on follow-up MRI scans.143 The rate of brain volume reduction was greatest in patients with secondary progressive MS who had the highest inflammatory lesion burden before treatment.141,143 Intense immunosuppression followed by autologous haemopoietic stem-cell transplantation (ASCT) is a relatively new therapeutic strategy for MS. Mancardi and colleagues75 used ASCT in ten patients with rapidly evolving secondary progressive MS who were transplanted with unmanipulated autologous peripheral blood stem cells mobilised with high-dose cyclophosphamide and granulocyte-colony-stimulating factor after a BEAM conditioning regimen (carmustine, etoposide, cytarabine, and melphalan). Triple-dose gadolinium-enhanced scans were undertaken monthly for a pretreatment period of 3 months, for the following 6 months, and then once every 3 months. These patients were followed up for an average of 15 months. The number of gadolinium-enhancing lesions decreased immediately after mobilisation with cyclophosphamide and dropped to zero in all cases after the conditioning regimen. Clinically, patients improved slightly or remained stable. However, the progression rate of brain atrophy after treatment remained significant.75 These results are consistent with those from a large retrospective analysis of patients with progressive MS who were treated with ASCT.144 In the latter series, 66% of 60 patients with secondary progressive MS had no disease progression over 3 years of follow-up. Although these positive results warrant further prospective study of ASCT in patients with secondary progressive MS, the short-term and long-term toxic effects associated with such treatment, including a reported mortality of about 5%, remain an important concern. In summary, the observed failures of immunosuppressive treatments suggest that once the cascade of events leading to neuronal and axonal loss is established, even an effective suppression of inflammation does not protect from clinical disease progression in secondary progressive MS. http://neurology.thelancet.com Vol 5 April 2006

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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 the Review.

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 disability suggests that, in secondary progressive MS, inflammation does play a minor part in driving the dysfunction and progressive loss of neurons and axons. Quantitative MRI-derived parameters are more sensitive to the progression of MS tissue degeneration than the conventional measures of lesion burden and activity; thus, their use is warranted to monitor natural history studies and therapeutic trials of secondary progressive MS. However, no established clinical or paraclinical predictors of the future transition from relapsing remitting to secondary progressive MS have been described yet. The development of treatments that promote neuroaxonal repair and remyelination remains, therefore, an important goal to enable the work-up of patients with secondary progressive MS in the near future. Acknowledgments LK’s work is supported by the Swiss MS Society. No funding was received to write this review. Authors’ contributions MR and MF wrote the introduction, neuroimaging, and conclusion sections. CC wrote the clinical aspects section. RF wrote the immunopathology section. LK wrote the treatment section. GC contributed to the preparation of the neuroimaging and treatment sections. MR and MF merged and integrated the individual co-authors’ contributions. All the authors reviewed and discussed the whole paper. We confirm that this review is solely the work of the authors listed, that all contributors to it are listed as authors and that none of the authors were asked to write, to be named on, or to submit the paper by any organisation. Conflicts of interest MR has received honoraria for lectures and travel expense refunds from Teva, Serono, and Biogen-Dompè. CC has been acting as an external expert and has given lectures at the request of Biogen-Idec, Sanofi-Aventis, Schering, Serono, and Teva laboratories. RF has received honoraria for lectures and travel expense refunds from Serono and Biogen-Dompé. LK has participated and is currently participating

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as principal investigator, member, or chair of planning and steering committees or advisory boards in corporate-sponsored clinical trials in MS. The sponsoring pharmaceutical companies for these trials include Abbott, Bayer, Bayhill, Berlex, Biogen Idec, Centocor, Eisai, Elan, Genzyme, Neurocrine, Novartis, Sanofi Aventis, Schering, Serono, Roches, Teva, and Wyeth. LK has also lectured at medical conferences or in public on various aspects of the diagnosis and management of MS. In many cases these talks have been sponsored by non-restricted educational grants from one or another of the above listed companies. Honoraria and other payments for these activities have been exclusively used for funding of research at LK’s department. Research and the clinical operations (nursing and patient care services) of the MS Center led by LK have been supported by non-restricted grants from one or more of these companies. GC and MF have received honoraria for lectures and travel expense refunds, as well as consulting fees as investigators in previous and on-going treatment trials from Teva, Serono, Schering, and Biogen-Dompè. References 1 Schumacher GA, Beebe G, Kibler RF, et al. Problems of experimental trials of therapy in MS: report by the panel on the evaluation of experimental trials of therapy in MS. Ann N Y Acad Sci 1965; 122: 552–68. 2 Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–31. 3 Confavreux C, Compston DAS, Hommes OR, et al. EDMUS, a European Database for Multiple Sclerosis. J Neurol Neurosurg Psychiatry 1992; 55: 671–76. 4 Thompson AJ, Polman CH, Miller DH, et al. Primary progressive multiple sclerosis. Brain 1997; 120: 1085–96. 5 McDonald WI, Compston A, Edan G et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–27. 6 Lublin FD, Reingold SC, for the National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46: 907–11. 7 Confavreux C, Compston DAS. The natural history of multiple sclerosis. In: Compston DAS, ed. McAlpine’s multiple sclerosis, 4th edn. London: Churchill-Livingstone, 2005. 8 McAlpine D, Compston ND. Some aspects of the natural history of disseminated sclerosis: incidence, course and prognosis, factors affecting onset and course. Q J Med 1952; 21: 135–67. 9 Confavreux C. L’histoire naturelle de la sclérose en plaques: etude par informatique de 349 observations. Lyon, France: Thèse de Médecine, Université Claude Bernard–Lyon, 1977. 10 Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980; 103: 281–300. 11 Vukusic S, Confavreux C. Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis. J Neurol Sci 2003; 206: 135–37. 12 Broman T, Andersen O, Bergmann L. Clinical studies on multiple sclerosis I: presentation of an incidence material from Gothenburg. Acta Neurol Scand 1981; 63: 6–33. 13 Eriksson M, Andersen O, Runmarker B. Long-term tollow-up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler 2003; 9: 260–74. 14 Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study I: clinical course and disability. Brain 1989; 112: 133–46. 15 Amato MP, Ponziani G. A prospective study on the prognosis of multiple sclerosis. Neurol Sci 2000; 21 (suppl 2): 831–38. 16 Myhr KM, Riise T, Vedeler C, et al. Disability an prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Scler 2001; 7: 59–65. 17 Müller R. Studies on disseminated sclerosis: with special reference to symptomatology, course and prognosis. Acta Med Scand 1949; 133 (suppl 222): 1–214.

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