Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Feb;19(2):188-98.
doi: 10.1177/1352458512451510. Epub 2012 Jun 26.

Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis

Melih Tutuncu  1 , Junger Tang, Nuhad Abou Zeid, Nilufer Kale, Daniel J Crusan, Elizabeth J Atkinson, Aksel Siva, Sean J Pittock, Istvan Pirko, B Mark Keegan, Claudia F Lucchinetti, John H Noseworthy, Moses Rodriguez, Brian G Weinshenker, Orhun H Kantarci
Affiliations

Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis

Melih Tutuncu et al. Mult Scler. 2013 Feb.

Abstract

Background: It is unclear if all patients with relapsing-remitting multiple sclerosis (RRMS) ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration-dependent. Some forms of progressive MS (e.g. primary progressive MS (PPMS)) are uncommon in population-based studies. Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age at progression onset between secondary progressive MS (SPMS) and PPMS but may introduce unclear biases.

Objective: Our aim is to confirm that onset of progressive disease course is more relevant to the patient's age than the presence or duration of a pre-progression relapsing disease course in MS.

Methods: We studied a population-based MS cohort (n=210, RRMS n=109, progressive MS n=101) and a clinic-based progressive MS cohort (n=754). Progressive course was classified as primary (PPMS; n=322), single attack (SAPMS; n=112) and secondary progressive (SPMS; n=421). We studied demographics (chi(2) or t-test), age-of-progression-onset (t-test) and time to Expanded Disability Status Scale of 6 (EDSS6) (Kaplan-Meier analyses).

Results: Sex ratio (p=0.58), age at progression onset (p=0.37) and time to EDSS6 (p=0.16) did not differ between the cohorts. Progression had developed before age 75 in 99% of patients with known progressive disease course; 38% with RRMS did not develop progression by age 75. Age at progression onset did not differ between SPMS (44.9±9.6), SAPMS (45.5±9.6) and PPMS (45.7±10.8). In either cohort, only 2% of patients had reached EDSS6 before onset of progression.

Conclusions: Patients with RRMS do not inevitably develop a progressive disease course. Onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course. Moderate disability is sustained predominantly after the onset of a progressive disease course in MS.

PubMed Disclaimer

Conflict of interest statement

Disclosures and Conflicts of Interest: The study was approved by the institutional review board of the Mayo Clinic and all patients included in the final study consented to the use of their medical record for research purposes. The authors report no conflict of interest

Figures

Figure-1
Figure-1
Study design, patient populations and final disease course classification. RRMS = relapsing remitting MS, PPMS = primary progressive multiple sclerosis, SPMS = secondary progressive multiple sclerosis, SAPMS = single attack progressive multiple sclerosis. * We included the 28 patients [SPMS (n= 22), SAPMS (n= 5), PPMS (n= 1)] overlapping between the two cohorts only in the population-based cohort. † “Progression” refers to insidious and irreversible worsening brain, brainstem-cerebellar and spinal cord syndromes most commonly characterized by progressive weakness, ataxia or bladder dysfunction of ≥1 year ‡ The term “No progression” refers to patients whose disability derives from incomplete recovery from ongoing relapses alone rather than from insidious accumulation of neurological deficits.
Figure-2
Figure-2
Kaplan-Meier estimates (with life-tables) of time to moderate disability after progression onset are shown for the population-based and clinic-based MS cohorts. All progressive MS patients (a) and bout-onset progressive MS patients (b) are shown separately. “ Progression” refers to insidious and irreversible worsening brain, brainstem-cerebellar and spinal cord syndromes most commonly characterized by progressive weakness, ataxia or bladder dysfunction of ≥1 year. In the population-based cohort from the Olmsted County, MN (n=210), patients with RRMS (n=109) and patients where age at onset of progression was not clear (n=1 SAPMS) were excluded. In the clinic-based referral patients (n=773), patients where pre-progression disease course was not clear (n=19) were excluded. This figure illustrates that for patients with progressive MS, there is no referral bias due to more severe disease after progression onset in the clinic-based cohort compared to the population-based cohort. PPMS = primary progressive multiple sclerosis, SPMS = secondary progressive multiple sclerosis, SAPMS = single attack progressive multiple sclerosis, EDSS6 = expanded disability status scale of 6
Figure-3
Figure-3
Kaplan-Meier estimates (with life-tables) of time to progression (a) and age at progression (b) are shown in the longitudinally followed population-based cohort of patients with MS older than age 18 in Olmsted County, MN (n=210). Patients whose date of onset could not be precisely defined [SPMS (n=4), SAPMS (n=6) and PPMS (n=15)] are excluded from the analyses. Model-1 assumes that some patients with MS will never develop progression and therefore includes only patients with already established SPMS (n=80). Model-2 assumes that patients with MS may at one point develop progression (censored data) and therefore includes patients still with RRMS (n=105) as of their last follow-up together with patients with already established SPMS. Model-3 assumes that all RRMS patients with censored data due to death or last follow-up before 2010 would have converted to SPMS within one year of their last follow-up establishing the upper extreme limit for model-2. Model-4 assumes that all of the RRMS patients who are deceased or lost to follow-up remain RRMS as of 2010 establishing the lower-extreme limit for Model-2. These models predict that that not all patients with MS develop progression despite sufficient follow-up. “ Progression” refers to insidious and irreversible worsening brain, brainstem-cerebellar and spinal cord syndromes most commonly characterized by progressive weakness, ataxia or bladder dysfunction of ≥1 year PPMS = primary progressive multiple sclerosis, SAPMS = single attack progressive multiple sclerosis, SPMS = secondary progressive multiple sclerosis, RRMS = relapsing-remitting multiple sclerosis
Figure-4
Figure-4
Age at developing first clinical symptoms MS (a) and age at reaching progression (b) curves, along with life-table analyses and mean (± standard deviation) values are shown for SPMS versus SAPMS versus PPMS. All patients with progressive MS from both cohorts are included in the analyses. In the population-based cohort from the Olmsted County, MN (n=210), we excluded patients with RRMS (n=109) and patients whose age at onset of progression was not clear (n=1 SAPMS). In the clinic-based referral patients (n=773), we excluded patients where presence or absence of pre-progression relapses were not well documented (n=19). Age at progressiondoes not differ according to whether there were preceding relapses, but age at onset of MS, defined either by the first relapse (SPMS and SAPMS) or progression onset (PPMS), is significantly earlier for SPMS compared to SAPMS compared to PPMS. “ Progression” refers to insidious and irreversible worsening brain, brainstem-cerebellar and spinal cord syndromes most commonly characterized by progressive weakness, ataxia or bladder dysfunction of ≥1 year SPMS = secondary progressive multiple sclerosis, SAPMS = single-attack progressive multiple sclerosis, PPMS = primary-progressive multiple sclerosis
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kantarci OH, Weinshenker BG. Natural history of multiple sclerosis. Neurologic Clinics. 2005;23(1):17–38. - PubMed
    1. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129(Pt 3):606–16. - PubMed
    1. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907–11. - PubMed
    1. Wolinsky JS. The diagnosis of primary progressive multiple sclerosis. Journal of the neurological sciences. 2003;206(2):145–52. - PubMed
    1. Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006;129(Pt 3):584–94. - PubMed

Publication types

MeSH terms