The natural history of multiple sclerosis:
a geographically based study
9: Observations on the progressive
phase of the disease
Brain (2006), 129, 584–594
M. Kremenchutzky,1G. P. A. Rice,1J. Baskerville,1D. M. Wingerchuk2and G. C. Ebers3
1Department of Clinical Neurological Sciences, University of Western Ontario London, Ontario, Canada,
2Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA and3Department of Clinical Neurology,
University of Oxford, Oxford, UK
Correspondence and reprint requests to: Professor G. C. Ebers, Department of Clinical Neurology, University of Oxford,
Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK
long-term outcome remains uncertain. We have analysed these clinical features within a well-studied natural
clinical onset of progression. However, there are circumstances where onset of progression is early, relatively
(i) cases of primary progressive (PP) disease, (ii) attack-onset disease where only a single attack has occurred
before onset of progression (SAP) and (iii) secondary progressive (SP) disease where recovery from relapses
at its onset, there was no difference in time to DSS 6, 8 and 10. These findings demonstrate that the progressive
course is independent of relapses either preceding the onset of relapse-free progression or subsequent to it.
Among SAP patients, the degree of recovery from the single defining exacerbation had no significant effect on
outcome. The site of the original attack was not usually where progression began. The relatively stereotyped
susceptibility to a process that appears degenerative in nature. The highly prevalent distal corticospinal tract
dysfunction in progressive disease and the pathologically demonstrated selective axonal loss seen in this tract
Despite considerable individual variation, the progressive course of disability seen in groups of PP, SAP and SP-
multiple sclerosis. The possibility that this is the primary process in some cases must be considered.
Keywords: multiple sclerosis; natural history; progressive clinical course
Abbreviations: DSS = Disability Status Scale; PP = primary progressive; RR = relapsing–remitting; SP = secondary
progressive; SAP = single-attack progressive
Received October 19, 2005. Revised November 15, 2005. Accepted November 15, 2005; Advance Access publication January 9, 2006
Multiple sclerosis is often divided into relapsing–remitting
(RR), secondary progressive (SP) and primary progressive
(PP) forms. These terms are only clinical descriptors and it
remains uncertain whether they serve to distinguish among
potentially different disease mechanisms. In the case of SP
multiple sclerosis, a progressive phase follows an exacerbating
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and remitting course in the same individual by consensus
definition (Lublin and Reingold, 1996). This occurs in
some80% of relapsingpatients
(Weinshenker et al., 1989a), and few clinically recognized
multiple sclerosis patients escape this evolution if they survive
long enough. However, those who have relapses only and
those with progression only serve as anchor points for further
study of the relationships between relapse and progression.
The relationships are especially important since the develop-
ment of progression is the key determinant of prognosis yet
relapses are what can be partially suppressed with currently
Mechanisms related to exacerbation, recovery and remis-
sion probably differ from those associated with unremitting
progression. This duality has long been considered and has
recently been supported by an apparent dissociation between
the effects of therapies on relapse frequency or MRI activity
versus effects on delaying progression. This has been striking
in several double-blind multi-centre trials, probably first seen
in the type 1 interferon studies (INFB multiple sclerosis Study
Group 1995; Jacobs et al., 1996; European Study Group, 1998;
PRISMS Study Group, 1998), and more clearly in the studies
of Campath (Moreau et al., 1994; Coles et al., 1998, 1999) and
cladribine (Rice et al., 1997, 2000). In the cladribine trial of
over 150 progressive patients, prolonged suppression of lym-
phocyte counts to levels seen in symptomatic HIV infection
was produced in the treated group. Although there was
prominent reduction of relapse frequency and MRI activity,
progression continued as in untreated patients (Rice et al.,
2000). Dissociation between progression on one hand and
both relapses and MRI activity on the other has also been
reported in studies of sulphasalazine (Noseworthy et al.,
1998), glatiramer acetate (Bornstein et al., 1991; Johnson
et al., 1995) and anti-CD4 antibodies (van Oosten et al.,
1996). The dissociation in some of these studies has become
increasingly apparent with time (Rice et al., 2001).
The relationship between relapse and progression is often
confounded in the short term as disability data can be con-
taminated by relapses. This is especially problematic in treat-
ment trials of relapsing–remitting disease. Here few studies
remain intact past 24 months and definitions for progression
have been shown to be unstable. Recent analyses of published
trials have demonstrated heavy contamination of disability
scores by recoverable relapse related influences (Rudick et al.,
1998). We have found it difficult to be confident of unremit-
ting changes in disability scores with less than a year of
confirmation. Certainly, the availability of relapse prevention
therapy has placed the relationship between relapses and
progressive disability in focus.
It might be expected a priori that relapse frequency and
of progression of unremitting disability. Indeed they were
associated in our studies of the early clinical course
(Weinshenker et al., 1991a) but only in the first 2 years.
The great majority of this effect came in the first year.
Although there are some patients in whom recovery from
initial or subsequent exacerbations does not occur, this
ordinarily cannot be determined with confidence with less
than a year of follow-up. Where recovery has not occurred
in this time period, the contribution to disability is unambig-
uous and most clearly seen in the Devic’s phenotype
(Wingerchuk et al., 1999). However, it is well recognized
that regardless of lesion location, the great majority of initial
attacks are associated with full or partial recovery. In patients
who may have begun to progress and continue to relapse, the
progression of disability is not discretely attributable either
to lack of recovery from the relapse or to the underlying
progression. The differentiation between the relative impact
of relapse and progression on disability is especially clear in
those cases in which attacks and progression are separated
by sufficient time such that destined recovery has occurred
prior to the onset of progression. If the early phase of
progression is uncontaminated by relapse, a clearer picture
of progression onset is possible. Both of these features
characterize patients whom we have termed single-attack
progressive (SAP). This patient group serves to usefully
isolate the characteristics of attack, recovery and later
We report here a detailed longitudinal study of the pro-
gressive course in several population-based series of patients
with progressive disease. These include 140 SAP patients
derived from two consecutive natural history cohorts of
1043 and 1059 multiple sclerosis patients. In an effort to
answer questions aimed at understanding the relationship
between exacerbations, progression and long-term disability,
long-term outcome in SAP was compared with SP and PP
multiple sclerosis where relapses are common or largely
The following hypotheses were posed:
(i) When only the original exacerbation is examined,
incomplete or lack of recovery in SAP patients will
shortenthetime toonsetofprogressivedeficit. Complete
recovery from the original attack (OA) is a positive
(ii) Latency to onset of progression is greater in SAP than in
those whose progressive phase begins following multiple
(iii) The rate of progression from onset of the progressive
phase in SAP, PP and SP will be closely similar, in
cases where onset of progression is relatively discrete
[e.g. Disability Status Scale 2 (DSS2)]. If progression
begins, it is a phenomenon that is independent of
relapses, implying that the key target in multiple sclerosis
should be the delay in onset or prevention of the pro-
(iv) Progression does not begin at a ‘locus minoris
resistentiae’ at the site of the OA. Progression evolves
gradually and encompasses a bilateral ascending focal
loss of motor corticospinal tract functions as a stereo-
typed and cardinal feature.
Multiple sclerosis: the progressive phaseBrain (2006), 129, 584–594585
by guest on December 26, 2015
McAlpine D. Course and prognosis of multiple sclerosis. In: McAlpine D,
Compston ND, Lumsden CE, editors. Multiple sclerosis. Edinburgh: ENS
Livingstone, 1955; 147.
Moreau T, Thorpe J, Miller D, Moseley I, Hale G, Waldmann H, et al.
Preliminary evidence from magnetic resonance imaging for reduction in
disease activity after lymphocyte depletion in multiple sclerosis. Lancet
1994; 344: 298–301.
Noseworthy JH, O’Brien P, Erickson BJ, Lee D, Sneve D, Ebers GC, et al. The
Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple
sclerosis. Neurology 1998; 51: 1342–52.
Noseworthy JH, Vandervoort MK, Hopkins M, Ebers GC. A referendum on
clinicaltrial researchinmultiple sclerosis:theopinionoftheparticipantsat
the Jekyll Island Conference. Neurology 1989; 39: 977–81.
Patzold U, Pocklington PR. Course of multiple sclerosis. First results of a
prospective study carried out of 102 multiple sclerosis patients from
1976–1980. Acta Neurol Scand 1982; 65: 248–66.
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al.
New diagnostic criteria for multiple sclerosis: guidelines for research pro-
tocols. Ann Neurol 1983; 13: 227–31.
PRISMS Study Group. Randomised double-blind placebo-controlled
study of interferon beta-1a in relapsing/remitting multiple sclerosis.
PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Sub-
cutaneously in Multiple Sclerosis) Study Group. Lancet 1998; 352:
Rice GPA, Cladribine Study Group. Cladribine and chronic progressive
multiple sclerosis: the results of a multicenter trial. Neurology 1997; 48:
prevent the progression of the disease? Arch Neurol 1998; 55: 1578–80.
Rice GPA, Filippi M, Comi G. Cladribine and progressive multiple sclerosis:
clinical and MRI outcomes of a multicenter controlled trial. Cladribine
MRI Study Group. Neurology 2000; 54: 1145–55.
Rice GPA, Lesaux J, Ebers GC, Kremenchutzky M, Karlik S. Long-term
safety, compliance and evolution of neutralizing antibodies in multiple
sclerosis patients treated with interferon beta 1b. Mult Scler 2001; 7: S54.
Rudick RA, Goodkin DE, Jacobs LD, Cookfair DL, Herndon RM, Richert JR,
et al. Impact of interferon beta-1a on neurological disability in relapsing
multiple sclerosis. Neurology 1997: 49: 358–63.
cohort with twenty-five years of follow-up. Brain 1993; 116: 117–34.
Schumacher GA, Beebe G, Kibler R, Kurland L, Kurtzke J, McDowell F, et al.
Problems of experimental trials of therapy in multiple sclerosis. Report by
the panel on evaluation of experimental trials of therapy in multiple sclero-
sis. Ann N Y Acad Sci 1965; 122: 552–68.
Serdaroglu P. Behcet’s disease and the nervous system. J Neurol 1998; 245:
Swanbeck G, Inerot A, Martinsson T, Wahlstrom J, Enerback C, Enlund F,
et al. Age at onset and different types of psoriasis. Br J Dermatol 1995; 133:
Thompson AJ, Polman CH, Miller DH, McDonald WI, Brochet B, Filippi M,
et al. Primary progressive multiple sclerosis. Brain 1997; 120: 1085–96.
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal
transaction in the lesions of multiple sclerosis. N Engl J Med 1998; 338:
Trojano M, Liguori M, Bosco Zimatore G, Bugarini R, Avolio C, et al.
Age-related disability in multiple sclerosis. Ann Neurol 2002; 51:
A phase II trial of anti-CD4 antibodies in the treatment of multiple sclero-
sis. Mult Scler 1996; 1: 339–42.
IgG synthesis as prognostic features in multiple sclerosis. Part I. J Neurol
1983; 229: 155–65.
Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J,
et al. The naturalhistory of multiple sclerosis: a geographically based study.
I. Clinical course and disability. Brain 1989a; 112: 133–46.
Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J,
et al. The natural history of multiple sclerosis: a geographically based
study. 2. Predictive value of the early clinical course. Brain 1989b; 112:
Weinshenker BG, Rice GP, Noseworthy JH, Carriere W, Baskerville J,
Ebers GC. The natural history of multiple sclerosis: a geographically
based study. 3. Multivariate analysis of predictive factors and models of
outcome. Brain 1991a; 114: 1045–56.
Weinshenker BG, Rice GP, Noseworthy JH, Carriere W, Baskerville J, Ebers
GC. The natural history of multiple sclerosis: a geographically based study.
4. Applications to planning and interpretation of clinical therapeutic trials.
Brain 1991b; 114: 1057–67.
Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The
clinical course of neuromyelitis optica (Devic’s syndrome). Neurology
1999; 53: 1107–14.
Appendix A Comparison of symptoms at onset of
disease for SAP and total population of multiple sclerosis
n = 71
n = 219
n = 1043
n = 8842
Visual–optic nerve 0.22
Appendix B DSS level for onset of progressive phase
for SP- and SAP-multiple sclerosis (multiple sclerosis)
n = 435*
n = 66**
*SP: data available for 435/480 cases. **SAP: data available for 66/71
594 Brain (2006), 129, 584–594M. Kremenchutzky et al.
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