0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Neurological Review |

Clinical and Demographic Predictors of Long-term Disability in Patients With Relapsing-Remitting Multiple Sclerosis:  A Systematic Review FREE

Annette Langer-Gould, MS, MD; Rita A. Popat, PhD; Stella M. Huang, MS; Kristin Cobb, PhD; Paulo Fontoura, MD; Michael K. Gould, MS, MD; Lorene M. Nelson, PhD
[+] Author Affiliations

Author Affiliations: Department of Health Research and Policy, Stanford University School of Medicine (Drs Langer-Gould, Popat, Cobb, Gould, and Nelson and Ms Huang), and Department of Neurology, Stanford University (Dr Langer-Gould), Stanford, Calif; Department of Immunology, Faculty of Medical Sciences, New University of Lisbon, Lisbon, Portugal (Dr Fontoura); and VA Palo Alto Health Care System, Palo Alto, Calif (Dr Gould). Ms Huang is now with Touro University College of Osteopathic Medicine, Vallejo, Calif.


Section Editor: David E. Pleasure, MD

More Author Information
Arch Neurol. 2006;63(12):1686-1691. doi:10.1001/archneur.63.12.1686.
Text Size: A A A
Published online

Objective  To identify clinical and demographic factors associated with long-term disability in patients with relapsing-remitting multiple sclerosis.

Data Sources  We searched the MEDLINE (1966-May 2005), EMBASE, CINAHL, Cochrane, and PsycINFO computerized databases, and reviewed reference lists of retrieved articles.

Study Selection  We included studies that examined predictors of long-term disability in patients with relapsing-remitting multiple sclerosis. We excluded studies that did not distinguish relapsing-remitting multiple sclerosis from primary progressive multiple sclerosis, enrolled fewer than 40 subjects, observed subjects for less than 5 years, or collected follow-up information in less than 80% of the inception cohort.

Data Extraction  Two reviewers assessed study quality in 4 domains: cohort assembly, definitions and assessments of prognostic factors and outcomes, and statistical methods. One reviewer extracted data on the direction, magnitude, precision, and statistical significance of the effect of each predictor on prognosis.

Data Synthesis  Heterogeneity of study designs precluded us from pooling the results of 27 eligible studies. Study quality was limited by cross-sectional design, enrollment of prevalent cases from referral centers, and lack of multivariate adjustment. Sphincter symptoms at onset (hazard ratio, 1.1-3.1), incomplete recovery from the first attack (hazard ratio, 1.3-3.3), and a short interval between the first and second attack (hazard ratio, 1.6-1.9) were most strongly and consistently associated with poor prognosis. Other factors widely believed to be of prognostic importance, including sex and age at onset, demonstrated inconsistent or weak effects on prognosis.

Conclusions  The most robust predictors of long-term physical disability in relapsing-remitting multiple sclerosis are sphincter symptoms at onset and early disease course outcomes. These factors can be used to guide treatment decisions for drugs with significant toxicities.

Figures in this Article

Multiple sclerosis (MS) is a chronic inflammatory illness that usually begins in young adulthood. Two clinical subtypes of MS are distinguishable. Approximately 80% of patients have an initial disease course characterized by relapses and remissions. The remainder have primary progressive MS (PPMS) and experience progressive decline in neurological function from onset. To our knowledge, there are no effective therapies for PPMS, and almost all patients experience severe and early disability.

In patients with relapsing-remitting multiple sclerosis (RRMS), disability can result from 1 or more of the following: incomplete recoveries from relapses, development of secondary progressive MS (SPMS) (a delayed progressive course), or cognitive impairment. However, as many as 40% of patients with RRMS never develop a clinically important physical disability.1

Immunomodulatory therapies for RRMS can reduce the relapse rate and slow the progression of mild disability, but are also expensive, and some are potentially toxic.2,3 Furthermore, with the introduction of a highly sensitive diagnostic test—brain magnetic resonance imaging—the fraction of milder MS cases will likely increase.4 Clinicians need information about prognostic factors to help them distinguish between patients who are likely to develop disability—and, thus, should be treated—and those who are likely to have a more benign course and should not be exposed to potentially harmful therapies.

We systematically reviewed all English- and non–English-language studies of predictors of long-term disability in patients with RRMS.

STUDY IDENTIFICATION

We searched the MEDLINE, EMBASE, CINAHL, Cochrane, and PsycINFO databases in April 2004 and updated the MEDLINE search 1 year later. We also scanned reference lists of retrieved articles and relevant conference proceedings. Based on titles and abstracts, full reports were selected and evaluated for inclusion.

STUDY SELECTION

We included studies that (1) examined the effect of any clinical or demographic prognostic factor in patients with RRMS on physical or cognitive disability; (2) included at least 40 relapsing-onset participants in a cohort study or at least 20 relapsing-onset subjects with and 20 relapsing-onset subjects without significant disability in a cross-sectional or case-control study; and (3) for cohort studies, reported at least 5 years of longitudinal follow-up data for at least 80% of the inception cohort.

STUDY QUALITY AND DATA ABSTRACTION AND SYNTHESIS

We prospectively developed criteria to assess 4 different aspects of study quality (cohort assembly, measuring prognostic factors, measuring outcomes, and statistical methods) and applied them to included studies.

One investigator (A.L.-G.) abstracted relevant data from each study. Calculations to standardize data presentation were performed by 2 investigators (A.L.-G. and S.M.H.).

We identified 2812 potentially relevant titles. Eighty-nine reports met the inclusion criteria, including 21 unique studies532 of clinical and demographic characteristics. Sixteen reports515,17,18,2023,32 examined multiple baseline characteristics and intermediate outcomes as potential predictors of long-term disability (Table). Eight studies19,2430 focused on a single predictor (African American race,26,27 pregnancy,24,25 early age at onset, treatment with azathioprine,29 early disability,19 and later disease course disability18) and are not discussed further.

Table Graphic Jump LocationTable. Characteristics of Prognostic Studies Examining Multiple Predictors in Patients With RRMS
STUDY CHARACTERISTICS

In most studies, selection of subjects and potential prognostic factors seemed to have been driven by convenience rather than a priori hypotheses. Only 2 studies prospectively enrolled incident cases and were population based.57 Most studies were cross-sectional studies that enrolled prevalent cases from referral centers with varying years of disease duration and unknown periods of follow-up.

The characteristics of the cross-sectional studies814,17,18,2123 that examined multiple predictors varied widely in sample size (range, 186-1844), but most had similar distributions of onset forms, proportions of patients with RRMS and SPMS, proportion of women, and mean age at onset.

STUDY QUALITY

As a whole, the 27 included published studies532 had acceptable methods for selecting participants, but methods were suboptimal for measurement of outcomes, measurement of prognostic factors, and analysis of data. Fifteen studies515,17,18,2023,25,28,30,32 satisfied at least half of the criteria for cohort assembly, whereas only 9,6,7,1315,20,22,31 7,57,13,15,20,27,30,32 and 55,1012,20 studies satisfied at least half of the quality criteria for measurement of outcomes, measurement of prognostic factors, and statistical methods, respectively. Reporting of methods was insufficiently detailed in most studies. All but 2 studies relied on records obtained at routine medical care to assess prognostic variables and outcomes.

Eight studies5,6,812,27 reported the results of multivariate analyses predicting prognosis in patients with RRMS. These analyses were of varying quality. One study8 used a hypothesis-driven approach when choosing variables for the multivariate model, but 4 studies5,6,9,10 chose factors based solely on the P values from univariate analyses. Only 1 study11 systematically examined potential confounders and subgroup effects, such as relapse frequency and relapse symptoms.

SPECIFIC PROGNOSTIC FACTORS

The Figure summarizes the results by study. Heterogeneity in patient populations, definitions of prognostic factors, and definitions of disability precluded us from pooling results across studies. Differences in the direction or magnitude of effects between studies could not be consistently explained by cross-sectional vs cohort study design, definition of disability (Expanded Disability Status Scale score of 4 vs Expanded Disability Status Scale score of 6 vs SPMS), or effect estimate reported (hazard ratio vs odds ratio). However, changing the definition of disability altered the effect sizes derived from the same study populations for relapse frequency, age, multiple neuroanatomical regions involved, multiple neurological symptoms, and motor symptoms at onset. For age and optic neuritis at onset, varying the definition of the predictor significantly influenced effect sizes between studies.

Place holder to copy figure label and caption
Figure.

Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) of long-term disability in patients with relapsing-onset multiple sclerosis for demographic and clinical predictors, including male sex (A), age at onset (B), motor symptoms (C), optic neuritis (D), sphincter symptoms (E), sensory symptoms (F), brainstem symptoms (G), cerebellar symptoms (H), incomplete recovery from the first attack (I), longer first to second attack interval (J), and early relapse frequency (K). Where CIs are missing, it is because studies did not report them. If a study reported only median time, an HR was calculated by dividing median times, but P values reported reflect the results of the study-reported log-rank test. Squares indicate unadjusted estimates and diamonds represent adjusted estimates. EDSS indicates Expanded Disability Status Scale; EDSS score of 4, moderate neurological disability but fully ambulatory without aid; EDSS score of 6, requiring unilateral assistance to ambulate (eg, a cane); EDSS score of 6 or more, cane or worse; EDSS score of 7, essentially restricted to a wheelchair; EDSS score of 7 or more, wheelchair or worse; NA, data not available; NS, not significant; SPMS, secondary progressive multiple sclerosis; asterisk, P≤.20; dagger, subgroup analysis of patients with more than 5 years' disease duration; double dagger, subgroup analysis of patients with 15 or more years' disease duration; section mark, odds ratio compared with patients with relapsing-remitting multiple sclerosis or patients with normal or mildly impaired walking (Poser13); parallel mark, P<.05; paragraph symbol, P<.001; and number sign, P<.01.

Graphic Jump Location
SEX

Male sex is commonly believed to be a risk factor for poor prognosis in RRMS, but the evidence is mixed. Of the 10 studies that considered sex,5,6,813,15,17 2 showed that men with RRMS were at significantly greater risk after adjusting for other factors10,11 and 3 showed a nonsignificant trend of increased risk among men.5,6,8 The remaining 5 studies9,12,13,15,17 found no effect for sex.

AGE AT ONSET

Older age at onset was associated with a worse prognosis in all but 1 study,12 but the strength of the association varied depending on how older age at onset was defined and how disability was defined. When continuous measures of age at onset were used,8,10,11,15 the risk of developing SPMS per decade ranged from 10% to 34%. When age was dichotomized,5,6,9,13,14 the increased risk of disability for patients who were older at onset ranged from 9% to 192%. A single study12 reported a better prognosis in patients with an older age at onset when the cut point for older age at onset was set at 25 years.

Differences in the definition of disability also affected the results. Varying the definition of disability from development of SPMS to “severely impaired or lost walking” changed the odds ratio from 2.12 to 1.09 in the same population of patients.13 Thus, age at onset does not seem to be a robust predictor of disability.

TYPE OF SYMPTOMS AT ONSET

Except for sphincter involvement, the studies showed mixed, weak, or no effect of different types of symptoms at onset on prognosis. Bowel and/or bladder involvement was associated with an unfavorable prognosis. In 4 studies,911,15 sphincter involvement at onset substantially increased the risk of disability (hazard ratio [HR], 1.5-3.1), although 1 study12 found no independent effect of sphincter symptoms on outcome. Bergamaschi et al11 found that relapses with sphincter involvement predicted worse prognosis than relapses without sphincter involvement.

Clinical symptoms consistent with the involvement of multiple neuroanatomical regions at onset were associated with a slightly worse prognosis in 1 study,5 but had no effect in 2 other studies.10,14 Multiple neurological symptoms at onset showed no effect on disability in 2 studies,6,12 increased risk of disability (HR, 1.84) in 1 study,15 and varied effect depending on the definition of disability in a fourth study.9 Motor/pyramidal symptoms increased the risk of disability,8,9,15 showed a trend toward an increased risk of SPMS,11 or showed no effect on disability.6,10,12 Sensory symptoms at onset had no beneficial or adverse effects on prognosis in 7 studies,6,9,10,12,15,17 and marginally decreased the risk of developing SPMS (HR, 0.71; P=.08) in 1 study.8 Brainstem symptoms at onset showed mixed results; 1 study15 showed an increased risk, 1 study14 reported decreased odds, and the 2 remaining studies8,12 reported no significant effect. Cerebellar symptoms at onset were associated with a 50% to 60% increased risk of developing SPMS in 2 studies,8,15 but had no effect in 3 other studies.12,14,17 Patients who had optic neuritis as a presenting symptom had a lower risk of developing SPMS in 2 studies (HR, 0.528; odds ratio, 0.4716), while 6 studies6,9,10,12,14,17 found no effect. One study15 found a large increased risk of developing SPMS (HR, 2.56; 95% confidence interval, 1.52-4.32) in patients with optic neuritis at onset, but this study defined optic neuritis as severe vs mild or no visual impairment, whereas the other studies defined optic neuritis as either present or absent.

EARLY OUTCOMES AS PREDICTORS

Early disease outcomes were remarkably consistent predictors of future disability. Incomplete recovery from the first attack was a consistently strong predictor of a poor prognosis in 5 studies (HR, 1.3-3.3).5,11,12,15,18 A longer time to a second attack decreased the risk of developing long-term disability despite variability in defining the attack interval and the definition of disability in 36,9,15 of 46,9,15,18 studies. Conversely stated, a shorter interval between the first and second attack confers a worse prognosis (HR, 1.6-1.9). In contrast, a higher early relapse frequency was not always associated with poor prognosis and, within studies, the magnitude of effect was influenced by the definition of disability. Bergamaschi et al11 showed that patients with high rates of motor and sphincter relapses are at high risk of developing SPMS. Thus, while relapse frequency is modestly predictive, the type of relapse may be more important. One study5 found that incomplete remission after last relapse, cognitive symptoms, and more severe deficits 5 years after the onset of MS were predictive of long-term disability. Achiron et al19 reported that having an Expanded Disability Status Scale score of less than 2 after 1 year was predictive of having an Expanded Disability Status Scale score of less than 3 after 10 years.

This systematic review found that the strongest and most consistent predictors of long-term physical disability in patients with relapsing-onset MS are sphincter symptoms at onset and early disease course outcomes. Bladder or bowel symptoms at onset, incomplete recovery from the first attack, a short interval between the first and second attack, and early accumulation of disability should alert clinicians to a potentially worse disease course.

Many MS experts believe that female sex, younger age at onset, optic neuritis, and sensory symptoms at onset indicate a more favorable prognosis in patients with RRMS, whereas motor or cerebellar symptoms at onset predict a more severe course.33,34

In this methodologically rigorous and systematic review, we show that many of these factors have no consistent influence (eg, optic neuritis), weak effects (eg, sex, age at onset, and cerebellar involvement), or no effect (eg, sensory symptoms) on prognosis. A critical review of the existing literature does not support using these factors to guide treatment decisions or predict prognosis for patients with RRMS.

Many clinical trials in RRMS routinely enroll patients with a normal neurological examination result, regardless of disease duration and the test drug safety profile. The enrollment criteria for these trials make no attempt to target patients at high risk of developing disability. While this may be acceptable for safe drugs, it seems unreasonable for drugs with serious or unknown toxicities. One woman who received natalizumab during one such recent trial2 died of progressive multifocal leukoencephalopathy. According to the findings of this systematic review, she had no significant risk factors for developing long-term disability, and would have been unlikely to benefit from therapy. Until other reliable indicators of prognosis are identified, we recommend that enrollment in clinical trials of drugs with unknown safety or efficacy profiles be restricted to patients with early accumulation of disability, incomplete recovery from a first attack, and/or bowel or bladder symptoms at onset.

Findings from this systematic review suggest that relapse frequency by itself is an inadequate predictor of long-term disability in RRMS. Because counting relapses does not distinguish between mild and severe relapses, it is not surprising that the severity and type of relapse may be more predictive than relapse frequency.11 Accordingly, clinical trials of MS therapies should use sustained disability as their primary outcome, rather than relapse frequency. We also suggest that clinical trialists report the extent and duration of disability at baseline to ensure that participants are balanced on these factors after randomization.

Some of the most commonly cited MS natural history studies33,35 did not meet our inclusion criteria because they did not distinguish between PPMS and RRMS. Prognosis differs considerably for patients with PPMS and patients with RRMS. Therefore, analyses that do not exclude patients with PPMS may obscure positive associations or identify spurious predictors of prognosis in patients with RRMS.

An important limitation of our review is that the quality of the primary studies was suboptimal. All of the studies used outdated diagnostic criteria, and none examined predictors of cognitive disability. There were few population-based studies, few cohort studies, and few studies that used multivariate models to estimate the independent effects of prognostic factors.

These limitations highlight the need for new prognostic studies that enroll incident cases diagnosed during an era in which brain magnetic resonance imaging is widely used, use a cohort design, and analyze data by using hypothesis-driven multivariate models.

Correspondence: Annette Langer-Gould, MS, MD, Stanford University School of Medicine, HRP Redwood Building, Room T202 MC 5405, Stanford, CA 94305 (annette1@stanford.edu).

Accepted for Publication: May 12, 2006.

Author Contributions:Study concept and design: Langer-Gould, Gould, and Nelson. Acquisition of data: Langer-Gould, Popat, Huang, and Fontoura. Analysis and interpretation of data: Langer-Gould, Huang, Cobb, and Nelson. Drafting of the manuscript: Langer-Gould, Cobb, Gould, and Nelson. Critical revision of the manuscript for important intellectual content: Langer-Gould, Popat, Huang, Cobb, Fontoura, Gould, and Nelson. Statistical analysis: Langer-Gould, Huang, Cobb, and Nelson. Obtained funding: Langer-Gould. Administrative, technical, and material support: Langer-Gould and Huang. Study supervision: Langer-Gould, Gould, and Nelson. Reviewed quality inclusion criteria: Popat.

Financial Disclosure: Dr Langer-Gould has received consulting fees from Genentech, Amgen, and Biogen Idec; and Dr Nelson has received consulting fees from Amgen. As of September 11, 2006, Dr Langer-Gould is a full-time employee of Genentech.

Funding/Support: This study was supported by K23 grant NS43207 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (Dr Langer-Gould); and Advanced Research Career Development Award RCD 99-023-2 from the VA Health Services Research and Development Service (Dr Gould).

Acknowledgment: We thank Chris Stave for his assistance with the literature searches; Jean Dominique Delacroix, PhD, Carolina Albers, PhD, Alexander Kleschevnikov, PhD, Damien Colas, PhD, Pavel Belichenko, PhD, and Chengbiao Wu, PhD, for reviewing the non–English-language articles; and Elizabeth Hoyte for her help in preparing the forest plots.

Pittock  SJMcClelland  RLMayr  WT  et al.  Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 2004;56303- 306
PubMed Link to Article
Kleinschmidt-DeMasters  BKTyler  KL Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353369- 374
PubMed Link to Article
Langer-Gould  AAtlas  SWGreen  AJBollen  AWPelletier  D Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353375- 381
PubMed Link to Article
Black  WCWelch  HG Screening for disease. AJR Am J Roentgenol 1997;1683- 11
PubMed Link to Article
Eriksson  MAndersen  ORunmarker  B Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler20039260274 [published correction appears in Mult Scler. 2003;9:641].
PubMed
Myhr  KMRiise  TVedeler  C  et al.  Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Scler 2001;759- 65
PubMed Link to Article
Runmarker  BAndersen  O Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 1993;116117- 134
PubMed Link to Article
Riise  TGronning  MFernandez  O  et al.  Early prognostic factors for disability in multiple sclerosis, a European multicenter study. Acta Neurol Scand 1992;85212- 218
PubMed Link to Article
Simone  ILCarrara  DTortorella  C  et al.  Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology 2002;591922- 1928
PubMed Link to Article
Kantarci  OSiva  AEraksoy  M  et al. Turkish Multiple Sclerosis Study Group (TUMSSG), Survival and predictors of disability in Turkish MS patients. Neurology 1998;51765- 772
PubMed Link to Article
Bergamaschi  RBerzuini  CRomani  ACosi  V Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis. J Neurol Sci 2001;18913- 21
PubMed Link to Article
Trojano  MAvolio  CManzari  C  et al.  Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events. J Neurol Neurosurg Psychiatry 1995;58300- 306
PubMed Link to Article
Poser  S Multiple sclerosis: an analysis of 812 cases by means of electronic data processing. Schriftenr Neurol 1978;201- 93
PubMed
Phadke  JG Clinical aspects of multiple sclerosis in north-east Scotland with particular reference to its course and prognosis. Brain 1990;1131597- 1628
PubMed Link to Article
Amato  MPPonziani  GBartolozzi  MLSiracusa  G A prospective study on the natural history of multiple sclerosis: clues to the conduct and interpretation of clinical trials. J Neurol Sci 1999;16896- 106
PubMed Link to Article
Potemkowski  A Optic neuritis as the initial manifestation of multiple sclerosis [in Polish]. Klin Oczna 2000;10295- 98
PubMed
Moreira  MAFelipe  EMendes  MFTilbery  CP Multiple sclerosis: descriptive study of its clinical forms in 302 cases [in Portuguese]. Arq Neuropsiquiatr 2000;58460- 466
PubMed Link to Article
Confavreux  CVukusic  SAdeleine  P Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003;126770- 782
PubMed Link to Article
Achiron  ABarak  YRotstein  Z Longitudinal disability curves for predicting the course of relapsing-remitting multiple sclerosis. Mult Scler 2003;9486- 491
PubMed Link to Article
Rudick  RACutter  GBaier  M  et al.  Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS. Neurology 2001;561324- 1330
PubMed Link to Article
Confavreux  CAimard  GDevic  M Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980;103281- 300
PubMed Link to Article
Bernardi  SButtinelli  CGrasso  MG  et al.  Evolution and severity markers in 233 MS patients. Riv Neurol 1987;57197- 200
PubMed
Thompson  AJHutchinson  MBrazil  JFeighery  CMartin  EA A clinical and laboratory study of benign multiple sclerosis. Q J Med 1986;5869- 80
PubMed
Runmarker  BAndersen  O Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain 1995;118253- 261
PubMed Link to Article
Roullet  EVerdier-Taillefer  MHAmarenco  PGharbi  GAlperovitch  AMarteau  R Pregnancy and multiple sclerosis: a longitudinal study of 125 remittent patients. J Neurol Neurosurg Psychiatry 1993;561062- 1065
PubMed Link to Article
Cree  BAKhan  OBourdette  D  et al.  Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis. Neurology 2004;632039- 2045
PubMed Link to Article
Weinstock-Guttman  BJacobs  LDBrownscheidle  CM  et al.  Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium. Mult Scler 2003;9293- 298
PubMed Link to Article
Boiko  AVorobeychik  GPaty  DDevonshire  VSadovnick  D Early onset multiple sclerosis: a longitudinal study. Neurology 2002;591006- 1010
PubMed Link to Article
Aimard  GConfavreux  CVentre  JJGuillot  MDevic  M Study of 213 cases of multiple sclerosis treated with azathioprine from 1967- to 1982 [in French]. Rev Neurol (Paris) 1983;139509- 513
PubMed
Confavreux  CVukusic  SMoreau  TAdeleine  P Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;3431430- 1438
PubMed Link to Article
Gaudino  EAChiaravalloti  NDDeLuca  JDiamond  BJ A comparison of memory performance in relapsing-remitting, primary progressive and secondary progressive, multiple sclerosis. Neuropsychiatry Neuropsychol Behav Neurol 2001;1432- 44
PubMed
Amato  MPPonziani  G A prospective study on the prognosis of multiple sclerosis. Neurol Sci 2000;21(suppl 2)S831- S838
PubMed Link to Article
Weinshenker  BGRice  GPNoseworthy  JHCarriere  WBaskerville  JEbers  GC The natural history of multiple sclerosis: a geographically based study, 3: multivariate analysis of predictive factors and models of outcome. Brain 1991;1141045- 1056
PubMed Link to Article
Waubant  EGoodkin  DE Multiple sclerosis.  In: R  EvansDS  BaskinFM  Yatsu eds. Prognosis of Neurological Disorders. New York, NY: Oxford University Press Inc; 2000:291313
Kurtzke  JFBeebe  GWNagler  BAuth  TLKurland  LTNefzger  MD Studies on the natural history of multiple sclerosis, 6: clinical and laboratory findings at first diagnosis. Acta Neurol Scand 1972;4819- 46
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) of long-term disability in patients with relapsing-onset multiple sclerosis for demographic and clinical predictors, including male sex (A), age at onset (B), motor symptoms (C), optic neuritis (D), sphincter symptoms (E), sensory symptoms (F), brainstem symptoms (G), cerebellar symptoms (H), incomplete recovery from the first attack (I), longer first to second attack interval (J), and early relapse frequency (K). Where CIs are missing, it is because studies did not report them. If a study reported only median time, an HR was calculated by dividing median times, but P values reported reflect the results of the study-reported log-rank test. Squares indicate unadjusted estimates and diamonds represent adjusted estimates. EDSS indicates Expanded Disability Status Scale; EDSS score of 4, moderate neurological disability but fully ambulatory without aid; EDSS score of 6, requiring unilateral assistance to ambulate (eg, a cane); EDSS score of 6 or more, cane or worse; EDSS score of 7, essentially restricted to a wheelchair; EDSS score of 7 or more, wheelchair or worse; NA, data not available; NS, not significant; SPMS, secondary progressive multiple sclerosis; asterisk, P≤.20; dagger, subgroup analysis of patients with more than 5 years' disease duration; double dagger, subgroup analysis of patients with 15 or more years' disease duration; section mark, odds ratio compared with patients with relapsing-remitting multiple sclerosis or patients with normal or mildly impaired walking (Poser13); parallel mark, P<.05; paragraph symbol, P<.001; and number sign, P<.01.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Characteristics of Prognostic Studies Examining Multiple Predictors in Patients With RRMS

References

Pittock  SJMcClelland  RLMayr  WT  et al.  Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 2004;56303- 306
PubMed Link to Article
Kleinschmidt-DeMasters  BKTyler  KL Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353369- 374
PubMed Link to Article
Langer-Gould  AAtlas  SWGreen  AJBollen  AWPelletier  D Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353375- 381
PubMed Link to Article
Black  WCWelch  HG Screening for disease. AJR Am J Roentgenol 1997;1683- 11
PubMed Link to Article
Eriksson  MAndersen  ORunmarker  B Long-term follow up of patients with clinically isolated syndromes, relapsing-remitting and secondary progressive multiple sclerosis. Mult Scler20039260274 [published correction appears in Mult Scler. 2003;9:641].
PubMed
Myhr  KMRiise  TVedeler  C  et al.  Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Scler 2001;759- 65
PubMed Link to Article
Runmarker  BAndersen  O Prognostic factors in a multiple sclerosis incidence cohort with twenty-five years of follow-up. Brain 1993;116117- 134
PubMed Link to Article
Riise  TGronning  MFernandez  O  et al.  Early prognostic factors for disability in multiple sclerosis, a European multicenter study. Acta Neurol Scand 1992;85212- 218
PubMed Link to Article
Simone  ILCarrara  DTortorella  C  et al.  Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology 2002;591922- 1928
PubMed Link to Article
Kantarci  OSiva  AEraksoy  M  et al. Turkish Multiple Sclerosis Study Group (TUMSSG), Survival and predictors of disability in Turkish MS patients. Neurology 1998;51765- 772
PubMed Link to Article
Bergamaschi  RBerzuini  CRomani  ACosi  V Predicting secondary progression in relapsing-remitting multiple sclerosis: a Bayesian analysis. J Neurol Sci 2001;18913- 21
PubMed Link to Article
Trojano  MAvolio  CManzari  C  et al.  Multivariate analysis of predictive factors of multiple sclerosis course with a validated method to assess clinical events. J Neurol Neurosurg Psychiatry 1995;58300- 306
PubMed Link to Article
Poser  S Multiple sclerosis: an analysis of 812 cases by means of electronic data processing. Schriftenr Neurol 1978;201- 93
PubMed
Phadke  JG Clinical aspects of multiple sclerosis in north-east Scotland with particular reference to its course and prognosis. Brain 1990;1131597- 1628
PubMed Link to Article
Amato  MPPonziani  GBartolozzi  MLSiracusa  G A prospective study on the natural history of multiple sclerosis: clues to the conduct and interpretation of clinical trials. J Neurol Sci 1999;16896- 106
PubMed Link to Article
Potemkowski  A Optic neuritis as the initial manifestation of multiple sclerosis [in Polish]. Klin Oczna 2000;10295- 98
PubMed
Moreira  MAFelipe  EMendes  MFTilbery  CP Multiple sclerosis: descriptive study of its clinical forms in 302 cases [in Portuguese]. Arq Neuropsiquiatr 2000;58460- 466
PubMed Link to Article
Confavreux  CVukusic  SAdeleine  P Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003;126770- 782
PubMed Link to Article
Achiron  ABarak  YRotstein  Z Longitudinal disability curves for predicting the course of relapsing-remitting multiple sclerosis. Mult Scler 2003;9486- 491
PubMed Link to Article
Rudick  RACutter  GBaier  M  et al.  Use of the Multiple Sclerosis Functional Composite to predict disability in relapsing MS. Neurology 2001;561324- 1330
PubMed Link to Article
Confavreux  CAimard  GDevic  M Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980;103281- 300
PubMed Link to Article
Bernardi  SButtinelli  CGrasso  MG  et al.  Evolution and severity markers in 233 MS patients. Riv Neurol 1987;57197- 200
PubMed
Thompson  AJHutchinson  MBrazil  JFeighery  CMartin  EA A clinical and laboratory study of benign multiple sclerosis. Q J Med 1986;5869- 80
PubMed
Runmarker  BAndersen  O Pregnancy is associated with a lower risk of onset and a better prognosis in multiple sclerosis. Brain 1995;118253- 261
PubMed Link to Article
Roullet  EVerdier-Taillefer  MHAmarenco  PGharbi  GAlperovitch  AMarteau  R Pregnancy and multiple sclerosis: a longitudinal study of 125 remittent patients. J Neurol Neurosurg Psychiatry 1993;561062- 1065
PubMed Link to Article
Cree  BAKhan  OBourdette  D  et al.  Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis. Neurology 2004;632039- 2045
PubMed Link to Article
Weinstock-Guttman  BJacobs  LDBrownscheidle  CM  et al.  Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium. Mult Scler 2003;9293- 298
PubMed Link to Article
Boiko  AVorobeychik  GPaty  DDevonshire  VSadovnick  D Early onset multiple sclerosis: a longitudinal study. Neurology 2002;591006- 1010
PubMed Link to Article
Aimard  GConfavreux  CVentre  JJGuillot  MDevic  M Study of 213 cases of multiple sclerosis treated with azathioprine from 1967- to 1982 [in French]. Rev Neurol (Paris) 1983;139509- 513
PubMed
Confavreux  CVukusic  SMoreau  TAdeleine  P Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;3431430- 1438
PubMed Link to Article
Gaudino  EAChiaravalloti  NDDeLuca  JDiamond  BJ A comparison of memory performance in relapsing-remitting, primary progressive and secondary progressive, multiple sclerosis. Neuropsychiatry Neuropsychol Behav Neurol 2001;1432- 44
PubMed
Amato  MPPonziani  G A prospective study on the prognosis of multiple sclerosis. Neurol Sci 2000;21(suppl 2)S831- S838
PubMed Link to Article
Weinshenker  BGRice  GPNoseworthy  JHCarriere  WBaskerville  JEbers  GC The natural history of multiple sclerosis: a geographically based study, 3: multivariate analysis of predictive factors and models of outcome. Brain 1991;1141045- 1056
PubMed Link to Article
Waubant  EGoodkin  DE Multiple sclerosis.  In: R  EvansDS  BaskinFM  Yatsu eds. Prognosis of Neurological Disorders. New York, NY: Oxford University Press Inc; 2000:291313
Kurtzke  JFBeebe  GWNagler  BAuth  TLKurland  LTNefzger  MD Studies on the natural history of multiple sclerosis, 6: clinical and laboratory findings at first diagnosis. Acta Neurol Scand 1972;4819- 46
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 55

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections