Background The influence of the patterns of onset of multiplesclerosis and relapses of the disease on the time course ofirreversible disability is controversial.
Methods In 1844 patients who had had multiple sclerosis fora mean (±SD) of 11±10 years, we determined thetime of the clinical onset of the disease, the initial course(relapsing–remitting or progressive) and the subsequentcourse (relapsing–remitting, secondary progressive, orprimary progressive), the times of relapses, the time to theonset of irreversible disability, and the time course of progressive,irreversible disability. We used three scores on the KurtzkeDisability Status Scale (range, 0 to 10, with higher scoresindicating more severe disability) as measures of the severityand progression of disability: a score of 4 (limited walkingability but able to walk more than 500 m without aid or rest),a score of 6 (ability to walk with unilateral support no morethan 100 m without rest), and a score of 7 (ability to walkno more than 10 m without rest while leaning against a wallor holding onto furniture for support). We used Kaplan–Meieranalyses to determine the influence of relapses on the timeto the onset of irreversible disability.
Results The median times from the onset of multiple sclerosisto the assignment of a score of 4, a score of 6, and a scoreof 7 on the disability scale were longer among the 1562 patientswith a relapsing–remitting onset of disease (11.4, 23.1,and 33.1 years, respectively) than among the 282 patients whohad progressive disease from the onset (0.0, 7.1, and 13.4 years,respectively; P<0.001 for all comparisons). In contrast,the times from the assignment of a score of 4 to a score of6 were similar in the two groups (5.7 and 5.4 years, P=0.74).The time course of progressive, irreversible disease among patientswith the primary progressive type of multiple sclerosis wasnot affected by the presence or absence of superimposed relapses.
Conclusions Among patients with multiple sclerosis, relapsesdo not significantly influence the progression of irreversibledisability. (N Engl J Med 2000; 343:1430-8.)
Multiple sclerosis is the most common chronic disabling diseaseof the central nervous system in young adults. It affects 1in 1000 people in Western countries.1 It is primarily characterizedby multicentric inflammation and demyelination, but the roleof axonal injury and gliosis increases as the disease evolves.2In most patients the disease begins at about 30 years of agewith acute episodes of neurologic dysfunction, followed by periodsof partial or complete remission with clinical stability betweenrelapses — the relapsing–remitting phase of thedisease. Except in patients with the relapsing–remittingtype of multiple sclerosis, this phase is usually followed byprogressive clinical disability, with or without superimposedrelapses and remissions.3,4,5 In a minority of patients, thedisease is progressive from the beginning, although there maybe superimposed relapses and remissions. Therefore, neurologicdisability may result from relapses with incomplete remissions,progression of the disease, or both.
Since 1993, two drugs — interferon beta and glatirameracetate — have been identified as disease-modifying treatments.6,7,8,9,10These drugs reduce the frequency of relapses by about one thirdbut are less effective in slowing the progression of disability.8,9,10The objective of this study was to determine the influence ofacute relapses on the rate of progression of irreversible disabilityin patients with multiple sclerosis.
Methods
Patient Population and Data Collection
Patients were identified through the Lyons multiple sclerosisdata base.3 This computerized surveillance system was establishedin 1976 and includes all patients with a diagnosis of multiplesclerosis who were examined at least once at the Clinique deNeurologie in Lyons, France. This clinic has served as the referralcenter for multiple sclerosis for the city of Lyons and theRhône–Alpes region since 1976. Decisions regardingdiagnostic tests and treatments for individual patients weremade by referring neurologists or neurologists in the clinic,or both, according to accepted guidelines. Relapses were usuallytreated with glucocorticoids. Since the late 1960s, azathioprineand cyclophosphamide have been used to treat multiple sclerosis.Azathioprine is administered mainly during the relapsing–remittingphase of multiple sclerosis and after the third relapse, andit is usually stopped when the disease becomes progressive.Cyclophosphamide therapy is used only in severe cases or duringthe progressive phase of the disease. A single, intense coursemay be given, or long-term treatment may be given, but it usuallylasts no longer than 12 months. Since the early 1990s, methotrexatehas been used, usually for no more than 12 months, in some patientswith the secondary progressive type of multiple sclerosis.
Each case report in the data base includes identifying and demographicdata, medical history, key episodes in the course of the disease(relapses, onset of progressive disease, and onset of irreversible,progressive disability), results of laboratory and electrophysiologictests, neuroimaging data, and treatment. Data are entered retrospectivelywhen the patient is first seen at the clinic and at each follow-upvisit, usually on a yearly basis. Since 1990, data have beenrecorded on the standardized computerized forms designed forthe European Database for Multiple Sclerosis.11 New data areautomatically compared with older information, and any inconsistenciesare identified. The confidentiality of the data is maintainedin accordance with the recommendations of the French CommissionNationale de l'Informatique et des Libertés. All patientsgave informed consent to have their data included in the database.
Definition of Cases
By April 1997, 2021 patients had been included in the data base.Multiple sclerosis was diagnosed according to the classificationof Poser et al.12 This classification scheme relies on threecriteria: dissemination of lesions in time (there must be atleast two distinct neurologic episodes in the course of thedisease); evidence of spatial dissemination of lesions in thecentral nervous system, provided by clinical findings or magneticresonance imaging, computed tomography, or testing of evokedpotentials; and quantitative or qualitative abnormalities ofimmunoglobulins in the cerebrospinal fluid. Cases are consideredclinically definite when the first two criteria are met, regardlessof the results of cerebrospinal fluid tests; laboratory-supporteddefinite cases meet the first and third criteria or the secondand third criteria; clinically probable cases meet the firstcriterion or the second criterion; laboratory-supported probablecases meet the third criterion; and possible cases do not fulfillany of the criteria but are characterized by neurologic abnormalitiesthat are compatible with the diagnosis of multiple sclerosis.
Assessment of Patients
A relapse of multiple sclerosis was defined as the occurrence,the recurrence, or the worsening of symptoms of neurologic dysfunctionthat lasted more than 24 hours and that stabilized or eventuallyresolved either partially or completely. Fatigue alone and transientfever-related worsening of symptoms were not considered relapses.Symptoms that occurred within a month after the initial symptomsof relapse were considered to be part of the same episode.
The onset of progressive disease was defined as a continualworsening of symptoms and signs for a period of at least sixmonths, with or without superimposed relapses.13 Once progressionhas developed, its course is continuous, although occasionalplateaus and temporary minor improvements may occur.5
Neurologic disability was assessed at each visit to the clinicwith use of the Kurtzke Disability Status Scale,14 which isbased on the results of a neurologic examination and the patient'sability to walk. Scores can range from 0 (no neurologic abnormality)to 10 (death from multiple sclerosis). We focused on scoresthat could be easily determined retrospectively: scores of 4(limited walking ability but able to walk without aid or restfor more than 500 m), 6 (ability to walk with unilateral supportno more than 100 m without rest), and 7 (ability to walk nomore than 10 m without rest while leaning against a wall orholding onto furniture for support). Disability was definedas irreversible when a patient had had a given score for atleast six months, excluding any transient worsening of disabilityrelated to relapses.
Statistical Analysis
Survival was estimated according to the Kaplan–Meier method,and the log-rank test was used for univariate analyses. Theend point was the time to irreversible disability, as indicatedby a score of 4, 6, or 7 on the Kurtzke Disability Status Scale.All computations were performed with the use of SPSS softwarefor Windows (version 9.0).15
Results
Characteristics of the Patients
Of the 2021 patients who were potentially eligible for the study,170 were excluded because they had possible cases accordingto the classification of Poser et al.12 and 7 were excludedbecause their initial symptoms were unknown (Figure 1). Thebase-line characteristics of the remaining 1844 patients witha definite or probable diagnosis of multiple sclerosis are givenin Table 1.
Table 1. Base-Line Characteristics of the 1844 Patients with Multiple Sclerosis.
A total of 903 patients (49 percent) had received one or moredrugs for multiple sclerosis. The most widely used treatmentwas azathioprine (given to 820 patients), followed by cyclophosphamide(given to 78), interferon beta (given to 72), methotrexate (givento 60), and mitoxantrone (given to 18). As compared with thepatients who had not received such drugs, the treated patientshad a higher frequency of relapses and a more severe initialcourse of the disease, findings that presumably reflect a selectionbias with respect to the use of drug therapy. Treatment statusdid not affect the results of our analyses. However, it shouldbe noted that the only treatment with proven efficacy is interferonbeta, and the first of these interferons, interferon beta-1b,was not available in our area until February 1996. Moreover,the treatment regimens were heterogeneous, and treatments wereusually given for fairly short periods relative to the overallduration of the disease in a given patient.
Initial Course of Multiple Sclerosis and Time to Onset of Irreversible Disability
A total of 1562 patients (85 percent) had relapsing–remittingdisease initially, whereas 282 patients (15 percent) had progressivedisease. In the entire group of 1844 patients, the median timefrom the onset of multiple sclerosis to the assignment of ascore of 4 on the Kurtzke Disability Status Scale was 8.4 years(95 percent confidence interval, 7.8 to 9.6). The median timefrom onset of multiple sclerosis to the assignment of a scoreof 6 was 20.1 years (95 percent confidence interval, 18.1 to22.5), and the median time from the onset of disease to theassignment of a score of 7 was 29.9 years (95 percent confidenceinterval, 25.1 to 34.5). The median interval from the onsetof disease to the assignment of each of these scores was significantlylonger (P<0.001 for each comparison) in the group of patientswith a relapsing–remitting onset of disease than amongthose who had progressive disease at onset (Table 2 and Figure 2).
Table 2. Kaplan–Meier Estimates of the Median Time from the Onset of Multiple Sclerosis to the Onset of Irreversible Disability among 1844 Patients with Multiple Sclerosis, According to the Initial Course.
Figure 2. Kaplan–Meier Estimates of the Time from the Onset of Multiple Sclerosis to the Assignment of a Score of 4 on the Kurtzke Disability Status Scale (Panel A), the Time from the Assignment of a Score of 4 to a Score of 6 (Panel B), and the Time from the Assignment of a Score of 6 to a Score of 7 (Panel C) among 1844 Patients with Multiple Sclerosis, According to the Initial Course.
Initial Course of Multiple Sclerosis and the Time Course of Progressive, Irreversible Disability
Among the 1844 patients, 1026 patients (56 percent) reachedthe end point of a score of 4 on the Kurtzke Disability StatusScale during follow-up. In this group, the median time fromthe assignment of a score of 4 to the assignment of a scoreof 6 was 5.7 years (95 percent confidence interval, 5.0 to 6.3).The median time from the assignment of a score of 4 to the assignmentof a score of 7 was 12.1 years (95 percent confidence interval,10.3 to 13.9). Similarly, 595 patients (32 percent) reachedthe end point of a score of 6. In this group, the median timefrom the assignment of a score of 6 to the assignment of a scoreof 7 was 3.4 years (95 percent confidence interval, 3.0 to 3.8).The median times required for each of these changes to occurwere similar whether the disease was initially relapsing–remittingor progressive (Table 2 and Figure 2).
Effect of Superimposed Relapses during the Progressive Phase on the Time Course of Progressive, Irreversible Disability
Among patients with the secondary progressive type of multiplesclerosis, the median time from the assignment of a score of4 on the Kurtzke Disability Status Scale to the assignment ofa score of 6 was not influenced by the presence or the absenceof superimposed relapses (Table 3 and Figure 3). In contrast,the median time from the assignment of a score of 4 to a scoreof 7 and from a score of 6 to a score of 7 was longer amongpatients with the secondary progressive type who had superimposedrelapses than among patients with this type of multiple sclerosiswho did not have superimposed relapses (Table 3). Among patientswith the primary progressive type of multiple sclerosis, themedian time from the assignment of a score of 4 to a score of6 or 7 or from a score of 6 to a score of 7 was not influencedby the presence or the absence of superimposed relapses (Table 3and Figure 3).
Table 3. Kaplan–Meier Estimates of the Median Time Course of Progressive, Irreversible Disability among Patients with the Primary or Secondary Type of Progressive Multiple Sclerosis, According to the Presence or Absence of Superimposed Relapses.
Figure 3. Kaplan–Meier Estimates of the Time from the Assignment of a Score of 4 on the Kurtzke Disability Status Scale to the Assignment of a Score of 6 among the 496 Patients with the Secondary Progressive Type of Multiple Sclerosis (Panel A) and the 282 Patients with the Primary Progressive Type of Multiple Sclerosis (Panel B), According to the Presence or Absence of Superimposed Relapses.
Among the 496 patients with the secondary progressive type of multiple sclerosis, only 483 reached the end point of a score of 4 during follow-up. Among the 282 patients with the primary progressive type of multiple sclerosis, 271 reached this end point.
Discussion
In this observational study of the natural history of multiplesclerosis, we found that irreversible disability occurred soonerin patients in whom the disease was progressive from its onsetthan in those in whom the onset was relapsing–remitting.In contrast, once irreversible disability occurred, the timecourse of progressive disability was similar in the two groups.In addition, the time course of progressive, irreversible disabilityamong patients with the primary progressive type of multiplesclerosis was not significantly influenced by the presence orabsence of superimposed relapses. Among patients with the secondarytype of multiple sclerosis (which occurs after a relapsing–remittingphase), the time course of the progressive phase of the diseasewas longer among patients who had superimposed relapses thanamong those who did not have superimposed relapses.
The Lyons multiple sclerosis data base is probably among thelargest and oldest of such registries. Data on patients withmultiple sclerosis who were referred to and subsequently followedin the clinic are entered in the data base by a group of neurologistswho use commonly accepted guidelines and a standardized approach.11In terms of their demographic characteristics, clinical course,and prognosis, our cohort of patients is similar to those inother major published studies.4,16,17
The first validated disease-modifying drug for multiple sclerosis,interferon-beta 1b,6 became available in France in February1996. Approximately half of our patients have received immunosuppressivedrugs — azathioprine, in most cases — for some periodof time; none of these drugs have a commonly recognized specificeffect on the course of multiple sclerosis.18
Our results are in accordance with and extend those of otherlarge studies of the natural history of multiple sclerosis.A group of Canadian researchers showed that, as compared withpatients with the primary progressive type of multiple sclerosis,patients with the secondary progressive type had a slower onsetof disability but a faster progression of the disability.19The same group also showed that the survival curves were almostidentical for patients with the primary progressive type ofmultiple sclerosis who had superimposed relapses and patientswith the primary progressive type who did not have superimposedrelapses with respect to the time from the onset of diseaseto the assignment of a score of 6, a score of 8, and death.20Others have reached similar conclusions with respect to thetime from the onset of primary progressive multiple sclerosisto the assignment of a score of 6.21
Relapses and progression are the two basic clinical phenomenaof multiple sclerosis. Relapses are considered to be the clinicalexpression of acute inflammatory focal lesions disseminatedin the central nervous system, whereas progression is consideredto reflect the occurrence of demyelination, axonal loss, andgliosis. We found that once a clinical threshold of irreversibledisability has been reached (a score of 4 on the Kurtzke DisabilityStatus Scale), the progression of disability is not affectedby relapses, either those that occur before the onset of theprogressive phase or those that supervene during this phase.The absence of a relation between relapses and irreversibledisability suggests that there is a dissociation at the biologiclevel between recurrent acute focal inflammation and progressivedegeneration of the central nervous system. This apparent paradoxis consistent with the persistence of the progression of disabilityin patients with multiple sclerosis despite infection with thehuman immunodeficiency virus22 or despite suppression of thecerebral inflammation after treatment with a potent antileukocytemonoclonal antibody.23 It also suggests that agents that havea short-term effect on relapses in patients with multiple sclerosismay not necessarily delay the development of disability in thelong term.
Supported by contracts with the Commission of the European CommunitiesDirectorate General XII (BMH1-CT93-1529, CIPD-CT94-0227, BMH4-CT96-0064)and by funds from the Ligue Française contre la Scléroseen Plaques.
We are indebted to the patients for their participation in theLyons multiple sclerosis data base; to Mr. Albert Biron formaintaining the data base; to Drs. Marie-Françoise Belin,Patricia Saddier, and Rachid Salmi for helpful discussions aboutthe paper; and to Mrs. Isabelle Pairel for assistance in preparingthe manuscript.
Source Information
From the European Database for Multiple Sclerosis Coordinating Center and Service de Neurologie A, Hôpital Neurologique (C.C., S.V., T.M.); and Unité de Biostatistique et Informatique Médicale, Hospices Civils de Lyon (P.A.) — both in Lyons, France.
Address reprint requests to Dr. Confavreux at the EDMUS Coordinating Center and Service de Neurologie A, Hôpital Neurologique, 59 Blvd. Pinel, 69394 Lyons CEDEX 03, France.
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Olindo, S., Cabre, P., Lezin, A., Merle, H., Saint-Vil, M., Signate, A., Bonnan, M., Chalon, A., Magnani, L., Cesaire, R., Smadja, D.
(2006). Natural History of Human T-Lymphotropic Virus 1-Associated Myelopathy: A 14-Year Follow-up Study. Arch Neurol
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Tremlett, H., Devonshire, V.
(2006). Is late-onset multiple sclerosis associated with a worse outcome?. Neurology
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Young, P. J., Lederer, C., Eder, K., Daumer, M., Neiss, A., Polman, C., Kappos, L., on behalf of the Sylvia Lawry Centre for Multiple,
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West, T., Wyatt, M., High, A., Bostrom, A., Waubant, E.
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Mikaeloff, Y., Caridade, G., Assi, S., Suissa, S., Tardieu, M., on behalf of the KIDSEP Study Group,
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Li, D.K.B., Held, U., Petkau, J., Daumer, M., Barkhof, F., Fazekas, F., Frank, J. A., Kappos, L., Miller, D. H., Simon, J. H., Wolinsky, J. S., Filippi, M., for the Sylvia Lawry Centre for MS Research,
(2006). MRI T2 lesion burden in multiple sclerosis: A plateauing relationship with clinical disability. Neurology
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Marrie, R. A., Cutter, G., Tyry, T., Vollmer, T., Campagnolo, D.
(2006). Does multiple sclerosis-associated disability differ between races?. Neurology
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Kremenchutzky, M., Rice, G. P. A., Baskerville, J., Wingerchuk, D. M., Ebers, G. C.
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Tremlett, H., Paty, D., Devonshire, V.
(2006). Disability progression in multiple sclerosis is slower than previously reported. Neurology
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Bielekova, B., Kadom, N., Fisher, E., Jeffries, N., Ohayon, J., Richert, N., Howard, T., Bash, C. N., Frank, J. A., Stone, L., Martin, R., Cutter, G., McFarland, H. F.
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Brettschneider, J, Maier, M, Arda, S, Claus, A, Sussmuth, S D, Kassubek, J, Tumani, H
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Thompson, A.
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Clanet, M, Kappos, L, Hartung, H-P, Hohlfeld, R, The European IFNss-1a Dose-Comparison Study Invest,
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Pittock, S. J., Mayr, W. T., McClelland, R. L., Jorgensen, N. W., Weigand, S. D., Noseworthy, J. H., Weinshenker, B. G., Rodriguez, M.
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Adalsteinsson, E., Langer-Gould, A., Homer, R. J., Rao, A., Sullivan, E. V., Lima, C. A., Pfefferbaum, A., Atlas, S. W.
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Pryce, G., Ahmed, Z., Hankey, D. J. R., Jackson, S. J., Croxford, J. L., Pocock, J. M., Ledent, C., Petzold, A., Thompson, A. J., Giovannoni, G., Cuzner, M. L., Baker, D.
(2003). Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain
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Nash, R. A., Bowen, J. D., McSweeney, P. A., Pavletic, S. Z., Maravilla, K. R., Park, M.-s., Storek, J., Sullivan, K. M., Al-Omaishi, J., Corboy, J. R., DiPersio, J., Georges, G. E., Gooley, T. A., Holmberg, L. A., LeMaistre, C. F., Ryan, K., Openshaw, H., Sunderhaus, J., Storb, R., Zunt, J., Kraft, G. H.
(2003). High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood
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Burt, R. K., Cohen, B. A., Russell, E., Spero, K., Joshi, A., Oyama, Y., Karpus, W. J., Luo, K., Jovanovic, B., Traynor, A., Karlin, K., Stefoski, D., Burns, W. H.
(2003). Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores. Blood
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Eriksson, M., Andersen, O., Runmarker, B.
(2003). Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler
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Chaudhuri, A., Behan, P. O., Miller, D. H., O'Connor, P. W.
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(2003). Mechanisms of disability progression in primary progressive multiple sclerosis: are they different from secondary progressive multiple sclerosis?. Mult Scler
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Confavreux, C., Vukusic, S., Adeleine, P.
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Simone, I. L., Carrara, D., Tortorella, C., Liguori, M., Lepore, V., Pellegrini, F., Bellacosa, A., Ceccarelli, A., Pavone, I., Livrea, P.
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Panitch, H., Goodin, D.S., Francis, G., Chang, P., Coyle, P.K., O'Connor, P., Monaghan, E., Li, D., Weinshenker, B.
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Clanet, M., Radue, E.W., Kappos, L., Hartung, H.P., Hohlfeld, R., Sandberg-Wollheim, M., Kooijmans-Coutinho, M.F., Tsao, E.C., Sandrock, A.W.
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Casanova, B., Coret, F., Valero, C., Landete, L., Pascual, A., Vilchez, J.
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