Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 153-155, 15 February 2003

Primary and secondary progressive multiple sclerosis

European Database for Multiple Sclerosis (EDMUS) Coordinating Center and Service de Neurologie A, Hôpital Neurologique, Hospices Civils de Lyon, 59 Boulevard Pinel, Lyons Cedex 03, 69394, France

Article Outline

Abstract 

The progressive phase of multiple sclerosis (MS) is the one most often associated with irreversible accumulation of disability. An important question remains about the place of primary progressive MS (PP-MS): does it form an integral part of the disease spectrum, or is it maybe a distinct entity? This question could apparently be very theoretical, but it is not, as patients with PP-MS remain orphans when regarding disease-modifying treatments. Thus, they are usually excluded from therapeutic trials. A clue to this question could be the comparison between the different MS subtypes with a progressive phase. We discuss here the clinical similarities and differences between secondary and primary progressive MS.

Keywords:  Multiple sclerosis, Primary and secondary progressive, Relapsing–remitting

 

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1. Introduction 

The progressive phase of multiple sclerosis (MS) is the one most often associated with irreversible accumulation of disability. In 1996, Lublin and Reingold [1] suggested a classification of disease course, defining four categories, three of which having a progressive period. The most consensual one is the secondary progressive group (SP-MS): it has been defined as “an initial relapsing–remitting course, followed by progression, with or without occasional relapses, minor remissions and plateaus”. SP-MS is considered to be the natural evolution of the relapsing–remitting MS (RR-MS), with about 90% of the initial RR-MS becoming SP-MS after a 26-year follow-up [2]. Primary progressive MS (PP-MS) is defined as “a disease progression from onset, with occasional plateaus and temporary minor improvements allowed, but not distinct relapses”. Progressive relapsing MS (PR-MS) is a disease that is progressive from onset, with superimposed relapses and continuing progression between relapses. An important question remains about the place of primary progressive MS: does it form an integral part of the disease spectrum, or is it maybe a distinct entity [3], [4], [5], [6], [7], [8], [9], [10]? This question could apparently be very theoretical, but it is not, as patients with PP-MS remain orphans when regarding disease-modifying treatments. Thus, they are usually excluded from therapeutic trials. A clue to this question could be the comparison between the different MS subtypes with a progressive phase.

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2. Clinical data 

At first sight, SP-MS and PP-MS seem to be very different. Age at MS onset is the same in SP-MS as in RR-MS, about 30 years, significantly lower than in PP-MS, which usually starts later, at about 40 years [2], [7], [8], [11], [12], [13], [14], [15], [16]. Two-thirds of the patients with SP-MS are female, in agreement with other autoimmune diseases. This difference tends to be smaller in PP-MS, with sex ratio being 1/1. Some authors even reported a male preponderance [17].

Symptoms at onset are also very different. PP-MS most often presents with a spastic paraparesia, a cerebellar syndrome, and less often a hemiparesia. Brainstem involvement, visual or sensory symptoms, which are very frequent in relapsing onsets, are rare in PP-MS. It is now well known that a progressive onset is associated with a worse disease course and a shorter time to disability. In the study by Confavreux et al. [11], the mean interval between MS onset and severe disability was 5.8 years in progressive onset patients, versus 11.4 years in relapsing–remitting onset patients. This difference was confirmed by Weinshenker et al. [2]. He evaluated the median time from MS onset to selected levels of disability, DSS 3, DSS 6 and DSS 8, and found, respectively, 7.7, 15 and 46.4 years in the whole population, versus 1.4, 4.5 and 24.1 years in the progressive onset group. Progressive versus relapsing–remitting onset is thus considered to be one of the strongest predictive factors in MS. However, other features tend to demonstrate that PP and SP-MS are not so different. If age at MS onset is significantly different in the two groups, age at onset of progression is by contrast very similar in the few studies that have addressed this issue [18]. Even though PP-MS is frequently considered to be a spinal cord disease, and SP-MS a more disseminated disease, involving both brain and spinal cord, a recent study of neuropsychological deficits in SP- and PP-MS matched for physical disability did not find significant differences in cognitive impairment between the two groups [19]. They also underlined the fact that the severity of cognitive impairment cannot be explained by the extent of T2 MRI abnormalities only. The London, Ontario group recently reevaluated data on progressive onset patients [20]. From clinical onset of the disease, they confirmed that the disability progression was faster in PP-MS than in SP-MS, but SP-MS evolved more rapidly when the same computations were done from the onset of the progressive phase. Our group [21] also compared the evolution of irreversible disability in relapsing–remitting versus progressive onset patients by the survival techniques. Median times from MS onset to DSS 4, DSS 6 and DSS 7 were significantly different in the two groups, with a worse outcome for the progressive ones. However, when calculating from onset of irreversible disability, there was no more difference between the two groups, as if accumulation of disability was evolving independently from possible previous relapses. One of the arguments to consider that PP-MS is a distinct entity is that there is no relapse during its evolution. Three recent studies have now shown that there is no difference in the evolution of disability in patients with or without superimposed relapses during the progressive phase of the disease. In the London cohort, Cottrel et al. [20] and Kremenchutzky et al. [22] found that 28% of the PP-MS group experienced a distinct relapse even decades after the onset. They compared time from MS onset to DSS 3, 6 and 8 in PP- and PR-MS and found no difference. Andersson et al. [3] and Confavreux et al. [21] confirmed this result in San Francisco, USA and Lyons, France. These results were confirmed in the secondary progressive patients with and without superimposed relapses [21]. Another MS subtype can be underlined. Some authors have distinguished transitional MS (TP-MS) as a small group of patients with a unique relapse, followed several years later by a progressive phase. The place of TP-MS in the clinical classification has also been discussed. Gayou et al. [18] compared TP-MS to other MS subtypes. Clinical evolution was similar with SP-MS, with the same age and symptoms at onset. Age at onset of the progressive phase was the same for TP-, SP- and PP-MS. There was no significant difference in conventional MRI between the three groups, but TP-MS tends to resemble PP-MS. These results were confirmed by a European multicentric study [13]. The percentage of patients with new lesions at 1 year, as well as the T2 lesion load, was similar for the three groups. An increase in T1 lesion load and atrophy, and spinal cord lesions, was found only in PP-MS. The authors concluded that TP-MS lied between SP- and PP-MS, with a kind of continuum in their spectrum.

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3. Conventional MRI data 

Several studies have shown that clinical subtypes of MS differ regarding MRI. Lycklama à Nyjeholdt [23] compared MRI finding in 28 RR-MS, 32 SP-MS and 31 PP-MS patients. He could distinguish some particularities for each subtype. RR-MS was characterized by the presence of active lesions and a high number of Gadolinium enhancing lesions. SP-MS has large, confluent T2 lesions, a large number of T1 lesions and brain and spinal cord atrophy. In PP-MS, there are few brain lesions, which are small, and diffuse abnormalities in brain and spinal cord. Correlation to disability was poor, and he postulated that disability could be explained more by brain lesions in RR- and SP-MS, and by spinal cord lesions in PP-MS.

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4. Pathological data 

MS is considered to be a primarily inflammatory disease, but the absence of relapses, which reflect this inflammation, in PP-MS raised the question of its place in the MS spectrum. The principal question was then to know if inflammation was present or not in lesions of PP-MS. Revesz [6] performed 45 autopsies in SP- and PP-MS that were at a high level of disability at the time of their death. He found that there are inflammatory lesions in PP-MS, but the number of inflammatory cells in perivascular cuffs and in lesions is smaller in PP- than in SP-MS, and concluded that “the observation of inflammation in PP-MS as well as SP-MS provided future evidence for similarity in the pathological process in the two forms of the disease”.

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5. Conclusion 

If previous clinical data seemed to distinguish PP-MS from other MS subtypes, recent epidemiological data tend to demonstrate that the evolution of the progressive phase is very similar whatever the course at onset, relapsing–remitting or progressive. Furthermore, when the Lublin and Reingold classification [1] separates progression with or without superimposed relapses, it seems today that they could be considered as the same subtype at the clinical level. However, concerning treatments, patients with relapses during the progressive phase could possibly benefit from disease-modifying treatments that are more anti-inflammatory, in contrast with patients without relapses that may not, as it has been the case with studies of interferon B-1b. Similarities between SP- and PP-MS could also lead to propose similar treatments in the two groups. Regarding these new data, maybe it is time to propose a new and simple classification in three subtypes (relapsing–remitting, secondary progressive and progressive from onset), without a cut between those with or without superimposed relapses.

MRI and pathological data show more differences than similarities between SP- and PP-MS, but these differences are not inconsistent with the different levels of the same disease.

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References 

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PII: S0022-510X(02)00427-6

Journal of the Neurological Sciences
Volume 206, Issue 2 , Pages 153-155, 15 February 2003

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