Views & Reviews
`
`Defining the clinical course
`of multiple sclerosis:
`Results of an international survey
`
`Fred D. Lublin, MD, and Stephen C. Reingold, PhD, for the National Multiple Sclerosis Society (USA)
`Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis*
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`Article abstract—Standardization of terminology used to describe the pattern and course of MSis essential for mutual
`understanding between clinicians and investigators. It is particularly important in design of, and recruitmentfor, clinical
`trials statistically powered for expected outcomes for given patient populations with narrowly defined entry criteria. For
`agents that prove safe and effective for MS, knowledge of the patient populations in definitive clinical trials assists
`clinicians in determining who may ultimately benefit from use of the medication. An international survey ofclinicians
`involved with MS revealed areas of consensus about some termsclassically used to describe types of the disease and other
`areas for which there was lack of consensus. In this report, we provide a summary of the survey results and propose
`standardized definitions for the most common clinical courses of patients with MS.
`NEUROLOGY 1996;46:907-911
`
`
`The clinical course of MS mayfollow a variable pat-
`tern over time but usually can be characterized by
`either episodic acute periods of worsening (relapses,
`exacerbations, bouts, attacks), gradual progressive
`deterioration of neurologic function, or combinations
`of both. Although the terms used to describe these
`clinical forms have been used for many years,!?
`there is no clear common meaning amongclinicians
`for the terms used to describe formsorclinical stages
`of the disease. There is often lack of clarity about
`exactly which patient group is described. This cre-
`ates real and potential problems in communication
`among investigators and in the design of, and re-
`cruitment for, multicenter clinical trials for new
`therapeutic agents that are based on expected clini-
`cal outcomes for defined patient groups and require
`narrow entrance criteria. The success of such trials
`may depend on the homogeneity of the population of
`MSpatients entered into the study.
`MSrecently joined the growing ranksof treatable
`neurologic diseases, with reports of data on new
`therapies demonstrating clinical efficacy in pivotal
`clinical trials, such as interferon beta-1b (Betaseron,
`manufactured by Berlex Laboratories, Richmond,
`CA),® interferon beta-la (Avonex, manufactured by
`Biogen, Cambridge, MA),® and copolymer I (Copax-
`one, manufactured by Teva Pharmaceutical Indus-
`tries, Petah Tiqwa, Israel).!° Many new trials begin
`each year. Although each of these studies uses a
`
`narrowly defined population of patients, clinicians
`look for guidance as to exactly which broaderpatient
`groups will likely benefit from treatment. The terms
`used to describe patient populations are crucial for
`this guidance.!!
`Informal discussions amongclinicians andclinical
`researchers and consensus developed amonginvesti-
`gators attending a 1994 MSclinical trials design
`workshop”? revealed that there was no unanimous
`agreement on definitions for the variousclinical sub-
`types of MS. This lack of unanimity resulted from
`the lack of clear biological markersto distinguish the
`various forms of MS. This required use of descriptive
`terms for these clinical subtypes, for which there was
`no consensus. These facts and perceptions under-
`scored the need for a reassessment of the terminol-
`ogy used to describe MS and for more uniform defini-
`tions of MSclinical subtypes.
`
`In the absence of agreed on biological mark-
`Methods.
`ers, the Advisory Committee on Clinical Trials of New
`Agents in MS of the National Multiple Sclerosis Society
`(NMSS) (USA) undertook a survey to develop a perspective
`and consensus on definitions and terminology used to de-
`scribe clinical outcomes and course patterns in patients
`with MS, to standardize terminology, and to facilitate a
`broader understanding of patient recruitment parameters
`in MS therapeutic trials. Those surveyed included 215
`membersof the international MSclinical research commu-
`nity, including members of the NMSS Medical Advisory
`
`* See page 910 for Committee members.
`From the Department of Neurology (Dr. Lublin), Jefferson Medical College, Philadelphia, PA; and the Research and Medical Programs Department (Dr.
`Reingold), National Multiple Sclerosis Society (USA), New York, NY.
`Received August 9, 1995. Accepted in final form August 18, 1995.
`Address correspondence and reprint requests to Dr. F.D. Lublin, Department of Neurology, Jefferson Medical College, Philadelphia, PA.
`
`Copyright © 1996 by the American Academy of Neurology 907
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`Hopewell EX1037
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`Hopewell EX1037
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`Board (current and past), members of the NMSS Advisory
`Committee on Clinical Trials of New Agents in MS,attend-
`ees at the 1994 International Workshop on Outcomes As-
`sessment in MSClinical Trials held in Charleston, South
`Carolina,'? and other individuals known to be principally
`involved in MS clinical research and care. Survey forms
`developed by the authors in consultation with others with
`known interest in this issue were mailed in early January
`1995, with respondents asked to reply by early February
`1995. Of the 215 surveys, 125 (58%) were completed and
`returned.
`The survey form asked respondents to choose among
`several possible clinical patterns commonly used to define
`the following MS disease courses and types: relapsing-
`remitting (RR), relapsing-progressive (RP), primary pro-
`gressive (PP), secondary progressive (SP), benign, and ma-
`lignant. The survey allowed respondents to provide their
`own definitions if they were not satisfied with those pro-
`vided in the survey. Because respondents were asked to
`indicate all definitions that, in their view, applied to the
`disease type, more than 125 total responses were collected
`for some questions.
`The results of the survey were collated and distributed
`to members of the NMSS Advisory Committee on Clinical
`Trials. After meeting, revising, and approving revised clin-
`ical definitions based on the survey responses, the defini-
`ij ESETa!>
`tions were presented to the executive committee of the
`NMSSMedical Advisory Board and the full NMSS Medical
`Advisory Board where additional clarifications and revi-
`sions were made. Thefinal definitions, presented here, did
`not differ substantively from those in the initial survey
`document.
`
`Figure 1. Relapsing-remitting (RR) MS is characterized
`by clearly defined acute attacks with full recovery (A) or
`with sequelae and residual deficit upon recovery (B). Peri-
`ods between disease relapses are characterized by lack of
`disease progression.
`
`Results. Clinical course definitions.
`
`Relapsing-remitting (RR) MS. The consensus defini-
`tion is as follows: clearly defined disease relapses with full
`recovery or with sequelae and residual deficit upon recov-
`ery; periods between disease relapses characterized by a
`lack of disease progression (figure 1, a and b).
`The defining elements of RR-MSare episodes of acute
`worsening of neurologic function followed by a variable
`degree of recovery, with a stable course between attacks.
`Although a clear majority (105/134) of responses included
`this definition, some (16/134) favored using the term re-
`lapsing-remitting only for those patients who fully recover
`between relapses. However, the lack of evidence for a bio-
`logical difference between those who recover fully (figure
`la) and those who recover partially (figure 1b) and poten-
`tial differences in the vigor with which one might seek to
`determine the extent of recovery (clinical examination,
`evoked potentials, and so on) favored the more inclusive
`definition.
`Primary-progressive (PP) MS. The consensus defini-
`tion is as follows: disease progression from onset with occa-
`sional plateaus and temporary minor improvements al-
`lowed (figure 2, a and b).
`The essential element in PP-MS is a gradual nearly
`continuously worsening baseline with minor fluctuations
`but no distinct relapses. Eighty-one of 131 responses in-
`cluded this definition. Although nearly continuous progres-
`sion is required, it was recognized that progression at a
`constant rate throughout disease (figure 2a) was unlikely
`and that accommodation must be made for variations in
`
`908 NEUROLOGY 46 April 1996
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`the rate of progression over time (figure 2b). A small num-
`ber of respondents suggested that the definition of PP-MS
`should include evidence from MRIto distinguish this from
`other forms of disease (see Discussion).
`
`Secondary-progressive (SP) MS. The consensusdefini-
`tion is as follows: initial RR disease course followed by
`progression with or without occasional relapses, minor re-
`missions, and plateaus (figure 3, a and b).
`SP-MS may be seen as a long-term outcome of RR-MS
`in that most SP patientsinitially begin with RR disease as
`defined here. However, once the baseline between relapses
`begins to progressively worsen, the patient has switched
`from RR-MS to SP-MS. Eighty-four of 124 respondents
`chose the above definition.
`
`Relapsing-progressive (RP) MS. There is no consensus
`definition.
`Although this has been one of the most commonly used
`terms to describe an important clinical form of MS charac-
`terized by a combination of relapse and progression, there
`was no consensusfor a definition of RP-MS. Some respon-
`dents used this term to describe RR patients who do not
`fully recover (39/138 responses), which was clearly favored
`for inclusion in the RR definition (above). Others used this
`term for those patients who are also defined above as SP
`(41/138). A smaller group (26/138) indicated that the best
`definition of this group included patients with disease pro-
`gression from onset with acute episodes of worsening. Be-
`cause of the lack of consensus and the overlap of defini-
`tions with other categories, we conclude that the term
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`Increasing
`disability
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`A
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`increasing
`disability
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` time
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`Figure 2. Primary progressive (PP) MS is characterized by
`disease showing progression of disability from onset, with-
`out plateaus or remissions (A) or with occasional plateaus
`and temporary minor improvements (B).
`
`Figure 3. Secondary progressive (SP) MS begins with an
`initial RR course, followed by progression of variable rate
`(A) that may also include occasional relapses and minor
`remissions (B).
`
`RP-MSdoes not correspond to a clearly defined and distin-
`guishable clinical population and should be abandoned.
`
`Progressive-relapsing (PR) MS. The consensus defini-
`tion is as follows: progressive disease from onset, with
`clear acute relapses, with or without full recovery; periods
`between relapses characterized by continuing progression
`(figure 4, a and b).
`Based on the survey and additional discussion, we de-
`termined that PR-MS wasan additional, albeit rare, clini-
`cal course that deserved a separate definition, as it was not
`included in the other definitions. We propose that this
`form of MS be termed PRto reflect its progressive onset
`and to distinguish it from the term RP, for which there
`was no consensus.
`
`Clinical severity definitions. The abovedefinitions per-
`tain to clinical courses that patients with MS mayfollow.
`The survey also queried respondents on twoseverity out-
`come definitions, for benign and malignant disease. There
`was no overwhelming consensus on definitions for these
`terms and less so for benign disease than malignant dis-
`ease. Further, many respondentsbelieved that precise def-
`initions were not needed or useful as these terms were not
`likely to be used as enrollment criteria or end point mea-
`sures in clinical trials. Although classic definitions have
`often indicated a set or minimal score on the Kurtzke
`Expanded Disability Status Scale (EDSS) clinical rating
`scale,”'3"* there was consensus that these should not be
`used, as they might narrow theclinical picture being de-
`
`scribed. Further, as these terms do not necessarily reflect
`future course, it was agreed that they should not be the
`sole determinant of the appropriateness of any available
`therapeutic measures. It was additionally emphasized that
`these terms were most useful in the context of research
`studies and should be used with care in communication
`with affected individuals, family members, and third-party
`payers.
`Benign MS. The consensusdefinition is as follows: dis-
`ease in which the patient remains fully functional in all
`neurologic systems 15 years after disease onset.
`Malignant MS. The consensusdefinition is as follows:
`disease with a rapid progressive course, leading to signifi-
`cant disability in multiple neurologic systems or death in a
`relatively short time after disease onset.
`
`Discussion. Wereport here the results of a survey
`of the international MSclinical research community
`on terminology commonly used to describe clinical
`course and outcomes for the disease. We weregrati-
`fied to find clear preferences and striking agreement
`on the meaningof the terms RR, PP, and SP forms of
`MS. Based on survey results and resultant consen-
`sus, we added a new term, PR, to represent those
`patients whose course differs, as diagrammed in fig-
`ures 1 to 4, from the other definitions. We expect
`that this represents a small fraction of MSpatients.
`We found no clear consensus on the definition of
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`April 1996 NEUROLOGY 46 909
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`Figure 4. Progressive-relapsing (PR) MS shows progres-
`sion. from onset but with clear acute relapses with (A) or
`without (B) full recovery.
`
`RP-MS, and because the survey results made it clear
`that its common usage overlaps with either RR or SP
`as defined here, we recommendthat the term RP-MS
`be abandoned. Similarly, as the classically used term
`chronic progressive (CP) MS includes the more re-
`cently distinguished groups of PP, SP, and PR pa-
`tients as newly defined here, we recommend that
`this term also be abandoned, as being too vague and
`including forms of MS that differ considerably in
`clinical course and MRI correlates.
`We have not included MRI parameters in these
`definitions, despite reported differences in MRI le-
`sion load in certain forms of MS (e.g., PP versus
`SP-MS)' because our respondents and committee
`members with special MRI expertise believed that
`the current level of knowledge did not allow suffi-
`ciently confident association of MS clinical course
`and MRIfindings. This situation could change in the
`future, as it could for developments relating to any
`potential biological or surrogate marker of disease
`activity. If so, we expect the definitions proposed
`here to be modified accordingly.
`Wealso have not defined a relapse. A relapse im-
`plies an acute episode of new disease activity, either
`a new lesion or fresh activity in an old area of in-
`volvement. Both MRI data and neuropathologic stud-
`ies detail a discordance between the occurrence of
`MSlesions in the CNSand the developmentof symp-
`910 NEUROLOGY 46 April 1996
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`toms or signs.'*!* A clinical relapse is dependent on
`involvement of an “eloquent” area of the CNS. Vari-
`ous authors provide definitions. McAlpine defined a
`relapse as a new symptom or the reappearance of a
`previous symptom at a time after an initial attack.'
`Schumacheret al.?° added a requirement for a dura-
`tion of symptomsof at least 24 hours when evaluat-
`ing a treatment. For the purposesof a clinical trial,
`the nature of a relapse will need to be defined by
`consensus among investigators for each protocol to
`ensure standardization of the study design. Simi-
`larly, for trials of agents being tested for their ability
`to slow or stop disease progression, duration and
`rate of progression need to be defined by consensus
`for inclusion and treatmentfailure criteria for each
`trial.
`Because at present there are no knownclearbio-
`logical markers that define the various clinical
`courses of MS, definitions must be madein clinical
`terms and by consensus among workersin thefield.
`We therefore conclude that the definitions we pro-
`pose are tenable because they derive from an inter-
`national survey and input from a large group of MS
`clinical investigators. Use of these definitions in a
`standardized fashion will allow more uniformity in
`clinical descriptions, both in reports in the literature
`and in designation of patient populationsfor clinical
`trials of new agents in MS.
`
`Acknowledgements
`We thank Drs. Alan Thompson, Brian Weinshenker, and John
`Whitaker for assistance in design of the survey.
`
`National Multiple Sclerosis Society (USA) Advisory Committee on
`Clinical Trials of New Agents in Multiple Sclerosis: M. Clanet
`(Lyon, France), D. Cookfair (Buffalo, NY), G. Ebers (London, On-
`tario, Canada), D. Goodkin (San Francisco, CA), H.P. Hartung
`(Wurzburg, Germany), R. Lisak (Detroit, MI), W.I. McDonald
`(London, UK), H. McFarland (Bethesda, MD), J. Noseworthy
`(Rochester, MN), H. Panitch (Baltimore, MD), C. Polman (Amster-
`dam, The Netherlands), A. Reder (Chicago, IL), P. Rudge (London,
`UK), W.Sibley (Tucson, AZ), J. Whitaker (Birmingham, AL), and
`J. Wolinsky (Houston, TX).
`
`References
`1. Matthews WB, Compston A, Allen IV, Martyn CN, eds.
`McAlpine’s multiple sclerosis. Edinburgh: Churchill Living-
`stone, 1991.
`2. Poser S. Multiple sclerosis: an analysis of 812 cases by means
`of electronic data processing. Berlin: Springer, 1978.
`3. Weinshenker BG, Bass B, Rice GPA,et al. The natura! history
`of multiple sclerosis: a geographically based study. I. Clinical
`course and disability. Brain 1989;112:133-146.
`4. Phadke JG. Survival patterns and cause of death in patients
`with multiple sclerosis: results from an epidemiological survey
`in northeast Scotland. J Neuro Neurosurg Psychiatry 1987;50:
`523-531.
`5. Confavreux C, Aimard G, Devic M. Course and prognosis of
`multiple sclerosis assessed by the computerized data process-
`ing of 349 patients. Brain 1980;103:281-300.
`6. Verjans E, Theys P, Delmotte P, Carton H. Clinical parame-
`ters and intrathecal IgG synthesis as prognostic factors in
`multiple sclerosis. Part I. J Neurol 1983;229:155-165.
`7. Confavreux C, Compston DAS, Hommes OR,et al. EDMUS, a
`European database for multiple sclerosis. J Neuro Neurosurg
`Psychiatry 1992;55:671-676.
`8. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b
`is effective in relapsing-remitting multiple sclerosis. I. Clinical
`
`4
`
`

`

`10.
`
`11
`
`results of a multicenter, randomized, placebo-controlled trial.
`Neurology 1993;43:655-661.
`. Jacobs LD, Cookfair DL, Rudick RA,et al. Results of a phase
`III trial of intramuscular recombinant beta interferon as
`treatment for multiple sclerosis [abstract]. Ann Neurol 1994;
`36:259.
`Johnson KP, Brooks BR, Cohen JA,et al. Copolymer I reduces
`the relapse rate and improves disability in relapsing-remit-
`ting multiple sclerosis: results of a phase III multi-center,
`double-blind, placebo-controlled trial. Neurology 1995;45:
`1268-1276.
`Alter M, Byrne TN, Daube JR, et al. Practice advisory on
`selection of patients with multiple sclerosis for treatment with
`Betaseron. Report of the Quality Standards Subcommittee of
`the American Academy of Neurology. Neurology 1994;44:
`1537-1540.
`Whitaker JN, McFarland HF, Rudge P, Reingold SC. Out-
`comes assessment in multiple sclerosis clinical trials: a critical
`analysis. Multiple Sclerosis 1995;1:37-47.
`Kurtzke JF, Beebe GW, Nagler B, et al. Studies on the natu-
`ral history of multiple sclerosis. 8. Early prognostic features of
`the later courseof the illness. J Chronic Dis 1977;30:819-—830.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`Thompson AJ, Hutchinson M, Brazil J, et al. A clinical and
`laboratory study of benign multiple sclerosis. Q J Med 1986;
`58:69 -80.
`Thompson AJ, Kermode AG, WicksD, et al. Major differences
`in the dynamics of primary and secondary progressive multi-
`ple sclerosis. Ann Neurol 1991;29:53-62.
`Isaac C, Li DKB, Genton M, et al. Multiple sclerosis: a serial
`study using MRI in relapsing patients. Neurology 1988;38:
`1511-1515.
`
`Miller DH, Rudge P, Johnson G, et al. Serial gadolinium en-
`hanced magnetic resonance imaging in multiple sclerosis.
`Brain 1988;111:927-929.
`Koopmans RA, Li DKB, Oger JJF, et al. Chronic progressive
`multiple sclerosis: serial magnetic resonance brain imaging
`over six months. Ann Neurol] 1989;26:248—256.
`Willoughby EW, Grochowski E, Li DKB, et al. Serial magnetic
`resonance scanning in multiple sclerosis: a second prospective
`study in relapsing patients. Ann Neurol 1989;25:43-49.
`Schumacher GA, BeebeG, Kibler RF, et al. Problemsof exper-
`imental trials of therapy in multiple sclerosis. Ann NY Acad
`Sci 1965;122:552-568.
`
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