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Clinical course in multiple sclerosis patients presenting with a history of progressive disease
Multiple Sclerosis and Related Disorders, 1, 3, pages 67 - 71
Determine the likelihood of worsening clinical status in the near-term course of progressive MS and evaluate the predictive validity of our diagnostic impression of progressive forms of MS.
Retrospective review of charts from 175 patients seen between 2000 and 2007 who were diagnosed with either primary or secondary progressive multiple sclerosis. Data extracted included demographic factors, neurological examination findings to determine EDSS, timed 25 foot walk (T25FW) when available, duration of symptoms, clinical course as documented on initial visit, and history of disease-modifying agent (DMA) use. Significant change in EDSS was defined as a change of one point or more from initial to final clinical evaluation. Significant change in T25FW was defined as a ±20% difference from baseline.
Of the 175 charts reviewed, 35 patients met criteria and had sufficient documentation to allow for EDSS abstraction. Twenty-four patients (68.6%) showed no significant change in EDSS from baseline while eleven patients (31.4%) worsened and none improved. For those patients that had T25FW data available, 6 out of 20 (30%) patients worsened while 11 (55%) showed no change. Three patients (15%) improved.
In this observational study at a tertiary care MS center, patients classified as progressive MS did not progress as often, or as rapidly, as previous studies have suggested. Greater than two-thirds of patients in this cohort, did not increase 1 step on the EDSS.
- 68.6% Of progressive patients showed no significant change in EDSS from baseline.
- 31.4% Of progressive patients worsened.
- For those patients that had T25FW data available, 30% worsened while 55% showed no change.
Keywords>: Primary progressive multiple sclerosis, Secondary progressive multiple sclerosis, Clinical course, Observational study, EDSS, T25FW.
In the absence of reliable radiological or biological markers, clinical phenotypes of multiple sclerosis were defined in the 1990's by their clinical course. Distinct from the Relapsing Remitting form of the disease, Primary progressive MS (PPMS) was defined as “disease progression from onset with occasional plateaus and temporary minor improvements,” and Secondary Progressive MS (SPMS) was defined as an “initial RRMS disease course followed by progression with or without occasional relapses, minor remissions, and plateaus”( Lublin and Reingold 1996 ). These definitions implied that the accumulation of disability in PPMS and SPMS can be variable in rate, but is inherently continuous. Natural history studies have further asserted that once progressive, MS is characterized by a steady and inexorable neurological decline, and that the course of PPMS and SPMS become indistinguishable (Tremlett et al, 2005 and Confavreux et al, 2000). However, such studies have also demonstrated that actual rates of disability accrual vary considerably, characterizing the dilemma of predicting clinical outcome in the individual patient, especially in shorter time intervals (Tremlett et al, 2005 and Confavreux and Vukusic, 2008).
Progressive clinical courses in patients with multiple sclerosis (MS) are the most therapeutically challenging forms of the disease primarily because of the lack of convincing clinical trial data and several recent negative studies (Wolinsky et al, 2007, Montalban, 2004, Leary et al, 2003, and Hawker et al, 2009). Attempts to assess the efficacy of immunomodulatory agents such as glatiramer acetate in progressive patients have been hampered by rates of progression being neither as continuous nor as rapid as predicted ( Wolinsky, 2004 ). This has resulted in inadequate numbers of subjects in clinical trials meeting disability outcomes to demonstrate a therapeutic effect.
Entrance criteria for clinical trials of PPMS and SPMS begin with the assumptions of continuous progression implicit in the definitions of these subtypes. At our tertiary care center, observations of patients felt to have progressive forms of MS have suggested protracted periods of clinical stability without clinical worsening. In this study we sought to determine the likelihood of worsening clinical status in the near-term course of progressive MS. To evaluate the predictive validity of our diagnostic impression of progressive forms of MS, we evaluated the rates of disability accrual in patients classified to have progressive MS at the time of their initial presentation to our MS Center.
After obtaining approval from Mount Sinai Medical Center's institutional review board (IRB), we reviewed charts of patients seen between 2000 and 2007 who were diagnosed with either primary or secondary progressive multiple sclerosis.
Patients included in the study were those who met diagnostic criteria for multiple sclerosis based on their clinical history, neurologic exam and supporting paraclinical data ( Polman et al., 2005 ). They were further classified into established PPMS or SPMS subtypes based on the patient's clinical history of ongoing progression ( Lublin and Reingold, 1996 ). At least two documented visits at a minimum of 1 year apart were also required, with available data to allow for Expanded Disability Status Score (EDSS) determination. Exclusion criteria were defined as a history of relapses at any point after onset of progression, insufficient clinical data to extract EDSS, and major superimposed non-MS related causes of neurological disease (stroke, neuropathy, etc.).
Data extracted included demographic factors, neurological examination findings and self-reported walking distance to determine EDSS, timed 25 foot walk (T25FW) when available, duration of symptoms, clinical course as documented on initial visit, and history of disease-modifying agent (DMA) use. Significant change in EDSS was defined as a change of one point or more from initial to final clinical evaluation ( Goodkin, 1991 ). Significant change in T25FW was defined as a ±20% difference from baseline (Schwid et al, 2002 and Kragt et al, 2006).
2.1. Statistical analysis
Continuous variables are reported with medians and ranges. Frequency tables were used to categorize patients as either worse, improved or no change for both clinical measures. To analyze patterns of progression, the group was divided into two subsets to see whether patients with an EDSS </=4 were less likely to show progression than those patients with an EDSS>4, utilizing a Pearson Chi-Square test (Confavreux and Vukusic, 2008 and Hobart et al, 2000). All statistical analyses were performed by using the Statistical Package for Social Sciences version 16.0. (SPSS, Inc., Chicago, IL,USA).
Of the 175 charts reviewed, 35 patients met inclusion criteria and had sufficient documentation to allow for EDSS abstraction. Of the patients that did not meet criteria, a majority of them were excluded due to insufficient clinical data to extract EDSS. Complete demographic and baseline data are summarized in Table 1 . Baseline EDSS scores at entry ranged from 2.0 to 9.5 with a median EDSS score at baseline of 5.5. Mean age at onset of progressive symptoms was 47.1 years. Mean duration of follow up was 43 months (range 17–96 months). The mean number of visits during follow-up (including the initial visit) was 4.5 (range of 2–8 visits).
|Outcome measure||Mean||Median||Standard deviation||Number|
|EDSS at baseline||5.36||6.0||2.24||35|
|EDSS at last visit||6.14||6.5||2.16||35|
|T25FW at baseline||10.32||8.0||5.35||21|
|T25FW at last visit||13.81||8.54||12.89||21|
Of the 35 patients included, twenty-four patients (68.6%) showed no significant change in EDSS from baseline while eleven patients (31.4%) worsened by at least 1 step and none improved. Of the eleven patients that worsened, six (54.5%) had an EDSS score ≤4, and five (45.5%) had an EDSS>4 at the time of their initial visit (p=0.41). Of the twenty-four patients that were stable, 18 (75%) were on a disease-modifying agent (p=0.65). Based on Chi-square analysis, none of these dichotomous variables significantly predicted ongoing progression. Mean disease duration for the group that worsened was 10.7 years (range 1–29 years) and 9.6 years for the group that was stable (range 3–20 years). None of the changes in the EDSS scores during the observation period of this study were attributed to relapses.
For those patients that had T25FW data available, average duration of follow up of T25FW was 22 months (range 7–40 months). Six out of 20 (30%) patients worsened while 11 (55%) showed no change. Three patients (15%) improved.
In order to visualize disease course and identify outliers, change in EDSS and T25FW for each patient was plotted individually over time (Fig 1 and Fig 2respectively). Distribution of clinical measures at baseline and final visits are shown in Table 1 .
In this observational study at a tertiary care MS center, patients that were classified as progressive MS did not progress as often, or as rapidly, as previous studies have suggested (Confavreux et al, 2000, Confavreux and Vukusic, 2006, and Vukusic and Confavreaux, 2007). Greater than two-thirds of patients in this cohort, followed for a mean of 43 months, did not increase 1 step on the EDSS. It has previously been shown that combining T25FW with EDSS in primary progressive patients is an appropriate methodology to detect meaningful clinical change ( Bosma et al., 2009 ). Although we were unable to combine the scores from both scales for all patients, as some were non-ambulatory, a similar percentage of patients worsened on either endpoint—approximately 30% by either measure. This suggests that these patients were clinically stable both in terms of gait and as assessed by the EDSS.
It is important to note that this study does not intend to replicate or invalidate rates of progression observed in other long-term natural history cohorts, but rather to highlight that a clinician's initial diagnostic impression that a patient is on a sustained progressive course may not predict ongoing progression. Rather, the diagnosis of “progressive MS” is a retrospective label based on a patient's clinical history, and our data suggest that in the majority of our progressive patients, an ongoing progressive clinical course over the subsequent two to five years was quite variable. Ongoing clinical course did not vary on the basis of EDSS score at the time of the diagnostic impression of progressive MS, indicating the degree of prior accrual of disability did not predict the likelihood of continued clinical worsening. The patients taking disease-modifying agents were not significantly more likely to remain clinically stable. This finding could reflect that patients who were neurologically worsening were more often treated with DMAs than those patients who were stable, however our small sample size cannot validate this.
There are both therapeutic and clinical trial implications of this study. Although as shown in Table 1 the mean and median values for both EDSS and T25FW increased, this was accounted for by the minority of patients who worsened and did not predict the clinical course for individual patients, the majority of whom remained stable. Identifying in advance those patients most likely to progress could afford clinical trials of progressive disease a greater likelihood of demonstrating the benefit of an investigational agent. If prior progression does not predict the ongoing clinical course, faulty assumptions inform the inclusion criteria of progressive clinical trials and may undermine the ability to demonstrate the clinical effect of an investigational agent. To refine the entrance criteria for clinical trials of progressive MS, attention to potential clinical markers of ongoing progression will need to be developed. Furthermore, the recognition of long periods of clinical stability in progressive MS reinforces the need for control groups in clinical trials of these forms of the disease, to avoid a natural history of disease inactivity being misconstrued as a therapeutic effect (Wolinsky et al, 2007 and Wolinsky, 2004).
Prolonged periods of clinical quiescence in patients who ostensibly have a progressive form of MS add an additional level of complexity to the problematic question of prognosis often presented to clinicians, and highlight the need for a more robust way to classify patients prospectively to guide therapeutic decisions. If classifying patients as having progressive forms of MS does not adequately predict their ongoing disease course, the clinical phenotype provides uncertain justification for starting patients on medications with limited efficacy and potential toxicities.
Our study design is unique in several respects. We evaluated clinical course not from the time of initial MS diagnosis or the onset of progression, but rather from the time of patients' initial visit to our center, at the time of our diagnostic determination that they have a progressive form of disease. In this way, the current study evaluates the predictive ability of the progressive diagnostic categories, rather than simply being a natural history study. Our cohort included both primary- and secondary-progressive patients, an admixture uncommon in modern MS clinical trials. We chose to combine these patients, as the SPMS and PPMS clinical subtypes define these patterns of continuous progression in similar terms, and it has become widely observed in natural history studies that once MS becomes progressive, the course is similar for both ( Confavreux and Vukusic, 2006 ). The comparative demographic and disease-related characteristics of patients with SPMS and PPMS from the Lyon, France cohort are indeed very similar (Confavreux et al, 2000 and Confavreux and Vukusic, 2006). Likewise, the cohort from Gothenburg, Sweden illustrated comparable accumulation in disability between SPMS and PPMS subtypes ( Runmarker and Anderson, 1993 ). Pathologically, no definitive differentiating factors between PPMS and SPMS have been elucidated ( Lassmann et al., 2001 ). With these assumptions in mind, it is notable that our study demonstrated long periods of stable disease, rather than a continuous accrual of disability, in a combined cohort of PPMS and SPMS patients.
Our cohort's baseline demographic data differ from that of natural history studies (Ebers, 2004 and Cottrell et al, 1999) with regard to median EDSS and age of progressive onset. In our population, median EDSS scores were slightly higher and patients had slightly longer durations of disease. One study suggested that a higher EDSS score at onset of progressive symptoms is associated with faster rates of disability accrual ( Tremlett et al., 2005 ). Despite a median EDSS of 5.5 in our cohort at the time of our initial diagnostic impression, 68.6% did not progress. A comparison of the stable patients to those who progressed indicated that stable patients were not limited to those with lower EDSS scores.
There are several limitations in our study. Our population was small and drawn from a single center, and thus may not be representative of the overall population of progressive MS patients. The long duration of follow-up did, however, afford us 123 patient-years of observation. There are also several methodological issues pertaining to the EDSS. Given that the EDSS is a non-linear, indirect method of measuring disability utilizing a quantitative neurological exam, the predictive value of the EDSS is insufficient, has threshold effects and confers its own limitations (Kragt et al, 2008 and Hobart et al, 2000). Scores in the range of 5.0–9.0 may be relatively insensitive to change ( Hobart et al., 2000 ). Additionally, retrospective EDSS abstraction is not as reliable a measure of disability progression as prospective examinations. Also, in our study, 500-m walks were not routinely obtained at every visit, therefore patients who were in the EDSS range of 4–5.5 could not be as accurately characterized.
This study demonstrates that the current progressive clinical subtypes, though based on a patient's clinical history, are of limited value in predicting subsequent clinical course. Prospective studies to assess the predictive validity of the established subtypes are warranted. Further analysis is underway to determine whether there is a better prospective assessment time point after the diagnosis of a progressive form of MS that will more reliably predict progression. The clinical subtype-delineations themselves may need to be updated as genetics and biomarkers become available to more precisely elucidate the pathologic substrates underlying the clinical patterns.
Conflict of interest
Dr. Pandey has received consulting and speaking honoraria from Acorda Therapeutics, Biogen Idec, EMD Serono, Inc., Novartis, Pfizer, and Teva Neuroscience, Inc.
Dr. Krieger serves as a consultant for and has received speaker honoraria from Bayer Schering Pharma, Biogen Idec, EMD Serono, Inc., Genzyme, Novartis, and Teva Neuroscience Inc.
Dr. DeAngelis has received consulting honoraria from EMD Serono and Teva Neurosciences Inc.
Dr. Miller receives research support from Acorda, Teva, Novartis, Genentech, Genzyme, Sanofi-Aventis, BiogenIdec, Roche. He is a consultant for Sanofi-Aventis,, BiogenIdec, Glaxo Smith Kline, EMD Serono, Daiichi Sankyo,, Merck Serono, Novartis, ONO, Acorda, BioMarin, Avanir, Chelsea Therapeutics, Nuron Biotech, La-Ser. He is on the speakers bureau for BiogenIdec, Pfizer, EMD Serono, Teva, Acorda.
Dr. Lublin receives research support from Acorda Therapeutics, Inc., Biogen Idec, Teva Neuroscience, Inc., Sanofi- Aventis, NINDS/NIH and NMSS. He has received consulting honoraria from Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Inc., Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, Sanofi-Aventis, Acorda, Questcor, Avanir, Roche, Celgene, Abbott, MorphoSys, Johnson & Johnson, Revalesio, Coronado Bioscience, and Genzyme. He is Co-Chief Editor of Multiple Sclerosis and Related Diseases. He has an equity interest in Cognition Pharmaceuticals, Inc.
Ms. Farrell and Ms. Hannigan have no disclosures to report.
Dr. Pandey was supported by the National Multiple Sclerosis Society Clinical Fellowship and Partners Multiple Sclerosis Clinical Fellowship Awards. Dr. Krieger was supported by a National Multiple Sclerosis Society Sylvia Lawry Fellowship.
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Corinne Goldsmith Dickinson Center for Multiple Sclerosis, The Friedman Brain Institute, Mount Sinai School of Medicine, 5 East 98th Street, Box 1138, New York, NY 10029, USA
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