Clinical Features and Natural History of Multiple Sclerosis

1

Clinical Features and Natural History of Multiple Sclerosis: The Nature of the Beast Sean Joseph Pittock

Disability Progression: What Happens to Patients over Time? Time from Onset to Disability Milestones Time from Onset to Disability Milestones Stratified by Multiple Sclerosis Clinical Subgroups What Affects Long-Term Disability Outcome? Clinical Relapses Clinical Status at 5 and 10 Years As a Predictor of Long-Term Outcome

Age at Disability Milestones: A Novel Approach to Data Analysis Benign Multiple Sclerosis Definition Predicting a Benign Course Cognitive Outcomes in Benign Multiple Sclerosis

For the practicing neurologist, knowledge of the natural history of multiple sclerosis (MS) that encompasses the overall course and prognosis is a prerequisite to the counseling of a patient who is given such a diagnosis. When confronted with the reality of MS for the first time, patients’ first questions relate to long-term prognosis: What will happen to me? From a health research point of view, knowledge of the natural history of MS affects how we think about the pathophysiology of MS, guides therapeutic trial design, assists in health care economics and service provision, and provides a benchmark against which therapeutic trial efficacy can be compared. Natural history data is best obtained from populations of patients that are representative of MS as a whole, such as all MS patients living within a well-defined geographic area. These population-based cohorts are more representative of the disease than hospital- or clinic-based cohorts, which tend to overrepresent more severe disability and may provide an overpessimistic view. The natural history of MS is among the best studied chronic medical illnesses. Despite a wealth of information gained from large, population-based studies on clinical features predictive of future course and outcome, the ability to apply this knowledge to an individual patient to allow prediction or prognostication has been problematic. This review focuses on recently published natural history studies, early clinical predictors of disability outcome and their application to an individual patient,





Multiple Sclerosis 3

the controversy surrounding the entity of benign MS, and some recent new approaches to data set analysis with emphasis on age at disability milestones rather than time to reach disability milestones.

Disability Progression: What Happens to Patients over Time? The evolution of MS over time is well studied worldwide, and results are generally consistent among investigators, although some recent natural history ­studies from North America have suggested a better global prognosis.1,2 It is important to note that these studies have relied heavily on measures of impairment, specifically the Expanded Disability Status Scale (EDSS) score, as an outcome measure.3 The EDSS scores range from 0 (no disability) to 10 (death). Cutoff scores most commonly used in natural history studies include mild to moderate disability, with an EDSS score of 3 (e.g., mild paralysis) or EDSS 4 (limited walking ability but able to walk without aid or rest for > 500 m); EDSS 6, which indicates the need for a cane or unilateral support and ability to walk no more than 100 m without rest; and EDSS 8 (need for wheelchair) or EDSS 7 (ability to walk no more than 10 m without rest while leaning against a wall or holding onto furniture for support). Time from Onset to Disability Milestones Natural history studies have focused on the time from onset or diagnosis of the disease to the assignment of one of these EDSS scores; these data provide information regarding the rate of disability progression. If one considers population-based studies of MS in general, median time from onset of MS to EDSS 3 or EDSS 4 ranged from 6 to 23 years.1,2,4-8 Median time from onset of disease to EDSS 6 was somewhat more consistent (because need for a cane is a more robust and reliable outcome measure) and varied between 16 and 28 years.1,5-8 Time from onset to the need for a wheelchair ranged from 30 to 52 years for population-based cohorts.1,5,8 In a retrospective review of prospectively collected data from all 2837 patients, followed prospectively for 22,723 patient years, registered with one of the four MS clinics in British Columbia, 21% required a cane after 15 years of disease.2 This frequency increased to 69% by 40 years after onset. At 30 and 40 years after onset, 14% and 22% of patients, respectively, required a wheelchair. Time from Onset to Disability Milestones Stratified by Multiple Sclerosis Clinical Subgroups The initial course has a significant impact on the time from onset to specific levels of disability. In 1996, a formal classification of MS disease subtypes was published that has become widely accepted.9 • Relapsing-remitting (RR): Clearly defined disease relapses with full recovery or with sequelae and residual deficit on recovery; periods between disease relapses characterized by a lack of disease progression • Secondary progressive (SP): Initial RR disease course followed by progression with or without occasional relapses, minor remissions, and plateaus

1  •  Clinical Features and Natural History of Multiple Sclerosis: The Nature of the Beast

• Primary progressive (PP): Disease progression from onset with occasional plateaus and temporary minor improvements allowed • Progressive relapsing (PR): Progressive disease from onset with clear acute relapses, with or without full recovery; periods between relapses characterized by continuing progression. A more recent proposed classification is ­illustrated in Figure 1-1.10 • Another classification type used by some investigators is that of single-attack progressive (SAP) MS, in which there is a single “onset attack” followed later by a progressive course.11 In population-based studies, an RR onset is most frequent (95% in Olmsted ­County, Minnesota; 66% in London, Ontario; 87.6% in British Columbia; 85% in Lyon, France).1,2,5,8 The frequency of conversion from RRMS to SPMS reported for the Ontario cohort increased with duration of disease (12% at 5 years, 41% at 10 years, 58% at 15 years, and 89% at > 26 years).8 Other studies have reported a lower frequency of conversion.1,2 Frequencies of PPMS and PRMS (both of which are considered progressive from onset) vary from 9% to 19% and from 6% to 15%, respectively.5,8 Patients with an RR course take a longer time from onset to reach disability milestones than do patients with an initially progressive course (Fig. 1-2). Myhr and colleagues reported a 72% probability of not needing a cane after 15 years of disease for patients with RRMS, compared with only 10% for those with PPMS.12 Similarly, RRMS patients had an 84% probability of not needing a wheelchair after 15 years, compared with 42% for those with PPMS. In the Olmsted County 2000 study, median time from onset to the need for a cane (see Fig. 1-2B) in patients who continued to have an RR course was 51 years, compared with 17.9 years for those with SPMS and 6.3 years for those with PPMS.1 In the French population-based Lyon cohort, the median time from onset to need for a cane was Onset of MS

Course of MS Relapsingremitting

Relapsingremitting

Secondary progressive nonrelapsing Secondary progressive relapsing Primary progressive nonrelapsing

Progressive Primary progressive relapsing

Secondary progressive

Primary progressive

Figure 1–1  Proposed classification of the onset and course of multiple sclerosis (MS). (Repro-

duced from Confavreux C, Vukusic S: Natural history of multiple sclerosis: Implications for counselling and therapy. Curr Opin Neurol 2002;15:257-266, with permission of Lippincott Williams and Wilkins, online at http://www.lww.com.)



Multiple Sclerosis 3

RR (n = 130) Total (n = 201)

SP (n = 60) PP (n = 11)

RR (n = 130) Total (n = 201)

100

80

80

Patients (%)

100 Patients (%)

60 40 20 0

A

0

20 25 30 5 10 15 Years from MS onset to EDSS 3

B

SP (n = 60) PP (n = 11)

60 40 20 0

RR (n = 130) Total (n = 201)

0

20 25 30 5 10 15 Years from MS onset to EDSS 6

SP (n = 60) PP (n = 11)

100 Patients (%)



80 60 40 20 0

20 25 30 5 10 15 Years from MS onset to EDSS 8 Figure 1–2  Time to Expanded Disability Status Scale (EDSS) score by multiple sclerosis (MS) subtype for the 2000 Olmsted County MS population. A, Years from MS onset to EDSS 3 (minimal ­disability but fully ambulatory). B, Years from MS onset to EDSS 6 (use of a cane). C, Years from MS onset to EDSS 8 (use of a wheelchair). RR refers to patients who continue to have a ­relapsing­remitting course and therefore excludes secondary progressive cases. PP, primary ­ progressive; SP, secondary progressive. (Data from Pittock SJ, Mayr WT, McClelland RL, et al: Disability ­profile of MS did not change over 10 years in a population-based prevalence cohort. Neurology 2004;62:601-606.)

C

0

23 years for patients with an RR course, compared with 7 years for patients with a PP course.5 In a recent natural history study of PPMS from British ­Columbia, ­Canada, progression of disability was slower than previously reported. The ­median time from onset to requiring a cane was 13.3 years; however, there was considerable variation. Although 25% of the patients had reached EDSS 6 after 7.3 years, ­another 25% did not require a cane after 25 years.13

What Affects Long-Term Disability Outcome? A multitude of demographic and clinical variables including female gender, a younger age at onset, sensory symptoms or optic neuritis, and a monosymptomatic presentation at onset have been associated with a favorable course.14-16 In contrast, prognostic variables associated with a poor outcome have included male gender; onset with motor, sphincter, or cerebellar features; poor recovery from initial or early attacks; higher attack rate in the first 5 years; and a

1  •  Clinical Features and Natural History of Multiple Sclerosis: The Nature of the Beast

­progressive course.8,14-16 These statistically significant associations have generally been reported in the context of univariate and, less frequently, multivariate analysis. Few predictors of outcome have been reported for PPMS.13 Although individual factors are often statistically significant when considering large population-based cohorts, their clinical prognostic applicability to an individual MS patient is much less reliable. There is little doubt that the initial course from onset is the strongest clinical predictor of how quickly a patient will reach disability milestones. Clinical Relapses Disease-modifying agents (DMAs) have been shown in large, randomized controlled trials to reduce the relapse rate and to reduce the accrual of lesions ­identified on magnetic resonance imaging.14,17-19 Whether they have a significant clinical benefit over the long term remains unclear. For RRMS, a central and highly controversial question is whether the frequency (and severity) of relapses influences disability progression in MS.20,21 Reported relapse rates have differed among MS studies, with prospective assessments at close intervals yielding the highest and probably the most sensitive results.20 A yearly relapse rate of 0.5 is probably a reasonable estimate in a population-based sample of patients with RRMS.20 In the Ontario study, 58% of 681 patients with RR disease had one attack during the first 2 years, 21% had two attacks, and only 20% had three or more attacks in the first 2 years of disease.22 Natural history studies from Lyon, Ontario, and Turkey have shown a weak association between number of relapses in the first 2 to 5 years and long-term disability outcome, although causality has not been ­established.5,6,16 Other studies failed to conclude that number of relapses in the first few years influences final outcome, and more recent, large natural history studies have provided convincing evidence of a dissociation between relapses and disability progression.11,21,23,24 In fact, at the Jekyll Island conference on MS clinical trial outcome measures, relapse frequency was ranked 11th in terms of perceived importance in measuring therapeutic response in MS.25 The Lyon group reported that, once a detectable threshold of irreversible disability (EDSS 4) was reached, the disease entered a state of uniform progression that did not appear to be influenced by the presence or absence of superimposed relapses (Fig. 1-3).21 Patients with a progressive course from onset reached ­irreversible disability much quicker than patients with an RR-onset course ­(median, 0.0 versus 11.4 years). However, once this point of irreversible disability was reached, the times to EDSS 6 (median, 5.7 versus 5.4 years) or EDSS 7 (median, 12.1 versus 12.0 years) were similar (P > .70) regardless of onset course.21 In the Olmsted County population-based study, the time to development of a clinical threshold of disability (EDSS 3), whether 2, 5, or 10 years, did not affect the rate of further progression (Fig. 1-4).1 Among patients with PPMS, the time course of progressive disability was not significantly influenced by the presence or absence of superimposed relapses (Fig. 1-5).21 For patients with SPMS (initially RR), the median time from EDSS 4 to EDSS 6 was similar for 292 patients without and 191 patients with superimposed relapses (4.0 versus 4.4, respectively; P = .68; see Fig. 1-5).21 Surprisingly, patients with superimposed relapses had a more favorable outcome than those without superimposed relapses, with a longer time from EDSS 4 to EDSS 7 (10 versus 7.8 years; P = .04). Similarly, superimposed relapses were





100

100 Patients (%)

Patients (%)

80

RR onset

60 P < .001

40 20 0

No. at risk RR onset Progressive onset

60 Progressive onset

40 20

Progressive onset 0

P = .74

10 20 30 Years after onset of MS

0

40

Multiple Sclerosis 3

80

RR onset 0

5 10 15 20 Years after assignment of EDSS 4

1,562

479

116

22

1

No. at risk RR onset

755

255

114

54

27

282

2

0

0

0

Progressive onset

271

103

36

18

10

A

B 100 Patients (%)

80

P = .48

60 Progressive onset

40 20 0

RR onset 0

5 10 15 20 Years after assignment of EDSS 6

No. at risk RR onset

426

93

31

15

4

Progressive onset

169

41

9

1

0

C Figure 1–3 Irreversible disability, based on Expanded Disability Status Scale (EDSS) score, occurs sooner in patients with a progressive course from onset, com-

pared with those with a relapsing-­remitting (RR) course from onset, although, once irreversible disability has occurred, the time course of progressive disability is similar regardless of the initial course (relapsing or progressive). Kaplan–Meier estimates are shown for time from onset of multiple sclerosis to assignment of EDSS 4 (A), time from EDSS 4 to EDSS 6 (B), and time from EDSS 6 to EDSS 7 (C) among 1844 MS patients stratified by initial course. (Data from Confavreux C, Vukusic S, Moreau T, Adeleine P: Relapse, remission, and progression in multiple sclerosis. N Engl J Med 2000;343:1430-1438.)

1  •  Clinical Features and Natural History of Multiple Sclerosis: The Nature of the Beast

100

100 Slow (n = 50) Quick (n = 42)

60 40 20 0

80 Patients (%)

Patients (%)

80

Slow (n = 37) Quick (n = 55)

60 40 20

0 20 25 30 5 10 15 0 5 10 15 20 25 30 A B Years from EDSS 3 to EDSS 6 Years from EDSS 3 to EDSS 6 Figure 1–4 Initial rate of progression (“quick” versus “slow”) from diagnosis to EDSS 3 as a predictor of further progression from Expanded Disability Status Scale (EDSS) 3 to EDSS 6. A, “Quick” progression is defined as progression from diagnosis to EDSS 3 within 2 years, “slow” progression as longer than 2 years (P = .57). B, “Quick” progression is within 5 years, and “slow” progression is longer than 5 years (P = .61). (Data from Pittock SJ, Mayr WT, McClelland RL, et al: Disability profile of MS did not change over 10 years in a population-based prevalence cohort. Neurology 2004;62:601-606.) 0

a­ ssociated with a more favorable course and longer time from EDSS 6 to EDSS 7 (4.3 versus 2.6 years; P = .002), compared with no superimposed relapses. Kremenchutzky and colleagues also showed that disability progression after one, multiple, or no relapses results in similar survival curves, suggesting that, once progression has begun, its rate is largely independent of factors that have preceded it (Fig. 1-6).11 Relapses and progression are the central clinical features of MS. Many in the field consider relapses to be the clinical product of an acute inflammatory focal lesion, whereas progression reflects a chronic diffuse degenerative process. The recent population-based studies from both Ontario, Canada, and Lyon, France, suggest a dissociation at the biologic level between the acute inflammatory process ­ (relapse) and the progressive degenerative process (disability ­progression).5,11,21,24 Although DMAs may significantly reduce the clinical relapse rate, their potential benefits in terms of disability progression may be small. The most important outcome measure in treatment trials with early RRMS should be, first, prevention and, second, attenuation of the progressive course.18 Patients who continue to have RR disease tend to do extremely well; in fact, it is only on entering the secondary progressive course of the disease that more rapid disability progression occurs. In the study by Myhr and colleagues, the probability of entering a progressive course after 20 years of disease was 57.5% for patients with an RR onset.12 Similarly, as previously discussed, 57.6% of patients with disease duration of 11 to 15 years in the Ontario relapsing-onset cohort developed a progressive course.8 In the Olmsted County 2001 study, patients remaining in the RR group had a favorable course, with fewer than 25% reaching EDSS 3 after 20 years of disease (see Fig. 1-2).1



Multiple Sclerosis 3

Secondary Progressive Type 100

Patients (%)

80 Relapses

60

P = .68 40 20 0

No relapses

0 5 10 15 20 Years after assignment of a score of 4

No. at risk No relapses

292

92

39

17

7

Relapses

191

56

19

9

4

A Primary Progressive Type 100

Figure 1–5  Among patients with 80 Patients (%)



60 P = .71 40 Relapses 20 0

No relapses 15 20 0 5 10 Years after assignment of a score of 4

No. at risk No relapses

163

61

22

7

3

Relapses

108

42

14

8

5

B

primary or secondary progressive multiple sclerosis, the time course of progressive irreversible disability (from Expanded Disability Status Scale [EDSS] 4 to EDSS 6) was not significantly influenced by the presence or absence of superimposed relapses. Kaplan–Meier estimates of time from EDSS 4 to EDSS 6 are shown according to the presence or absence of superimposed relapses among 496 patients with secondary progressive disease (A) and 282 patients with progressive primary disease (B). (Data from Confavreux C, Vukusic S, Moreau T, Adeleine P: Relapse, remission, and progression in multiple sclerosis. N Engl J Med 2000;343:1430-1438.)

Clinical Status at 5 and 10 Years As a Predictor of Long-Term Outcome In 1977, Kurtzke and associates reported that the level of disability in a U.S. World War II MS cohort at 5 years from diagnosis was one of the best predictors of disability at 10 and 15 years.26 Similarly, multiple groups have shown in multivariate analyses that a low EDSS score at 5 and 10 years is predictive of a benign course.27-29 For PPMS, there are few predictors of disability progression. A recent

1  •  Clinical Features and Natural History of Multiple Sclerosis: The Nature of the Beast

100

Patients (%)

80

PP SP SAP

60 40 20 0

A

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Years

100

Patients (%)

80

PP SP SAP

60 40 20

Figure 1–6  Progression after one,

0

B

0

3

6

9 12 15 18 21 24 27 30 33 36 39 Years

100 80 Patients (%)

multiple, or no relapses results in similar survival curves, suggesting that, once progression has begun, its rate is largely independent of factors that have preceded it. ­Patients with single-attack progressive (SAP), secondary progressive (SP), and primary progressive (PP) multiple sclerosis are compared, showing time to Expanded Disability Status Scale (EDSS) 6 (A), EDSS 8 (B), and EDSS 10 (C) from onset of progressive disease. (Data from Kremenchutzky M, Rice GP, ­Baskerville J, et al: The natural history of multiple sclerosis: A geographically based study. 9: Observations on the progressive phase of the disease. Brain 2006;129:584-594.)

60 40

PP SP SAP

20 0

C

0

3

6

9 12 15 18 21 24 27 30 33 36 39 42 Years

natural history study of 352 PPMS patients found that “sooner to cane, sooner to wheelchair” was the only predictor of longer-term outcome.13 Age at Disability Milestones: A Novel Approach to Data Analysis Despite years of epidemiologic, histopathologic, and radiographic study, the underlying pathogenesis of MS remains poorly understood. How MS is initiated, how it changes over time, how it correlates with clinical course and symptoms



10

Multiple Sclerosis 3

and other markers of disease activity, and how it is affected by therapeutic interventions are all largely unknown.30 The discovery of heterogeneity in demyelinating lesions has suggested that different mechanisms may be involved in MS pathogenesis.31 It remains unclear whether the RR phase and the progressive phase of MS (see Fig. 1-1) are on an immunopathologic continuum or are distinctly different. Previous studies of MS natural history have focused on time from onset or diagnosis of MS to specific disability milestones. They have paid little attention to the age at which patients reached these landmarks. Younger age at MS onset has been previously considered associated with a better prognosis, and older age at onset with a worse prognosis. Median age at onset for RRMS range in the late twenties to early thirties, whereas median age of onset for progressive MS is in the late thirties to early forties.13 Analysis of MS disability in regard to date of birth creates a unique perspective, reduces reliance on imprecise dates (for onset), and allows more accurate assessment of the age at which patients attained disability milestones. Recently, Confavreux and colleagues analyzed their natural history data in this novel way, with a focus on the age at which disability milestones were reached, rather than the time from onset to disability milestone.23 They showed that, if one considers age at disability milestones, MS appears to have a very homogenous prognosis that is not influenced significantly by relapses or by the initial course of the disease (Fig. 1-7; Table 1-1).23 32 These authors analyzed 1562 patients with an RR course and 282 with a progressive course at onset. Surprisingly, the age at assignment of a score of EDSS 7 was similar in both groups, despite the fact time from onset to EDSS 7 was much greater for the former group. For lower disability milestones (EDSS 4 and EDSS 6), patients with an RR onset were older than those with a progressive onset; the differences, although statistically significant, were very small (2.7 years for EDSS 4 and 2.3 years for EDSS 6), and there appeared to be overlap in the 95% confidence intervals of the median.23 Overall, the data suggest that the initial course of the disease, whether RR or progressive, does not appear to have substantial influence on the age at which disability milestones are reached in MS, providing further evidence that neurologic relapses have only a limited influence on development of disability over the long term. Tremlett and colleagues also showed that younger age at onset predicts a slower progression, but those patients who were older at onset were consistently older when reaching EDSS 6.2,33 These authors suggested that younger age at MS onset should no longer be considered a good prognostic factor.2 The age at onset is different for patients with SP, PP, and SAP MS, but the age at which progression begins appears to be similar and is not dependent in any way on the number of previous relapses.11 Although times from MS onset to disability landmarks are longer for patients with RRMS/SP and SAP MS than for PPMS, the times from irreversible disability (progressive phase) to disability landmarks are similar in all three groups (Tables 1-2 and 1-3; see Fig. 1-6).11,21 The authors of these recent papers suggested that the progressive phase of MS (which accounts for most of the time course of the disease and most of the disability) could be an age-dependent degenerative process independent of previous

1  •  Clinical Features and Natural History of Multiple Sclerosis: The Nature of the Beast

100 Progressive onset

Patients (%)

80

P < .001

60 40

Exacerbatingremitting onset

20 0 10

20 30 40 50 60 70 80 Age at assignment of EDSS 4 (yr)

No. at risk Exacerbating- 1559 1502 1151 625 remitting onset 282 275 228 153 Progressive onset

189

28

3

0

59

10

0

0

A 100 Patients (%)

80 60

Progressive onset

Exacerbatingremitting onset

20 0 10

from the Lyon, France, populationbased cohort, median ages at time of assignment of Expanded Disability Status Score (EDSS) 4, EDSS 6, and EDSS 7 were 44.3 years (95% confidence interval [CI], 43.3 to 45.2 years), 54.7 years (95% CI, 53.5 to 55.8 years), and 63.1 years (95% CI, 61.0 to 65.1 years), respectively. These results were essentially similar whether the initial course of multiple sclerosis was exacerbating-remitting or progressive. Kaplan–Meier estimates of the age of the patients at EDSS 4 (A), EDSS 6 (B), and EDSS 7 (C) are shown according to the initial course of multiple sclerosis. (Data from Confavreux C, Vukusic S: Age at disability milestones in multiple sclerosis. Brain 2006;129:595-605.)

No. at risk Exacerbatingremitting onset Progressive onset

20 30 40 50 60 70 80 Age at assignment of EDSS 6 (yr)

1562 1521 1246 761

305

73

11

0

282

115

39

4

0

281

254

193

B 100 80 Patients (%)

Figure 1–7  For the 1844 patients

P = .002

40

Progressive onset

60 P = .24

40 20 0 10

No. at risk Exacerbatingremitting onset Progressive onset

C

Exacerbatingremitting onset 20 30 40 50 60 70 80 Age at assignment of EDSS 7 (yr)

1562 1524 1272 806

347

97

14

0

282

126

54

5

1

281

256

209

11

12

Multiple Sclerosis 3

TABLE 1–1

Comparative Demographic and Clinical Characteristics of Multiple Sclerosis Patients with a Progressive Initial Course and Patients with an Exacerbating RelapsingRemitting (RR) Initial Course

Parameter

RR Onset (n = 1562)

Progressive Onset (n = 282)

Probability Value

Gender (% male) Age at onset (yr) Time from onset to EDSS 6 (yr) Time from onset to EDSS 7 (yr) Time from EDSS 4 to EDSS 7 (yr) Age at EDSS 6 (yr) Age at EDSS 7 (yr)

34 29.6 23.1 33.1 12.1 55.3 62.8

43 39.3 7.1 13.4 12.0 53.0 63.1

.006 <.001 <.001 <.001 .70 .002 .24

EDSS, Expanded Disability Status Scale score. Data from Confavreux C, Vukusic S: Natural history of multiple sclerosis: A unifying concept. Brain 2006;129:606-616.

TABLE 1–2

Age at Onset of Disease and Age at Onset of Progression for Multiple Sclerosis Clinical Subgroups

Subgroup

Age at Onset (mean, yr)

Age at Onset of Progression (mean, yr)

Secondary progressive (SP) Primary progressive (PP) Single-attack progressive (SAP)

29.8 38.6 33.3

39.4 38.6 40.9

Data from Kremenchutzky M, Rice GP, Baskerville J, et al: The natural history of multiple s­ clerosis: A geographically based study. 9: Observations on the progressive phase of the disease. Brain 2006;129:584-594.

TABLE 1–3



 omparison of Patients with Secondary Progressive (SP), C Single-Attack Progressive (SAP), and Primary Progressive (PP) Multiple Sclerosis: Time from Onset of Progressive Disease to EDSS 6, EDSS 8, and EDSS 10

Years to

SP

SAP

PP

Probability Value

EDSS 6 EDSS 8 EDSS 10

  6.63 18.20 NA

  5.71 13.62 32.96

  6.4 16.81 31.24

.08 .47 .86

EDSS, Expanded Disability Status Scale score; NA, not applicable. Data from Kremenchutzky M, Rice GP, Baskerville J, et al: The natural history of multiple ­sclerosis: A geographically based study. 9: Observations on the progressive phase of the disease. Brain 2006;129:584-594.

1  •  Clinical Features and Natural History of Multiple Sclerosis: The Nature of the Beast

clinical relapses.11,23 The aging-related mechanisms that may be accelerated in MS should provide potential additional therapeutic targets in acute recurrent inflammation and chronic neurodegeneration.11,23 Figure 1-8 provides an illustrative interpretation of these recent data analyses.

Benign Multiple Sclerosis Definition Controversy exists regarding the precise definition of “benign MS,” mainly because not all patients fulfilling criteria for benign MS at one time point will ­remain benign at a later time point.34 Although most studies suggest that about one third of patients have minimal disease progression with little or no disability after many decades of disease, there is a wide range of reported frequencies, 6% to 64%.15 This wide range is the result of several factors, including definition used (more

Effect of disease modifying agents on disability Mild (±) Early

Subclinical ?

None (–) Irreversible disability EDSS EDSS EDSS 4 6 7

10 8

Relapsing onset

Two degree progressive with relapses

6 Clinical Onset

4 2

One degree progressive

0

Single attack progressive EDSS at 5 years (+)

Relapsing progressive

EDSS at 10 years (++)

EDSS

Two degree progressive without relapses

10 8

Two degree progressive with relapses

6

Progressive onset

4

Subclinical disease?

2 Subclinical ?

0

10

20

30

0

Early

40

50

60

70

80

Age

Figure 1–8  Schematic representation of the natural history of multiple sclerosis, ­ incorporating

recent natural history data from Lyon, France15,17; London, Ontario18; and Olmsted County, ­Minnesota.1,23 The median age at which disability milestones Expanded Disability Status Score (EDSS) 3 (or 4), EDSS 6, and EDSS 7 (or 8) were reached are similar regardless of early course (relapsing or progressive). The majority of the clinical disease course falls within the progressive phase. Subclinical onset precedes clinical onset by an unknown length of time. Once a ­threshold of disability is reached (EDSS 3 or EDSS 4, termed “irreversible disability”), the median rate of ­further ­progression is similar for all clinical subtypes. The time of onset of the disease is unclear. EDSS scores at 5 and 10 years appear to be the best clinical predictors of long-term outcome. Although disease-modifying agents (DMAs) may have mild to moderate benefit (relapse rate reduction, ­delayed early disability) in the “early” course of the disease, there is no proven benefit once “­irreversible disability” is reached.

13

14

Multiple Sclerosis 3

conservative definitions lower the frequency) and type of population studied (hospital-based versus community-based). The concept of benign MS was suggested in 1872 by Charcot when he wrote, “It is not rare to encounter complete remission which is hoped to be definitive.”35 In a study of 241 hospital-based patients monitored over a mean disease duration of 18.2 years, McAlpine reported that 26% of the patients, although not necessarily symptom free, could walk for more than 500 m without assistance and were unrestricted in regard to employment.36 After the introduction of the EDSS score by John Kurtzke in 1983,3 investigators began to define benign MS in terms of having a low disability score (EDSS 0 to EDSS 4) after a long disease duration (5 to 20 years). The most commonly used definition of benign MS is EDSS 3 after a disease duration of 10 or more years, although more conservative definitions have been suggested recently. The National Multiple Sclerosis Society of the United States performed a survey and arrived at the following consensus definition of benign MS: “fully functional in all neurologic systems 15 years after onset.”9 More recently, the definition “EDSS score of less than or equal to two for greater than or equal to ten years” was proposed based on a longitudinal follow-up study of benign MS in the Olmsted County MS population-based cohort (Fig. 1-9).27 In that study, the prevalence of benign MS (EDSS ≤ 2 for >10 years) was 17%. If this figure is applied to the U.S. MS population as a whole, then approximately

1991 prevalence cohort n = 162

1991 Minimal disability n = 49 EDSS � 4, duration > 10 years

EDSS 0-2 Duration > 10 years n = 28

Dead n=1 Incidental death

2001

Benign n = 25

Others n = 113

EDSS 2.5-4 Duration > 10 years n = 21

Alive n = 27

Nonbenign n=2

Dead n=1

Duration < 10 years n = 44, 1 lost to followup

Alive n = 20

Benign n=9

Nonbenign n = 68 EDSS > 4, duration > 10 years

Dead n = 18

Alive n = 50

Nonbenign n = 11

Figure 1–9  Patient profile of original 1991 Olmsted County multiple sclerosis prevalence cohort

(above broken line) and 2001 data (below broken line). Benign MS in 2001 is defined as an Expanded Disability Status Scale (EDSS) score of 4 or lower and duration of MS longer than 20 years. Nonbenign is defined as an EDSS score higher than 4 and duration of MS longer than 20 years. (From Pittock SJ, McClelland RL, Mayr WT, et al: Clinical implications of benign multiple sclerosis: A 20-year population-based follow-up study. Ann Neurol 2004;56:303-306. © 2004 American Neurological Association. Reproduced with permission from John Wiley & Sons, Inc.)

1  •  Clinical Features and Natural History of Multiple Sclerosis: The Nature of the Beast

36,000 patients in the United States have benign MS and probably would not ­benefit from potentially lifelong pharmacotherapy.19 The difficulty arises in trying to identify these patients early in their disease course. Predicting a Benign Course

EDSS score

Three recent papers have contributed to the literature on this subject and have supported Kurtzke’s previous observation that the level of disability at 5 years is a reliable predictor of later outcome.26 In the 2001 Olmsted County MS study, 93% of patients who had an EDSS of 2 or less after at least 10 years of disease duration in 1991 continued to have low levels of disability (EDSS ≤ 3) a decade later (Fig. 1-10).27 In contrast, only 42% of patients with a moderate level of disability (EDSS 2.5 to EDSS 4.0) after 10 or more years of disease duration in 1991 continued to have low levels of disability (EDSS ≤ 3) in 2001 (see Fig. 1-10). Therefore, the lower the level of disability after 10 years, the more likely a patient is to remain with that low level of disability in the future. This study suggested a more conservative definition of benign MS: EDSS 2 or less after at least 10 years of disease duration. In a much larger British Columbia MS cohort of 2204 patients, investigators reported that 68% of patients with an EDSS score of 2 or less after 10 years of disease remained benign with EDSS of 2 or less at the 20-year time point.29

10 9 8 7 6 5 4 3 2 1 0

1991 2001 Benign 1991 Benign 1991 and 2001

0 Disability Status Scale (EDSS) score over 10 years versus duration of disease in 1991. Each line represents an individual patient. A, How are patients with minimal disability (EDSS ≤  2 for ≥ 10 years) doing a further decade later? B, How are patients with moderate disability (EDSS 2.5 to EDSS 4 for ≥ 10 years) doing a further decade later? (From Pittock SJ, McClelland RL, Mayr WT, et al: Clinical ­ implications of benign multiple sclerosis: A 20-year ­population-based follow-up study. Ann Neurol 2004;56:303-306, ­reproduced with permission.)

EDSS score

Figure 1–10  Change in Expanded

5

A 10 9 8 7 6 5 4 3 2 1 0

1991 2001 Benign 1991 Benign 1991 and 2001

0

B

10 15 20 25 30 35 40 45 50 55 Duration of disease (years)

5

10 15 20 25 30 35 40 45 50 55 Duration of disease (years)

15

16

Multiple Sclerosis 3

If a similar analysis is used for the Olmsted County Study, then 67% of patients would remain with EDSS of 2 or less after 20 or more years.27 Ramsaransing and De Keyser investigated a cohort of 496 patients who had had MS for at least 10 years. They found that 151 (30%) of these patients had an EDSS score of 3 or less and were considered to have benign MS29; 69% of these patients continued to have benign disease 10 years later. However, when a more conservative definition with cutoff of EDSS 2 after 10 years (as proposed by the Mayo Clinic group) was used, 84% still had benign disease at the 20-year time point. In a multivariate regression analysis, an RR course, a low EDSS score at 5 years, and a low number of relapses during the first 5 years were predictive for benign MS at 10 years, in agreement with other previously published studies. Other variables such as gender, age at clinical onset, disease course, number of systems involved at onset, degree of recovery from first symptoms, and time between first and second relapse had no additional value in outcome prediction, again in line with most other studies. Although the Olmsted County study focused on EDSS score at 10 years or more as a predictor of outcome at 20 years or more, a review of the data suggested that the 5-year time point may also be a robust and reliable cutoff point for outcome prediction. In a subgroup analysis of EDSS and number of relapses, Ramsaransing showed that patients with lower EDSS scores at 5 years had a high probability of remaining benign at the 10-year time point, but the probability of developing disability was somewhat dependent on the number of relapses in the first 5 years. Patients with EDSS 1 at 5 years but with two, three, or four relapses had an 85%, an 80%, and a 74% chance, respectively, of remaining benign at the 10-year time point. In contrast, patients with EDSS 3 at 5 years but with two, three, or four relapses had a 36%, a 28%, and a 22% chance of remaining benign at the 10-year time point. Patients with an EDSS score between 1 and 3 at 5 years had probabilities that were dependent on the frequency of relapses distributed between these two extremes. In summary, the longer the duration of MS and the lower the disability level, the more likely a patient is to remain stable and not progress. The predictive power of this measure appears to be greatest after 10 years or longer, although there is some evidence that the 5-year cutoff point may have reasonable predictive value. However, it does not appear possible to accurately predict outcome within the first 5–6 years after onset of MS. Cognitive Outcomes in Benign Multiple Sclerosis Most studies on the natural history of MS, and particularly benign MS, have focused on physical impairment. Some researchers have argued appropriately that patients may remain well physically but have significant cognitive problems, and that current definitions of benign MS based on EDSS alone therefore overestimate its frequency. A recent study examined cognitive, psychosocial, and social aspects of benign MS in 163 patients with an EDSS score of 3 or less after 15 or more years of disease duration.37 Patients’ cognitive performances were compared with those of 111 demographically matched, healthy controls. Cognitive impairment, significant ­ fatigue, and depression were found in 45%, 49%, and 54% of patients, respectively. Using a more conservative definition of benign MS (EDSS ≤2 for

1  •  Clinical Features and Natural History of Multiple Sclerosis: The Nature of the Beast

≥15 years), the frequency of cognitive impairment was 39%. This is lower than the frequency of 58.5% in patients who had an EDSS score between 2.5 and 3 after 15 or more years. Though this study raised important concerns regarding the issue of nonambulatory disorders in benign MS, there were some significant limitations of the study that most likely overestimated the frequency of these problems in benign MS. First, the study was not population based and therefore was not likely to be representative of benign MS in the general population. Second, as the authors pointed out, patient “self-selection” probably contributed to the high frequencies of problems encountered, because patients with MS who are doing well physically but experiencing depression or cognitive problems are more likely to seek medical treatment and thus more likely to be attending a hospital-based clinic. Third, the high frequency of depression may be a significant confounder. Population-based studies of nonambulatory impairments and clinical ­disability are needed to address this issue. Such studies can help better define the ­phenotypic variability in patients with MS and guide better patient selection for treatment ­trials and future genotype-to-phenotype analyses. References   1. Pittock SJ, Mayr WT, McClelland RL, et al: Disability profile of MS did not change over 10 years in a population-based prevalence cohort. Neurology 2004;62:601-606.   2. Tremlett H, Paty D, Devonshire V: Disability progression in multiple sclerosis is slower than previously reported. Neurology 2006;66:172-177.   3. Kurtzke JF: Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983;33:1444-1452.   4. Confavreux C, Aimard G, Devic M: Course and prognosis of multiple sclerosis assessed by the computerized data processing of 349 patients. Brain 1980;103:281-300.   5. Confavreux C, Vukusic S, Adeleine P: Early clinical predictors and progression of irreversible disability in multiple sclerosis: An amnesic process. Brain 2003;126(Pt 4):770-782.   6. Kantarci O, Siva A, Eraksoy M, et al: Survival and predictors of disability in Turkish MS patients. Turkish Multiple Sclerosis Study Group (TUMSSG). Neurology 1998;51:765-772.   7. Runmarker B, Andersen O: Prognostic factors in a multiple sclerosis incidence cohort with ­twentyfive years of follow-up. Brain 1993;116(Pt 1):117-134.   8. Weinshenker BG, Bass B, Rice GP, et al: The natural history of multiple sclerosis: A geographically based study. I: Clinical course and disability. Brain 1989;112(Pt 1):133-146.   9. Lublin FD, Reingold SC: Defining the clinical course of multiple sclerosis: Results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996;46:907-911. 10. Confavreux C, Vukusic S: Natural history of multiple sclerosis: Implications for counselling and therapy. Curr Opin Neurol 2002;15:257-266. 11. Kremenchutzky M, Rice GP, Baskerville J, et al: The natural history of multiple sclerosis: A geographically based study. 9: Observations on the progressive phase of the disease. Brain 2006; 129(Pt 3):584-594. 12. Myhr KM, Riise T, Vedeler 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;7:59-65. 13. Tremlett H, Paty D, Devonshire V: The natural history of primary progressive MS in British ­Columbia, Canada. Neurology 2005;65:1919-1923. 14. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG: Multiple sclerosis. N Engl J Med 2000;343:938-952. 15. Ramsaransing GS, De Keyser J: Benign course in multiple sclerosis: A review. Acta Neurol Scand 2006;113:359-369. 16. Weinshenker BG, Bass B, Rice GP, et al: The natural history of multiple sclerosis: A geographically based study. 2: Predictive value of the early clinical course. Brain 1989;112(Pt 6):1419-1428.

17

18

Multiple Sclerosis 3

17. Frohman EM, Havrdova E, Lublin F, et al: Most patients with multiple sclerosis or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis. Arch Neurol 2006; 63:614-619. 18. Pittock SJ: Interferon beta in multiple sclerosis: How much BENEFIT? Lancet 2007;370:363364. 19. Pittock SJ, Weinshenker BG, Noseworthy JH, et al: Not every patient with multiple sclerosis should be treated at time of diagnosis. Arch Neurol 2006;63:611-614. 20. Confavreux C: The natural history of MS. In Compston A, McDonald IR, Noseworthy J, et al (eds): McAlpine’s Multiple Sclerosis, 4th ed. New York, Churchill Livingstone, 2005, pp 183-272. 21. Confavreux C, Vukusic S, Moreau T, Adeleine P: Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438. 22. Ebers GC: Natural history of multiple sclerosis. In McDonald WI, Noseworthy JH (eds): Multiple Sclerosis, 2nd rev. ed. London, Butterworth-Heinemann, 2003, pp 21-32. 23. Confavreux C, Vukusic S: Age at disability milestones in multiple sclerosis. Brain 2006;129(Pt 3): 595-605. 24. Vukusic S, Confavreux C: Natural history of multiple sclerosis: Risk factors and prognostic indicators. Curr Opin Neurol 2007;20:269-274. 25. Noseworthy JH, Vandervoort MK, Hopkins M, Ebers GC: A referendum on clinical trial research in multiple sclerosis: The opinion of the participants at the Jekyll Island workshop. Neurology 1989;39:977-981. 26. Kurtzke JF, Beebe GW, Nagler B, et al: Studies on the natural history of multiple sclerosis: 8. Early prognostic features of the later course of the illness. J Chronic Dis 1977;30:819-830. 27. Pittock SJ, McClelland RL, Mayr WT, et al: Clinical implications of benign multiple sclerosis: A 20-year population-based follow-up study. Ann Neurol 2004;56:303-306. 28. Ramsaransing GS, De Keyser J: Predictive value of clinical characteristics for ‘benign’ multiple sclerosis. Eur J Neurol 2007;14:885-889. 29. Sayao AL, Devonshire V, Tremlett H: Longitudinal follow-up of “benign” multiple sclerosis at 20 years. Neurology 2007;68:496-500. 30. Pittock SJ, Lucchinetti CF: The pathology of MS: New insights and potential clinical applications. Neurologist 2007;13:45-56. 31. Lucchinetti C, Bruck W, Parisi J, et al: Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707-717. 32. Confavreux C, Vukusic S: Natural history of multiple sclerosis: A unifying concept. Brain 2006; 129(Pt 3):606-616. 33. Tremlett H, Devonshire V: Is late-onset multiple sclerosis associated with a worse outcome? Neurology 2006;67:954-959. 34. Pittock SJ, Rodriguez M: Benign multiple sclerosis: A distinct clinical entity with therapeutic implications. Curr Top Microbiol Immunol 2008;318:1-17 35. Charcot J: Leçons sur les maladies du système nerveux faites à La Salpetière. Paris, 1872. 36. McAlpine D: The benign form of multiple sclerosis: Results of a long-term study. Br Med J 1964; 2:1029-1032. 37. Amato MP, Zipoli V, Goretti B, et al: Benign multiple sclerosis: Cognitive, psychological and social aspects in a clinical cohort. J Neurol 2006;253:1054-1059.