Before reading these, imagine a future statement: With the diagnostic entrance of a male at 26 years and then a remittant-relapsing course with 3 long-lasting remittances during the first two years and an EDSS < 2.0, progression to EDSS 4.0 and 6 can be expected to last ... years without therapy, ... years with treatment A, ... with treatment B, etc. This time span is further increased if (this and that precondition is met). Not quite easy for an ill-defined condition like MS but accepting certain uncertainties, a multiparameter register with ten-thousands of patients included (covering several decades), a kind of control could be offered to future studies without maltreating patients with an unnecessary (and therefore unethical) untreated control group.
Weinshenker BG. Databases in MS
research: pitfalls and promises. Multiple Sclerosis 1999;5:206-11.
A database is an organized repository of data. Prospective collection of patient information in a database ('databasing') has been attempted by a few consortia of MS investigators over the past 10 years. This approach promises to facilitate epidemiological research in MS and investigation of the natural history of the disease and how it might be altered by long-term treatments such as interferon beta. Data basing has some advantages over clinical trials in assessing new therapies, primarily because the focus is on long-term effectiveness in an entire population rather than short-term statistical significance in a highly selected population. The limitations of data basing and strategies to overcome these limitations are addressed.
Cutter GR, Baier M,. Rudick RA,
Cookfair DL, Fischer JS, Petkau J, Syndulko K, Weinshenker BG, Antel JP,
Confavreux C, Ellison GW, Lublin F, Miller AE, Rao SM, Reingold S, Thompson
A, Willoughby E. Development of a multiple sclerosis functional composite
as a clinical trial outcome measure. Brain 1999;122:871-82.
The primary clinical outcome measure for evaluating multiple sclerosis in clinical trials has been Kurtzke's EDSS. New therapies appear to favorably impact the course of multiple sclerosis and render continued use of placebo control groups more difficult. Consequently, future trials are likely to compare active treatment groups which will most probably require increased sample sizes in order to detect therapeutic efficacy. Because more responsive outcome measures will be needed for active arm comparison studies, the National Multiple Sclerosis Society's Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis appointed a Task Force that was charged with developing improved clinical outcome measures. This Task Force acquired contemporary clinical trial and historical multiple sclerosis data for meta-analyses of primary and secondary outcome assessments to provide a basis for recommending a new outcome measure. A composite measure encompassing the major clinical dimensions of arm, leg and cognitive function was identified and termed the multiple sclerosis functional composite (MSFC). The MSFC consists of three objective quantitative tests of neurological function which are easy to administer. Change in this MSFC over the first year of observation predicted subsequent change in the EDSS, suggesting that the MSFC is more sensitive to change than the EDSS. This paper provides details concerning the development and testing of the MSFC.
Amato MP, Ponziani G, Bartolozzi
ML, Siracusa G. A prospective study on the natural history of multiple
sclerosis: clues to the conduct and interpretation of clinical trials.
J Neurol Sci 1999;168:96-106.
The study's objectives were to assess the predictive significance of different sets of demographic, clinical and extraclinical variables in identifying multiple sclerosis patients with various risk levels of worsening during the follow-up, in order to provide clues to inclusion criteria and selection of primary clinical end-points in therapeutic trials. 224 patients at their first diagnosis of multiple sclerosis admitted to our Department between 1983 and 1990 were prospectively followed-up until the end of 1996. We considered as end-points time to reach non-reversible disability levels corresponding to EDSS scores of 4.0 and 6.0 and the beginning of a secondary progressive phase in the relapsing-remitting subgroup of patients. ..... An initially progressive course and higher basal EDSS scores proved to be the best predictors of unfavorable prognosis; a greater number of functional systems involved at onset as well as higher residual deficits in pyramidal, visual, sphincteric and cerebellar systems were other factors predictive of a poor outcome, whereas sensory system involvement turned out to be favorable. In the relapsing-remitting subgroup, a longer first inter-attack interval was associated with a better prognosis; however, overall number of relapses in the first two years of the disease was of no prognostic value. The presence of oligoclonal banding in the cerebrospinal fluid and a cerebral MRI 'strongly suggestive' or 'suggestive' of MS in the early phases of the disease were associated with a higher probability of a worse outcome.
Jacobs LD, Wende KE, Brownscheidle
CM, Apatoff B, Coyle PK, Goodman A, Gottesman MH, Granger CV, Greenberg
SJ, Herbert J, Krupp L, Lava NS, Mihai C, Miller AE, Perel A, Smith CR,
Snyder DH. A profile of multiple sclerosis: the New York State Multiple
Sclerosis Consortium. Multiple Sclerosis 1999;5:369-76.
We have obtained a current profile of multiple sclerosis York State through a centralized patient registry and standardized data collection instrument associated with the New York State Multiple Sclerosis Consortium of 12 MS centers located throughout the state. Data from the first 3019 patients with clinically definite MS revealed a clear relationship between MS disease type, duration of disease, and severity of physical disability. Patients with relapsing disease had disease durations approximately half as long as those with progressive forms of the disease (means approximately 6 years versus 11 years). The majority of patients with relapsing disease had Expanded Disability Status Scale (EDSS) scores of 4.0 or less (self-sustained, fully ambulatory), whereas the majority of patients with progressive disease types had EDSS scores of 6.0 or greater (at least unilateral assist for walking). These findings emphasize the importance of early intervention in patients with relapsing disease to slow or prevent the accumulation of physical disability associated with progressive types of disease. Progressive disease was associated with lack of full-time employment and being disabled before the age of 60 years. .....
Hohol MJ, Orav EJ, Weiner HL. Disease
steps in multiple sclerosis: a longitudinal study comparing disease steps
and EDSS to evaluate disease progression. Multiple Sclerosis 1999;5:349-54.
Clinical assessment of outcome in MS patients is problematic since the disease can affect different aspects of the central nervous system and follow a variable course. Recently, we developed Disease Steps, a simple approach for evaluating disease progression. Previously, we found that Disease Steps was easy to use, had uniformly distributed scores and low inter-rater variability. ..... Over 4 years, 804 patients were classified using both EDSS and Disease Steps. ..... We found that the two scales behaved similarly and correlated strongly with each other. For both Disease Steps and EDSS, patients with milder levels of disability and relapsing-remitting disease demonstrated a higher likelihood of changing scores over time and shorter median staying times compared to more disabled, chronic progressive patients. These findings have important implications for patient selection in clinical trials and for the design of future measurements of clinical outcome in MS. Furthermore, Disease Steps may serve as a simple, practical tool for the nonspecialty neurologist to follow patients over time and serve as a guide in therapeutic decision making ......
Wingerchuk DM. Weinshenker BG. The
natural history of multiple sclerosis: implications for trial design. Curr
Op Neurol 1999;12:345-9.
The understanding of the natural history of multiple sclerosis has many implications for the design and interpretation of randomized controlled trials. Selection criteria, patient stratification, outcome measurements, and definitions of treatment failure can influence randomized controlled trial results and limit comparisons among trials. The focus of future studies should shift from short-term determinations of efficacy to definitive evaluations of long-term effectiveness. This will require novel investigative strategies such as the use of historic controls derived from natural history studies.
Ajdacic-Gross V, Schmid M, Tschopp
A, Gutzwiller F. [Recording of multiple sclerosis in Swiss cause of death
statistics. A 10-year mortality follow-up of the Bern prevalence study]
(in German) Sozial- und Praventivmedizin 1999;44:30-5.
Based on data from a MS prevalence study which had been carried out in 1986 in the canton of Berne, Switzerland, a follow-up was performed 10 years later to gather information on mortality in the original study population. ..... 21% of the cases died during the ten-year period; 70% of them have an MS entry in the cause of death statistics, mostly as the main cause of death. A large proportion of the non-identifiable cases appear to be related to mortality; thus, the findings here do not provide a promising basis for certain further analyses. In conclusion, continuous updating of personal data is the only way to avoid loss to follow-up in the carefully assembled prevalence database.
Cottrell DA, Kremenchutzky M, Rice
GP, Koopman WJ, Hader W, Baskerville J, Ebers GC. The natural history of
multiple sclerosis: a geographically based study. 5. The clinical features
and natural history of primary progressive multiple sclerosis. Brain 1999;122:625-39.
We report a natural history study of 216 patients with primary progressive (PP)- multiple sclerosis defined by at least 1 year of exacerbation-free progression at onset. This represents 19.8% of a largely population-based patient cohort having a mean longitudinal follow-up of 23 years. This subgroup of PP-multiple sclerosis patients had a mean age of onset of 38.5 years, with females predominating by a ratio of 1.3:1.0. The rate of deterioration from disease onset was substantially more rapid than for relapsing-remitting multiple sclerosis, with a median time to disability status score (DSS) 6 and DSS 8 of 8 and 18 years, respectively. Forty-nine percent of patients were followed through to death. Examination of the early disease course revealed two groups with adverse prognostic profiles. Firstly, a shorter time to reach DSS 3 from onset of PP-multiple sclerosis significantly adversely influenced time to DSS 8. Second, involvement of three or more neurological systems at onset resulted in a median time to DSS 10 of 13.5 years in contrast to PP-multiple sclerosis patients with one system involved at onset where median time to death from multiple sclerosis was 33.2 years. However, age, gender and type of neurological system involved at onset appeared to have little influence on prognosis. Life expectancy, cause of mortality and familial history profile were similar in PP-multiple sclerosis and non-PP-multiple sclerosis (all other multiple sclerosis patients from the total population). From clinical onset, rate of progression was faster in the PP-multiple sclerosis group than in the secondary progressive (SP)-multiple sclerosis group. When the rates of progression from onset of the progressive phase to DSS 6, 8 and 10 were compared, SP-multiple sclerosis had a more rapid progressive phase. A substantial minority (28%) of the PP-multiple sclerosis cohort had a distinct relapse even decades after onset of progressive deterioration. These studies establish natural history outcomes for the subgroup of multiple sclerosis patients with primary progressive disease.
Cottrell DA, Kremenchutzky M, Rice
GP, Hader W, Baskerville J, Ebers GC. The natural history of multiple sclerosis:
a geographically based study. 6. Applications to planning and interpretation
of clinical therapeutic trials in primary progressive multiple sclerosis.
The natural history of primary progressive multiple sclerosis (PP-multiple sclerosis) recently has been defined in a geographically based multiple sclerosis population. For a series of prognostically defined hypothetical entry criteria based upon current trends in presentation to the London Multiple Sclerosis Clinic, we determined the number of patients who would have been trial eligible. Using 23 year mean longitudinal natural history data, we identified the observed rate of deterioration for frequently used trial endpoints. ..... It is expected that the considerations outlined here will prove useful for both trial design and interpretation of trials in PP-multiple sclerosis which will require multi-centre collaborative efforts.