Natural History ofMultiple Sclerosis:Long-Term PrognosticFactors

Christel Renoux, MD, PhD

KEYWORDS

� Multiple sclerosis � Prognosis � Prognostic factors� Disability � Epidemiology

Multiple sclerosis (MS) is a chronic neurologic disease with onset occurring predom-inantly in young adults. As such, the disease evolves throughout several decades andthe affected individuals will be faced with the perspective of disability for a large part oftheir life. Such characteristics may explain why this disease has received so muchattention and is among the most well described chronic diseases in terms of its naturalhistory. The now well characterized natural history of MS has been complementedwith numerous studies designed to delineate potential prognostic indicators of anunfavorable long-term prognosis. This aspect was already of importance years agofor counseling patients at a time when they had to make most of their personal andprofessional choices as young adults. It has become even more crucial nowadayswhen, with the so-called disease-modifying drugs now available, enlightened andweighted decisions regarding the initiation of treatment must be made.Studying prognostic factors can achieve two goals: (1) helping to predict the long-

term course and disability at the individual level, and (2) giving some insights about thepathogenesis of MS. The latter goal has definitely givenmore results, whereas the indi-vidualized prediction remains limited. The most scrutinized and earliest identifiedpotential predictors are clinical characteristics at onset and during the early courseof the disease, because they are easily obtained and more relevant if identified earliestin the course of the disease. Efforts are being made to supplement these indicationswith imaging data, as well as with biologic parameters and genetic or environmentalfactors. These additional factors will probably grow in importance as predictors asour knowledge of the pathogenesis of the disease increases. After a brief description

Disclosure: Dr Renoux is the recipient of a postdoctoral fellowship from the Multiple SclerosisSociety of Canada.Center for Clinical Epidemiology, Jewish General Hospital, McGill University, 3755 CoteSte-Catherine, H464, Montreal, QC H3T 1E2, CanadaE-mail address: christel.renoux@mail.mcgill.ca

Neurol Clin 29 (2011) 293–308doi:10.1016/j.ncl.2011.01.006 neurologic.theclinics.com0733-8619/11/$ – see front matter � 2011 Elsevier Inc. All rights reserved.

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of the methodological concepts and material available for studying such factors, theauthors first review the main demographic and clinical characteristics that influencethe long-term course of MS, then describe the potential paraclinical information thatmay help predict the long-term evolution of MS.

THE PROGNOSIS OF MSGeneral Considerations: Definition of Prognosis

MS causes the accumulation of irreversible disability over time whereas survival is onlyslightly affected. Therefore, when concerned with prognosis, the interest is usuallytoward the potential for accrual of disability milestones. Disability can encompassvarious aspects as originally defined by the World Health Organization, and corre-sponds to limitation or inability in performing tasks. However, studies of MS prognosishave tended to focus mainly on physical disability and particularly on ambulation. Thisfocus is not surprising, because difficulty with walking represents one of the first andmost visible manifestations of the disease. Cognitive dysfunction has receivedcomparatively less interest until recently.1 Severe cognitive impairment and dementiaare rare in MS.2 Cognitive performances are rather affected by subtle changes but theprevalence of such alterations may be high, as figures most frequently reported varybetween 40% and 60%.1–4 Studies on the long-term evolution and prognosis of suchcognitive changes are lacking, therefore this subject is not further reviewed here.Several scales are available to measure disability in MS. The most widely used in

prognostic studies as well as in clinical trials is the Disability Status Scale (DSS) orits extended version, the Expanded Disability Status Scale (EDSS), proposed byKurtzke.5,6 The EDSS is an ordinal scale based on the results of the neurologic exam-ination and the patient’s ability to walk. Scores range from zero (no neurologic abnor-mality) to 10 (death from MS), with increments of 0.5 points. Some drawbacks of thescale are that it actually combines impairment (in the lower scores) and disability (inthe higher scores), and relies heavily on ambulation.7 It is quite insensitive to cognitiveand upper limb dysfunction. Despite these well-recognized limitations, no other scalehas yet gained such acceptance, probably because of the lack of better psychometricproperties and the difficulties in designing a scale that measures all aspects of theimpact of MS.8 Moreover, the requirements of a particular scale for the purpose ofstudying long-term outcomes may differ from the properties needed in short-termevaluation such as in clinical trials. Also, some outcomes relevant in the short termmay be less relevant in the long term. Consequently, natural history studies, includingthose mentioned here, use the DSS or EDSS as a clinical outcome, focusing ondisability scores both clinically relevant and readily identified, even in retrospect.

Natural History Cohorts

Numerous cohort studies have described the natural course of MS, including theaccrual of irreversible disability over time. A complete description of the characteris-tics of these studies has been made elsewhere.9 Major cohorts have been character-ized by a well-defined and representative population, and essentially prospective,standardized and long-term follow-up. Of note, the majority of patients in thesecohorts were untreated, or treated with drugs with no proven benefit and for a shorttime as compared with the duration of the disease, which gives little doubt aboutthe absence of impact on the course of the disease. Such cohorts have allowed theestimation of the time from MS onset to the assignment of clinically relevant disabilitylandmarks using survival analysis. From the London, Ontario, Canada cohort, mediantime from onset of MS to the assignment of a DSS score of 3 (defined as moderate

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disability) has been estimated to be 7.7 years, and time to DSS 6 (defined by the inves-tigators as ambulatory but requiring walking aids) and DSS 8 (restricted to bed but witheffective use of arms) to be 15.0 and 46.4 years.10 From the Lyon, France cohort, esti-mated median times to reach irreversible DSS 4 (limited walking ability but ability towalk more than 500 m without aid or rest), 6 (ability to walk with unilateral supportno more than 100 m without rest), and 7 (ability to walk no more than 10 m withoutrest while using a wall or furniture for support) were 8.4, 20.1, and 29.9 years,respectively.11,12 From the Goteborg, Sweden cohort, median time to DSS 6 was18 years.13 Few recent studies found longer times to reach disability milestones14,15

although others found estimates closer to those of earlier cohorts, notably for timeto reach DSS 6.16 The reasons for these discrepancies are not clear and may includemethodological problems,17 but also differences in the interpretation of the definitionof the same DSS score, and possibly some inherent cohort factors influencing diseaseprogression, such as race or vitamin D status.These large cohorts of patients have constituted the basis for the study of prognostic

factors associated with time to reach these clinically relevant disability milestones.

Methodological Insights

A detailed discussion of methods is beyond the scope of this article, but a few pointsdeserve attention. One common consideration is that a study should be representativeof the population of patients with MS. Some investigators describe their study popu-lation as population-based whereas others are clinic-based or hospital-based.Although in theory a hospital-based cohort would be more prone to selection towardmore severe cases and therefore to the problem of selection bias, the reality is lessstraightforward. In practice, many patients with MS are likely to be seen at leastonce in a referral center for MS, and depending on the geographic location and rela-tion with other neurology facilities, even a tertiary referral center may well capturevirtually all MS patients of a particular region. Even if this is not the case, patientsmay still be referred in a manner that leads to an unbiased sample. Knowledge ofthe setting and organization of health care for a particular study helps to judge if thestudy population is reasonably well representative, or if the recruitment of patientswith MS is complete or near complete. On the other hand, the population-based labelis sometimes assigned based on loose criteria that do not protect with certaintyagainst bias.Potentiallymoreproblematic, althoughoftenneglected, are thequality andcomplete-

ness of information available in databases. The increasing implementation of comput-erized files and access to technology allows rapid and easier collection of data.However, a database dedicated to research purposes is more than accumulation ofcomputerized data. Without a coherent, standardized, and systematic collection ofinformation from all patients by each participating physician, as well as recordingof data by qualified personnel and regular maintenance and checking of quality andcompleteness, results obtained may be surprisingly divergent between studies. Theconstantly increasing number of observational studies performed using computerizeddatabasesnotonly inMSbut in virtually every fieldofmedicinemust raise theawarenessof the potential flaws attached to data quality. In this respect, major natural historystudies that have established the description of the long-term course and prognosisofMShave gathered clinical information during regular and frequent follow-up in a stan-dardizedway. The long-termpurposeof these studies is to build a complete descriptionof the natural course of the disease, and as such, particular attention has been paid tothe avoidance of potential bias related to assembly and follow-upof the cohort. Patientswith MS are often seen some time after the first symptoms, and the retrospective

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assessment of the patient’s history before the first visit is unavoidable and even crucialto ensure accurate description of the course of the disease. Solutions that consist ofselecting only patients seen from onset, or taking into account only data collectedprospectively after the first visit because the efforts to collect the history have notbeen made must be avoided, and results drawn from such methods regarded withcircumspection. Similarly, avoiding the retrospective assignment of some disabilityscores and considering only scores assigned when a patient is seen at the clinic maybe a source of bias. Indeed, when substantial gaps occur between visits, which is notso infrequent in practice, a subsequent disability score may have been reached duringthis time period. In this case, assigning the date of the visit for the date of assignment ofdisability will systematically overestimate the time to reach disability milestones. Thisfactor is particularly problematic in databases only containing clinical informationcollected at the time of the visit with no information on clinical history between visits,because this problemcannot be fixed. Follow-up canbe amajor challenge for a diseasethat evolves over decades, and loss to follow-up is probably one of themajor threats tovalidity if it is related to the outcomeof interest, namely disability. This canbe true even ifthe percentage lost to follow-up is low, although this information is often less well iden-tified in natural history studies for twomain reasons: first, because it may prove difficultto define at which point a particular patient is considered lost to follow-up, and the defi-nition is somewhat arbitrary; second, it is not easy to determine whether the reason isrelated to the outcome of interest.In the particular context of the study of prognostic factors in MS, it must be acknowl-

edged that many of the characteristics studied are not independent but rather highlyassociated, particularly regarding clinical variables. Consequently, depending onwhich variables are studied and included in multivariate analysis, different and some-times divergent findings may result, an important fact to keep in mind when interpret-ing results of different studies. Also, the interpretation of the respective importance ofdifferent potential prognostic factors may be difficult, and is best achieved when sup-ported by extensive knowledge of the pathogenesis of the disease and clinical expe-rience in order to avoid misinterpretation of the results. Simply stated, association isnot causation, and the fact that a clinical characteristic is associated with prognosisdoes not mean that modifying this characteristic will necessarily change the long-term prognosis. Finally, the quality of measurement of the variables of interest isa prerequisite, as already mentioned, because no statistical techniques can correctfor questionable data.

LONG-TERM PROGNOSTIC FACTORS OF IRREVERSIBLE DISABILITYDemographic and Clinical

The following description of the potential prognostic factors mirrors the process inplace in clinical practice where the prognosis is reevaluated regularly, taking intoaccount all information available at a point in time, beginning with the most accessibleinformation, which is demographic and clinical (Fig. 1). Preference is given to resultsfrom studies having achieved a substantial cohort follow-up, that is, around a decadeor more, and using survival analysis when dealing with time-to-event data.

At onset of MSWhile it is well established that the risk of developing MS varies with race and ethnicbackground, being highest for Caucasian individuals, possible variation in the severityof the disease course is also suspected. Several studies suggest that AfricanAmericans with MS have a more aggressive course than Caucasian Americans withMS.18–21 In a recent retrospective cohort study, patients with MS of African American

Fig. 1. Demographic and clinical characteristics associated with time to assignment of long-term irreversible disability in patients with MS along the course of the disease.

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origin had a higher risk of ambulatory disability even after adjustment for other clinicalvariables such as age at onset.18 It was also suggested that they may be at greater riskof disability in other domains such as hand and visual function.20 Similarly, a retrospec-tive cohort study conducted in France showed that patients of North African origin withMS had shorter time to irreversible disability (DSS 4 and 6) compared with patientsfrom Europe.22 In these studies ethnicity was self-defined and may be related to vari-able genetic ancestry.The influence of sex on the long-term prognosis of MS has been assessed in

numerous studies. Many have found that male sex is associated with a less favorableoutcome than female sex in terms of time to major disability landmarks.12,13,23,24

However, some have found no effect.25–27 More importantly, overall it was foundthat sex did not have a strong influence on the long-term prognosis of MS when takingother factors into account, that is, in multivariable analysis.How the age at onset of MS is placed in the list of relevant prognostic factors is quite

different. Age at onset of MS exerts a strong influence on the long-term evolution ofMS. A younger age at onset has been associated with a longer time to reach disabilitylandmarks in most studies,12,13,23,24,26,28 with some exceptions.25,27 Moreover, theyounger the age at onset, the more pronounced this phenomenon becomes.28,29

However, the overall impact of age at onset can be seen from another perspective.Despite a longer time to reach disability landmarks, younger individuals at onset stillreach these landmarks at a younger age than individuals with first symptoms at anolder age.15,29 Therefore, they reach the same level of disability earlier in life and aredisabled for a longer part of their life, which leads to the conclusion that a youngerage at onset cannot be considered a good prognosis.The initial symptomatology in the form of motor, cerebellar, or sphincter dysfunction

has been associated with a worse prognosis,12,13,23–26 in contrast with an opticneuritis usually associated with longer time to disability.12,13,24,26 However, the prog-nostic value was weak when taking other clinical information into account. A highernumber of functional systems involved or, using another definition and terminology,a polyregional onset as opposed to symptoms from one region of the central nervoussystem, have also been mentioned as an indicator of worse prognosis by someinvestigators.13,25

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Virtually every study assessing the prognostic value of the initial course of MS, thatis, relapsing-remitting versus primary progressive (with or without superimposedrelapses), has found that a progressive course from onset is associated with a shortertime to disability landmarks.11–13,23–25,27,28 This finding persists even after taking intoaccount other potential prognostic variables, and the initial course is the most influen-tial clinical variable at onset.

During the course of MSIncomplete recovery from the first neurologic episode has been associated witha worse prognosis in the few studies that have assessed this clinical variable.12,13,25,26

The influence of the time from the first to the second neurologic episode has beenintensively studied, and most studies have concluded that the longer this time interval,the better the prognosis.12,24,25,27,28,30 However, when the impact on disability is appro-priately assessed from the date of this second neurologic episode, the associationbetween time from the first to the second episode and time to irreversible disabilityno longer exists (Refs.13,26 and Renoux and colleagues, personal communication, 2008).Similarly, several studies have assessed the impact of relapses during the early

course of the disease on long-term disability. A higher number of relapses duringthe first 2 or 5 years of the disease is associated with a higher risk of dis-ability,12,23,24,28,30 with few exceptions.25 When appropriately (and logically) takingthe end of the fifth year after onset of MS as a starting point in the survival analysisto evaluate prognosis value of relapses in the first 5 years of the disease, it was shownthat relapses had either no long-term impact or only influenced prognosis for a rela-tively high number of relapses (5 relapses or more in the last 5 years).13,26 A similarconclusion was reached when studying the impact of relapses after a certain thresholdof irreversible disability had been reached, in which case early relapses had no influ-ence on subsequent accrual of irreversible disability.12 From another perspective,studying the impact of all relapses and not only of early relapses, and using a time-dependent analysis, there was a minimal impact of relapses on long-term disability.31

Clinical characteristics and accrual of disability in the early course may also provideinformation on the long-term prognosis. A higher DSS score in the first 2 and 5 years ofthe disease and a shorter time from MS onset to the assignment of DSS 3 or DSS 4have been associated with a faster rate to subsequent disability scores.12,24,30

Studying only patients with a relapsing-remitting onset, a high number of affectedneurologic systems, a poor recovery from the last relapse, and a higher disabilityscore, all characteristics evaluated at 5 years from onset, also best predicted an unfa-vorable long-term prognosis.13,26 By contrast, some of the significant prognosticfactors measured at onset such as sex, age, and symptoms were no longer associ-ated with a worse long-term prognosis.13,26 When assessed at the time when a certaindetectable threshold of irreversible disability had been reached (DSS 4 in their study),Confavreux and colleagues11,12 also showed that those demographic and clinicalcharacteristics measured at onset no longer predicted time to subsequent disabilitymilestones, and suggested that the disease then enters a final common pathwaywhere accrual of irreversible disability is a self-perpetuating process, amnesic of theearlier clinical history.Finally, time interval from MS onset to secondary progression was found to predict

the time to DSS 7 but, secondary progression being a remote event in the course ofthe disease, it is a less useful predictor in practice.26

As expected, prognostic factors of time from onset to secondary progression in thesubgroup of patients with relapsing-remitting onset are virtually one and the same asthose described for the whole population, age at onset playing the major role in most

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studies.13,16,25,26,28,32–35 In patients with a primary progressive onset, very few andsometimes contradictory prognostic factors associated with a worse outcome havebeen found, including the involvement of 3 or more functional systems at onset anda shorter time to reach DSS 3,36 or the presence of motor, sensory, or brainstemsymptoms at onset.34 In a recent study, however, sensory symptoms at onset wereassociated with a longer time (and therefore an older age) to DSS 6 compared withthe absence of such symptoms; younger age at onset was also associated witha longer time to disability.37 For others, the number of functional systems involved3, 4, and 5 years after disease onset, and bowel and bladder involvement 4 and 5 yearsafter the onset of the first symptom rather than characteristics at onset, werecorrelated with progression to EDSS scores of 6.0 and 6.5.38

To conclude, it must be realized that the aforementioned demographic and clinicalcharacteristics have been determined at the population level, contrasting with a greatinterindividual variability in the course of the disease. It is acknowledged that most ofthese characteristics are of limited value in clinical practice when making a reliableprognosis for a particular patient. To date, a few studies have attempted to validatemodels for the purpose of prognosis, but they have dealt mainly with short-term prog-nosis or have included too few patients to be reliable.39–41 On the other hand, asdescribed below, important concepts in the understanding of MS have been broughtforth by prognostic studies.

Lessons drawn from epidemiology: implications for pathogenesisAside from the importance of identifying prognostic factors for the purpose of coun-seling patients and guiding the choice of treatment, natural history studies haveproved useful for giving some clues about the pathogenesis of MS. In this respect,understanding the role of relapses in the accrual of irreversible disability is of utmostimportance, because the impact of currently approved disease-modifying therapiesrelies mainly on the reduction of relapses rate with the underlying assumption thatthe demonstrated short-term effect on relapses will delay or deflate the accrual oflong-term disability. The same reasoning has prevailed when testing the effect ofdisease-modifying therapies on delaying the time from the first to the second demye-linating neurologic episode and hence, conversion to clinically definite MS. Althoughthe effect of currently approved treatments on relapses is not disputed, with a possibleinfluence on short-term disability, uncertainty remains regarding their potential long-term effect on the course of the disease.42 Indeed, disability worsening as assessedin the short-term clinical trials is not similar to truly irreversible disability as assessedin long-term natural history cohorts over many years.The progression and accumulation of irreversible disability is believed to reflect the

diffuse cumulative axonal loss. Therefore, questioning the relationship betweenrelapses and accumulation of irreversible disability comes down to examination ofthe relation between acute focal inflammation and chronic axonal loss. Increasingevidence supports the view of a limited effect of relapses on long-term irreversibledisability and therefore of acute focal inflammation on neurodegeneration.9,43

For instance, the rate of progression of disability from MS onset has been shown tobe similar in progressive forms from onset with or without superimposedrelapses.38,44,45 Confavreux and colleagues11,12 also showed that once a clinicallydetectable threshold of irreversible disability has been reached, namely DSS 4, thesubsequent accrual of irreversible disability is not influenced by relapses irrespectiveof when they occur, before or during the progressive phase of MS. Taking a differentapproach, other investigators showed that time from onset of the progressive phase(when identified at DSS 2 or less for the purpose of the study) to long-term disability

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was similar whether numerous relapses, an isolated relapse, or no relapses precededthe onset of progression.46

From a different perspective, looking at age of assignment of disability instead oftime to disability milestones, the initial course of MS, whether relapsing-remitting orprogressive, had minor influence on the age at assignment of irreversible disability.29

Similarly, age at onset of the progressive phase was found to be similar in primary andsecondary progressive MS, that is, whether the progressive phase was preceded byrelapses or not.44,46 Aside from giving further credit to the limited influence of relapseson long-term disability and the dissociation between relapses and progression, theselatter observations suggest that the progressive phase and the accrual of irreversibledisability are rather, at least partly, under the influence of current age, along with age atonset as previously described. These factors may interact with each other to influencethe rate of disability accrual.47

Complementary information on the relationship between focal inflammation andprogression has been provided by neuropathology. Some investigators found thatthe progressive phase of MS, whether progressive from onset or secondary progres-sive, was characterized by diffuse white matter injury consisting in diffuse axonal injuryon a background of a global inflammatory response compartmentalized behind theblood-brain barrier.48,49 These characteristics were present in patients withrelapsing-remitting MS, but to a lesser extent. No significant correlation was foundbetween axonal damage in the normal-appearing white matter and the focal lesionsload,49 suggesting an independent development of diffuse white matter injury fromfocal demyelinated plaques. The timing of progression of this diffuse injury in the earlyphase of the disease remains to be fully determined, and the exact relation betweenfocal inflammation, global inflammation, and neurodegeneration at the very onset ofthe disease is opened to speculation.

Paraclinical Prognostic Factors

The contribution of paraclinical data to the evaluation of the risk of long-term disabilityis currently limited, but this situation is likely to change owing to the growing interest insupplementing the information provided by clinical data, in parallel with the improve-ments in genetic, imaging, and biological techniques.To date, there is no evidence to support the use of genetic information to predict the

long-term course of MS. For instance, although the susceptibility to MS conferred bythe human leukocyte antigen (HLA) class II is not disputed, its influence on the severityof the disease has been examined in several large studies, with conflicting results. Assuch, no convincing association between HLA DR15, or any other HLA allele, andlong-term disability has been shown to date.50–53 The role of the apolipoproteinE gene, in particular the e4 allele, has also been studied in relation to the severity ofMS; whereas some earlier studies suggested an association of the e4 allele witha more severe disease evolution,54–59 or a protective effect of e2 allele,59–61 somerecent large studies and a meta-analysis did not confirm these results.62–66 Variousother genetic traits have been proposed as disease-modifying genes, but thesestudies await replication.67 The difficulty in revealing consistent effects across studiesmay lie in part in the search for a small effect size of candidate genes on the long-termdisease severity.The utility of magnetic resonance imaging (MRI) in predicting the occurrence of

a second neurologic episode and, therefore, conversion to clinically definite MS inpatients with a first demyelinating event, is well established. The place and contribu-tion of imaging in evaluating the long-term prognosis is less obvious, as illustrated ina prospective cohort study of 140 patients with a first neurologic episode suggestive

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of MS.68,69 Among the 107 mostly untreated patients reevaluated after a mean follow-up of 20 years, brain T2 lesion volume at all time points, namely, baseline and 5, 10, 14,and 20 years, correlated moderately with EDSS at the end of follow-up.69 Similarconclusions were reached when analysis was restricted to the subgroup of patientswith clinically definite MS. The change in T2 lesion volume on brain MRI over the first5 years of the disease also correlated with concurrent change in EDSS and weakenedthereafter. While patients with a higher number of T2 lesions at baseline on brainimaging were more likely to be disabled 20 years later, about one-third of patientswith more than 10 T2 lesions at baseline had minimal disability at the end of follow-up, and the investigators acknowledged that lesion counts provided limited predictionfor long-term disability.69 It is unclear whether the T2 lesion on cord imaging wouldcorrelate more strongly with the long-term disability.Other paraclinical investigations performed at onset, such as the search for oligo-

clonal immunoglobulin G bands (OCB) in the cerebrospinal fluid, have led to contradic-tory results regarding prognosis value. Whereas some investigators found that thepresence of OCB carried no prognostic significance,70,71 others found that patientswith OCB had a higher risk of long-term disability than patients without OCB25,72–74

and an earlier age at assignment of DSS 6.75 The small number of patients withoutOCB combined with methodological disparities, including different control groups orvarious adjustments for other prognostic factors, may explain these findings. More-over, the frequent lack of information on characteristics such as type of clinical courseor duration of follow-up hampers comparison between some studies. In any case, thesmall percentage of patients without OCB in MS raises questions about the usefulnessof this biological parameter for prognostic purposes in practice. By contrast, furtherinvestigations of differences between patients with and without OCB may shed newlight on some aspects of the pathogenesis of the disease. Recently, in a small groupof 29 patients with MS with mean disease duration of 11 years, those with IgM oligo-clonal bands (n5 11) had a shorter time to secondary progression and DSS 6 than the18 patients without IgM (17 patients with IgG OCB and 1 patient without OCB).76 Theinvestigators further showed that IgM directed against myelin lipids were more specif-ically associated with a worse prognosis.77 Other markers, such as glial or axonalbiomarkers, which may be relevant with respect to long-term prognosis and mayimprove the prediction based solely on previously described demographic and clinicalcharacteristics, have yet to be found.

Pregnancy

The impact of pregnancy on the course of MS has been the subject of several studies.The absence of influence of pregnancy on the short-term course of the disease hasbeen well characterized.78 There is some question as to whether pregnancy has noeffect,79–83 or even a favorable effect in a few studies on the long-term course,84–86

and thus should not be discouraged. The difficulty in interpreting these results comesfrom the fact that women with less severe disease are more likely to decide to getpregnant than women with a more active disease. Despite efforts to adjust for differ-ences in terms of demographic or clinical factors, residual confounding cannot beexcluded and may, at least in part, explain these findings.

Environmental Factors

The influence of external factors on the course of MS, not to mention the long-termprognosis, is not well documented. Smoking is one exception, with an increasingamount of evidence indicating an adverse effect of smoking on the course of MSand, consequently, on the prognosis. Despite the debatable methodology of the

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available studies, which includes the source population not being the most appro-priate for studying a clinical outcome,87 and the imprecision in measurement or themodeling of smoking exposure, virtually all studies found that smoking increasedthe rate of conversion to secondary progression in patients with relapsing-remittingMS,87–89 with one exception.90 In cross-sectional analysis, smokers were also morelikely to have primary progressive MS and to have more severe disease overall thannonsmokers.88,89 However, an association with disability after a few years of follow-up has not been consistently found, and one study showed the difficulty of disentan-gling the effects of smoking from other factors that influence the course of the diseasesuch as gender, age, and duration of the disease. All of these factors are often asso-ciated with smoking duration or intensity, and may confound the association.89 Nodose effect has been found that can be related to methodological problems citedearlier. In summary, smoking likely influences the course of the disease but the poten-tial impact, if any, on the long-term disability is difficult to quantify. Evidence regardingother extraneous factors is either weak or anecdotal.

CHILDHOOD-ONSET MS

The subpopulation of patients with MS onset in childhood has received great atten-tion recently, and an increasing number of studies are devoted to the delineation ofthe characteristics of the disease in this group. As an illustration of the influence ofage at onset, it has been shown that patients with childhood-onset MS take longerto reach disability landmarks than patients with adult-onset MS. In the KIDMUSstudy, characteristics of a cohort of 394 patients who had MS with an onset at16 years of age or younger and a group of 1775 patients who had MS with an onsetafter 16 years were compared.91 For patients with childhood-onset MS, the esti-mated median time from onset to DSS scores of 4, 6, and 7 were 20.0, 28.9, and37.0 years, respectively, and the corresponding median ages were 34.6, 42.2, and50.5 years for later onset. In comparison with patients with adult-onset disease,those with childhood onset took approximately 10 years longer to irreversibledisability. However, they reached these landmarks at an age approximately 10 yearsyounger. Using the same cohort, potential prognostic factors of assignment to thesame disability scores were assessed from 3 different time points during the earlycourse of the disease: at MS onset, at the time of the second neurologic episode,and finally 2 years after onset of MS. At MS onset, a progressive onset was asso-ciated with shorter times to reach irreversible disability (DSS 4, 6, and 7) comparedwith a relapsing-remitting onset. At the time of the second neurologic episode, thetime interval from onset of the disease to reach this second neurologic episodedid not influence the time to reach irreversible disability. Two years after MS onset,a progressive course at onset remained the main prognostic factor associated withthe highest increased risk of disability. The other significant prognostic factor was thenumber of relapses during the first 2 years of the disease. Each additional relapseincreased the rate of disability, although to a lesser extent than the initial course.Sex, age at onset, and initial symptoms were not associated with times to disabilityscores in any analysis. Age at assignment of irreversible disability (DSS 4, 6, and 7)was only influenced by the initial course of the disease: a progressive initial coursewas associated with a younger age at development of disability. Others assessedthe predictors of the assignment of an EDSS score of 4 in a cohort of 83 patients,all with a relapsing-remitting onset of MS and onset before the age of 16 (mediandisease duration 14.1 years).92 In multivariate analysis, only sphincter symptoms atonset of the disease and a secondary progressive evolution were associated with

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a higher risk of EDSS 4. Age at onset and time between first and second neurologicepisode were not prognostic factors.In conclusion, useful clinical predictors of long-term disability are lacking in

childhood-onset MS because the most influential predictor, a primary progressivepresentation, is rare in children. For the majority of patients, individualized prognosticis currently limited.

SUMMARY

Several prognostic factors of long-term irreversible disability have been describedin MS, mostly of demographic and clinical types. At onset, these prognosticfactors are ethnicity, sex, age, type of symptoms, and initial course. Later on,they include recovery from the initial symptoms, delay to the second neurologicepisode, number of relapses in the first few years, and clinical characteristics inthe early phase of the disease. This apparent profusion of predictors hides twoessential facts: most predictors have a minor influence on the long-term prog-nosis, and its corollary, which is that they are of limited value when applied atthe individual level, even in combination. Consequently, from a clinical perspective,efforts are currently shifting toward finding relevant paraclinical predictors anddeveloping validated prognostic models to improve the accuracy of individualprognosis. By contrast, the study of prognostic factors has given some insightsinto the pathogenesis of MS with the emergence of the following concepts.Relapses that are the clinical manifestation of acute focal inflammation havea minor impact on the accrual of long-term irreversible disability, which reflectschronic axonal loss. Rather, neurodegeneration seems to be, at least partly, anage-dependent process. From a therapeutic perspective, elucidating the exactmechanisms underlying neurodegeneration will hopefully lead to the developmentof new therapeutic targets, aside from those currently directed toward the controlof relapses and acute inflammation.

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