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Use of the Multiple Sclerosis Functional Composite as an Outcome Measure in a Phase 3 Clinical Trial
Jeffrey A. Cohen, MD;
Gary R. Cutter, PhD;
Jill S. Fischer, PhD;
Andrew D. Goodman, MD;
Fedor R. Heidenreich, MD;
Amy J. Jak, MA;
Judith E. Kniker, MA;
Mariska F. Kooijmans, MD, PhD;
Julia M. Lull, BA;
Alfred W. Sandrock, MD, PhD;
Jack H. Simon, MD;
Nancy A. Simonian, MD;
John N. Whitaker, MD;
for the IMPACT Investigators
Arch Neurol. 2001;58:961-967.
ABSTRACT
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Background The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional
clinical outcome measure that includes quantitative tests of leg function/ambulation
(Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function
(Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure
in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex)
in patients with secondary progressive MS.
Objective To assess the practice effects, reliability, and validity of the MSFC
clinical outcome measure.
Design Examining technicians underwent formal training using standardized materials.
The MSFC was performed according to a standardized protocol. The 436 patients
enrolled in the International Multiple Sclerosis Secondary Progressive Avonex
Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization.
Results Practice effects were evident initially for the MSFC but stabilized
by the fourth administration. The Paced Auditory Serial Addition Test demonstrated
the most prominent practice effects. The reliability of the MSFC was excellent,
with an intraclass correlation coefficient for session 3 (final prebaseline
session) vs session 4 (baseline) of 0.90. The MSFC at baseline correlated
moderately strongly with the Kurtzke Expanded Disability Status Scale. Among
the MSFC components, the Timed 25-Foot Walk correlated most closely. Correlations
among the 3 MSFC components were weak, suggesting they assess distinct aspects
of neurologic function in patients with MS.
Conclusions The MSFC demonstrated excellent intrarater reliability in this multinational
phase 3 trial. Three prebaseline testing sessions were sufficient to compensate
for practice effects. The pattern of correlations among the MSFC, its components,
and the Kurtzke Expanded Disability Status Scale supported the validity of
the MSFC.
INTRODUCTION
TO ADDRESS THE poor reliability and insensitivity to change over time
of the available multiple sclerosis (MS) clinical rating scales, including
the Kurtzke Expanded Disability Status Scale (EDSS),1
the National MS Society's Clinical Assessment Task Force (NMSS Task Force)
developed the MS Functional Composite (MSFC).2, 3, 4, 5
The MSFC includes quantitative tests of leg function/ambulation (Timed 25-Foot
Walk [T25FW]), arm function (9-Hole Peg Test [9HPT]), and cognitive function
(Paced Auditory Serial Addition Test [PASAT]). Although vision was recognized
as an important clinical dimension in MS, the measures of visual function
for which longitudinal data were available were found not to be sufficiently
sensitive to change to include in the initial version of the MSFC. In recent
studies,6 contrast sensitivity showed promise
as a measure of visual function for potential inclusion in the MSFC.
Several studies demonstrated that the MSFC correlated with disability
as measured by the EDSS,4, 7, 8
disease course,7 and patient self-report measures
of symptoms and quality of life.8 Preliminary
studies7, 9, 10 suggested
that magnetic resonance imaging measures of cranial lesion burden and atrophy
correlated better with the MSFC compared with the EDSS. Preliminary studies9, 10 also showed that the MSFC score in
patients with early relapsing-remitting MS and the change in the MSFC score
over 2 years were strongly predictive of brain atrophy and clinically significant
disability 6 to 8 years later. Taken together, these results provided strong
support for the validity of the MSFC.
Progression of neurologic disability as reflected by the MSFC score
is the primary outcome measure in the ongoing multinational phase 3 trial
of interferon beta-1a (Avonex) in patients with secondary progressive (SP)
MS (International Multiple Sclerosis Secondary Progressive Avonex Controlled
Trial [IMPACT]). Because it was anticipated that most clinicians and most
patients with MS would be unfamiliar with the MSFC, standardized examiner
training materials and patient testing procedures were developed in preparation
for IMPACT. A pilot study11 confirmed the effectiveness
of training procedures for the MSFC examining technicians, the practicality
of the MSFC testing protocol, and the excellent intrarater and interrater
reliability of the MSFC. As expected, practice effects were evident in the
initial testing sessions but stabilized by the fourth administration. Since
practice effects potentially could obscure changes in disease status over
time, these factors were used in designing the IMPACT protocol and in implementing
MSFC testing.
PATIENTS AND METHODS
PATIENT ENROLLMENT
Informed consent for participation in IMPACT was obtained after the
potential risks and benefits of the study were reviewed with potential subjects.
TECHNICIAN TRAINING
Examining technicians at 42 study sites in the United States, Canada,
and Europe, most without previous experience with the MSFC, were trained to
administer the MSFC at a prestudy investigators' meeting. Formal training
included a standardized didactic description of the MSFC background and testing
procedures, review of the MSFC administration and scoring manual, viewing
of a training videotape, and an interactive MSFC administration practice session
with feedback. Examiners' knowledge and performance were assessed at the end
of the training session to confirm familiarity with the MSFC procedures. Examiner
training required approximately 4 hours.
MSFC TESTING PROTOCOL
The MSFC was administered to patients using a standardized protocol.
The order of testing in a session was as follows: (1) T25FW (trial 1 and trial
2), (2) 9HPT (dominant hand: trial 1 and trial 2; and nondominant hand: trial
1 and trial 2), and (3) PASAT (3-second interstimulus interval and 2-second
interstimulus interval).
Patient instructions for the T25FW, 9HPT, and PASAT were available in
English, French, German, Dutch, Greek, and Hebrew. Two alternate forms for
the PASAT were used. The order in which the 2 forms was used varied among
patients and among sessions for an individual patient. The same examining
technician at each study site administered the MSFC to a given patient at
each study visit. To compensate for practice effects and to achieve a stable
baseline before randomization, the IMPACT protocol incorporated 3 prebaseline
testing sessions over 28 days before randomization. Examining technicians
did not have access to the results of previous testing sessions once completed.
STATISTICAL ANALYSES
The MSFC score was derived from 3 components: (1) T25FW (the mean of
the scores of the 2 T25FW trials), (2) 9HPT (the 2 trials for each hand were
averaged, then converted to reciprocals, and the 2 reciprocals were then averaged),
and (3) PASAT3 (the number correct on the PASAT with a 3-second interstimulus
interval). The MSFC score was calculated as the mean of the z scores of the 3 components (T25FW, 9HPT, and PASAT3). A z score is a standardized score representing the number of SD units
a given value is from a population mean and is calculated by subtracting the
mean of the reference population from the test result, then dividing by the
SD of the reference population. z Scores for the
T25FW, 9HPT, and PASAT3 were calculated with reference to the pooled data
set derived from the IMPACT baseline visit (session 4). For the T25FW and
9HPT, a higher raw score (time to complete the task in seconds) represents
deterioration, whereas for the PASAT3, a lower raw score (number correct)
represents deterioration. Consequently, in combining the 3 components into
a single z score, the sign of the T25FW z score was reversed, and the z score of the
inverse of the 9HPT time was used so that the direction of change was consistent
across components. Thus, a decrease in the z scores
of the 3 components and of the MSFC z score all represent
deterioration in neurologic function.
Correlations among the MSFC, its components, and the EDSS were analyzed
using Spearman rank correlations. The intraclass correlation coefficient was
used to measure the session-to-session intrarater reliability of the MSFC.12 The MSFC score for session 3 (the last prebaseline
session) was compared with that of session 4 (the baseline session) as the
primary measure of reliability. All statistical analyses were performed using
SAS statistical software (SAS Institute Inc, Cary, NC).
RESULTS
BASELINE PATIENT CHARACTERISTICS
A total of 436 subjects with SP MS and an EDSS score of 3.5 to 6.5 were
enrolled in IMPACT. Baseline demographic and clinical characteristics are
as follows:
Figure 1 illustrates the distribution
of patients across the range of baseline EDSS scores. As expected, there was
an overrepresentation of patients with EDSS scores of 4.0, 6.0, and 6.5, with
a relative underrepresentation of patients with EDSS scores of 4.5 to 5.5,
as has been seen in most population distributions for the EDSS.13, 14
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Figure 1. Distribution of Kurtzke Expanded
Disability Status Scale (EDSS) scores at baseline. The number of patients
is given in parentheses.
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COMPARISON WITH THE NMSS TASK FORCE DATA SET
The z scores for the MSFC components were calculated
with reference to the group means and SDs from the IMPACT baseline visit (session
4). The sample size estimate for IMPACT was based on an analysis of a cohort
of 326 patients in the NMSS Task Force data set with SP MS and an EDSS score
of 3.5 to 6.5. The values at baseline in IMPACT were comparable to those in
the NMSS Task Force data set (Table 1),
aside from the somewhat greater mean and SD of the T25FW score in the IMPACT
baseline data set.
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Table 1. Comparison of the NMSS Task Force Data Set and IMPACT Investigators'
Baseline Data*
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PRACTICE EFFECTS
Practice effects on the MSFC, manifested as improved performance and
decreased session-to-session variability, were evident in the first 3 prebaseline
sessions but stabilized by the fourth session (Table 2). At the time of this analysis, pooled data blind to treatment
group from the first postenrollment assessment at month 3 were available for
426 patients. The mean MSFC z score decreased slightly
from 0.00 at baseline to -0.12 at month 3.
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Table 2. Practice Effects as Indicated by Session-to-Session Change
in the MSFC* z Score
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The 3 MSFC components contributed differentially to the practice effects
observed for the overall composite (Figure
2). Progressive improvement in performance over the first 4 sessions
was most evident for the PASAT3. The 9HPT exhibited less prominent practice
effects, with most of the improvement occurring from the first testing session
to the second. There were no discernible practice effects on the T25FW.
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Figure 2. Practice effects on the components
of the Multiple Sclerosis Functional Composite. T25FW indicates Timed 25-Foot
Walk; 9HPT, 9-Hole Peg Test; and PASAT3, Paced Auditory Serial Addition Test
with a 3-second interstimulus interval.
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RELIABILITY
The MSFC demonstrated excellent intrarater reliability in IMPACT. The
intraclass correlation coefficient for the MSFC for session 3 (the last prebaseline
session) vs session 4 (the baseline visit) was 0.90. The intraclass correlation
coefficient for the 4 sessions taken together was 0.87, despite the increased
variability in the early testing sessions due to practice effects.
MSFC-EDSS CORRELATIONS
Table 3 provides the Spearman
rank correlations among the MSFC, its components, and the EDSS at baseline.
Similar to the analysis of the NMSS Task Force data set,4
correlation between the MSFC and the EDSS was moderately strong, even over
the more restricted EDSS score range in IMPACT. Figure 3A illustrates the distribution of the baseline MSFC z scores as a function of baseline EDSS scores. For the
patients as a group, there was nearly linear worsening in the mean MSFC z score from an EDSS score of 3.5 to 6.0. For an EDSS score
of 6.5, there was substantially greater worsening and intersubject variability
in the MSFC.
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Table 3. Correlation of the MSFC and EDSS at Baseline*
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Figure 3. Distributions of baseline z scores (given as mean ± SD) for the Multiple Sclerosis Functional
Composite (MSFC) (A), the Timed 25-Foot Walk (T25FW) (B), the 9-Hole Peg Test
(9HPT) (C), and the Paced Auditory Serial Addition Test with a 3-second interstimulus
interval (PASAT3) (D) as a function of the Kurtzke Expanded Disability Status
Scale (EDSS) score.
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Correlations among the individual components of the MSFC were modest
(Table 3), indicating that each
measured an independent clinical dimension. The 3 components correlated comparably
with the overall MSFC, indicating that each contributed information to the
MSFC for the group as a whole. As expected, the T25FW was the MSFC component
that correlated most strongly with the EDSS in this EDSS range. The 9HPT correlated
moderately, and the correlation between the PASAT3 and the EDSS was weak. Figure 3B-D illustrates the distributions
of the 3 MSFC components at baseline as a function of the EDSS. For the patients
as a group, there was progressive worsening in the T25FW score from an EDSS
score of 3.5 to 6.0, with relatively little variability in the T25FW score
at each EDSS level. There was dramatic worsening and an increase in intersubject
variability in the T25FW score at an EDSS score of 6.5. In contrast, the 9HPT
and PASAT3 demonstrated substantial intersubject variability at all EDSS steps
and a less prominent trend toward worsening with an increased EDSS score.
COMMENT
Quantitative assessment of neurologic impairment and disability in patients
with MS is difficult because of the marked clinical heterogeneity exhibited
by the disease, between patients and within individual patients over time.
There is variability in the manifestations that are present, their severity,
and the time course over which they develop. Also, some of the common manifestations
of MS that can have substantial impact on quality of life, such as cognitive
dysfunction, are difficult to quantify using the standard neurologic examination
and the rating scales based on it. The EDSS1
has been the most widely used clinical outcome measure in MS therapeutic trials.
However, the EDSS has several well-recognized shortcomings.14, 15, 16, 17
The MSFC developed by the NMSS Task Force is anticipated to have better reliability,
advantageous psychometric properties, and greater sensitivity to change compared
with the EDSS and other available MS clinical outcome measures.2, 3, 4, 5
The results of previous studies and those presented herein demonstrate that
the MSFC meets many of these goals.
It was anticipated that most clinicians and most patients with MS would
be unfamiliar with the MSFC. Therefore, in preparation for IMPACT, standardized
examiner training materials and a patient testing protocol were developed.
A pilot study11 confirmed the effectiveness
of the examiner training procedures and the feasibility of the testing protocol
in terms of ease of administration, the time required, and patient acceptance.
The MSFC demonstrated excellent intrarater and interrater reliability in this
small pilot study carried out at a single site. The MSFC again demonstrated
excellent reliability in IMPACT, a multinational study with 42 participating
sites, virtually none of which had prior experience with the measure. The
reliability of the MSFC in IMPACT was substantially better than that previously
reported for the EDSS in other trials.18, 19, 20, 21, 22
Because of previous clinical experience with quantitative measures and
analysis of the NMSS Task Force pooled data set,4
practice effects on the MSFC were expected to occur. That is, performance
and variability were anticipated to improve as subjects (and examiners) became
familiar with the tasks. In the pilot study11
carried out before IMPACT, practice effects appeared to stabilize by the fourth
testing session. Therefore, the IMPACT protocol included 3 prebaseline testing
sessions over 28 days before randomization. The experience in IMPACT confirmed
that the MSFC is susceptible to practice effects. The substantial variability
in the change from session to session before baseline suggested that the magnitude
and time course of practice effects differed among patients. This potential
variability could obscure underlying biological change and impede the detection
of a treatment effect in the context of a clinical trial. Three prebaseline
sessions appeared to be sufficient to compensate for practice effects on the
MSFC, which stabilized by the fourth session. The pooled MSFC data from month
3 demonstrated neither substantial improvement, which would suggest further
practice effects, nor substantial worsening, which would suggest "forgetting."
With the small sample size in the pilot study,11
it was not possible to discern the relative contributions of the 3 MSFC components
to the practice effects seen for the overall measure. With the larger sample
size in IMPACT, it was clear that the primary source of practice effects on
the MSFC was the PASAT3. Strong practice effects on the PASAT have been reported
previously in normal and neurologically impaired subjects23, 24, 25
and in subjects with MS.26 In IMPACT, modest
practice effects on the 9HPT also were evident. We are unaware of any previous
systematic study of variability over time or practice effects on the 9HPT
in patients with impaired upper extremity function, including those with MS.
No practice effects were seen on the T25FW in IMPACT. A previous study of
63 subjects with MS undergoing T25FW testing on 5 consecutive days also failed
to detect any systematic trend suggesting practice effects (Steven Schwid,
MD, written communication, March 1999). Although the main source of MSFC practice
effects is the PASAT3, we recommend that prebaseline testing include all 3
components to familiarize subjects and examiners with the standardized MSFC
testing protocol.
Two remaining key issues with the MSFC are its validity as a measure
of disability in patients with MS and its utility as an outcome measure in
clinical trials. Preliminary studies7, 9, 10
demonstrated good correlation between magnetic resonance imaging measures
of cranial lesion burden and atrophy and the MSFC. Three previous studies4, 7, 8 have shown that the
MSFC correlated with the EDSS, the most widely used measure of neurologic
disability in MS clinical trials. The MSFC was shown to be worse in patients
with SP MS compared with those with relapsing-remitting disease.7
Finally, the MSFC correlated well with patient self-report measures of symptoms
and quality of life.8
The results reported herein for IMPACT provide further support for the
validity of the MSFC from analysis of a fourth independent data set. First,
the population values for the T25FW, 9HPT, and PASAT3 at baseline in IMPACT
were comparable to those calculated for the cohort of patients with SP MS
and an EDSS score of 3.5 to 6.5 in the NMSS Task Force data set used to estimate
sample size for the trial. The somewhat greater mean and SD shown for the
T25FW at baseline in IMPACT likely was due to the higher proportion of patients
with EDSS scores of 6.0 and 6.5.
More important, correlations among the MSFC, its components, and the
EDSS, which were collected prospectively in IMPACT, were similar to those
previously reported by the NMSS Task Force based on retrospective analysis
of existing data sets. Correlations among the 3 components of the MSFC were
modest. Thus, although patients with MS tend to demonstrate parallel impairment
in several domains, the T25FW, 9HPT, and PASAT3 clearly measure independent
clinical dimensions of MS. As expected, the correlation was strongest between
the T25FW and 9HPT, but neither correlated well with the PASAT3. The strengths
of the correlations between the MSFC and its 3 components were roughly comparable,
suggesting that all 3 contribute information to the MSFC for the patient population
as a whole. The MSFC correlated moderately with the EDSS, supporting the convergent
validity of the MSFC (correlation with another measure of neurologic disability)
and its divergent validity (measurement of aspects of MS not covered by the
EDSS). As expected, among the components of the MSFC, the T25FW correlated
best with the EDSS. For an EDSS score between 3.5 and 6.5, the range used
as an enrollment criterion for IMPACT, the EDSS is primarily an ambulation
scale with the score determined solely by how far a patient can walk and the
type of assistive device required. It was not surprising that walking speed
and distance would be related. Correlation between the 9HPT and EDSS was less
strong. Patients with motor impairment affecting ambulation also tend to have
motor impairment in the arms. However, arm function does not affect EDSS scoring
in the range studied in IMPACT. Correlation between the PASAT3 and the EDSS
was weak. The EDSS, like all clinical rating scales based on the standard
neurologic examination, measures cognitive dysfunction in patients with MS
poorly throughout its range.
In summary, the results of the previously reported pilot study and the
baseline data from IMPACT reported herein confirmed the excellent reliability
of the MSFC when standardized procedures are used to train examiners and to
assess patients. Incorporation of 3 prebaseline testing sessions compensated
for practice effects on the MSFC. The baseline IMPACT results corroborated
the results of previous studies correlating the MSFC and the EDSS. The pattern
of correlations among the MSFC, its components, and the EDSS supported the
validity of the MSFC. These results again indicated that the MSFC assesses
aspects of neurologic function not measured by the EDSS, suggesting that it
will be more sensitive to detect change over time and better able to demonstrate
a therapeutic effect when one exists.
AUTHOR INFORMATION
IMPACT Investigators
University of California Davis Medical Center, Sacramento: M. Agius, MD; J. Adams, RN; R. Beale; D. Richman, MD; N. Vijayan,
MD; V. Wheelock, MD. University of Maryland School of Medicine,
Baltimore: C. Bever, MD; K. Costello, RN; S. Dhib-Jalbut, MD; K. Johnson,
MD; E. Katz, RN; H. Panitch, MD. Minneapolis Clinic of Neurology,
Golden Valley, Minn: G. Birnbaum, MD; I. Altafullah, MD; G. Christenson,
RN; K. Stillwell. University of Washington Medical Center,
Seattle: J. Bowen, MD; A. Gianas, RN; E. Krause, MD; E. Yuen, MD. Rhode Island Hospital–Brown University, Providence:
P. Calabresi, MD; L. Alderson, MD; G. Johnson, MD; P. Mills, RN; J. Quinless;
J. Wilterdink, MD. Mayo Clinic, Scottsdale, Ariz:
J. Carter, MD; J. Buckner; R. Caselli, MD; K. MacElwee, RN; K. Nelson, MD;
J. Takata, MD. Mellen Center for Multiple Sclerosis Treatment
and Research, The Cleveland Clinic Foundation, Cleveland, Ohio: J.
Cohen, MD; D. Bolibrush; C. Hara-Cleaver, RN; R. Kinkel, MD; R. Rudick, MD;
L. Stone, MD. University of Medicine and Dentistry–New
Jersey Medical School, Newark: S. Cook, MD; D. Cadavid, MD; A. Jotkowitz,
RN; Y. Maeda, MD; J. Quinless, RN. University of Colorado
Health Sciences Center, Denver: J. Corboy, MD; J. Bainbridge, PharmD;
J. LaGuardia, MD; H. Neville, MD; R. Taggert, RN; R. Wright, MD. Georgetown University Hospital, Washington, DC: H. Crayton, MD; D.
Bartlett, RN; S. Cohan; T. Gustafson, RN; J. Richert, MD; C. Tornatore, MD. University of New Mexico Health Science Center, Albuquerque:
C. Ford, MD; G. Graham; A. Kradochvil; J. Maldonado, MD. University of Pennsylvania, Philadelphia: S. Galetta, MD; L. Balcer,
MD; F. Gonzalez-Scarano, MD; R. Grossman, MD; D. Kolson, MD; G. Liu, MD; M.
Mills; D. Pfohl, RN; A. Pruitt, MD; A.-M. Rostami, MD, PhD; D. Silberberg,
MD. University of Rochester, Rochester, NY: A. Goodman,
MD; M. Petrie, RN; E. Schwid, RN; S. Schwid, MD; D. Shrirer, MD. Yale School of Medicine, New Haven, Conn: J. Guarnaccia, MD; J. Hayes;
S. Novella, MD; H. Patwa, MD; M. Rizzo, MD; M. Shepard, RN; T. Vollmer, MD. University of Mississippi Medical Center, Jackson: R. Herndon,
MD; J. Corbett, MD; R. Fredericks, MD; J. Pittman, PharmD; P. Reynolds, MD;
M. Umberger, RN; R. Wier, RN. Buffalo General Hospital,
Buffalo, NY: L. Jacobs, MD; R. Bakshi, MD; E. Gallagher, RN; S. Greenberg,
MD; F. Munschauer III, MD; K. Murray, MD; K. Patrick; B. Weinstock-Guttman,
MD. University of Southern California, Los Angeles:
N. Kachuk, MD; L. Adobo, MA; C. Cooper; R. Cowan, MD; D. Ko, MD. MS Center at Carolinas Medical Center, Charlotte, NC: M. Kaufman, MD;
A. Diedrich, MD; D. Lutz; R. Follmer, MD; S. Putman, MD; S. Presley. Alleghany University of the Health Sciences, Philadelphia:
F. Lublin, MD; R. Elfont, MD, PhD; L. Kelly, PhD; M. Weber. Oregon Health Sciences University, Portland: M. Mass, MD; D. Bourdette,
MD; R. Camicioli, MD; S. Cooper-Hanel; D. Griffiths, RN; R. Whitham, MD. Indiana University School of Medicine, Indianapolis: D.
Mattson, MD, PhD; M. Farlow, MD; J. Fleck, MD; J. Hayes; D. Jackson, RN; R.
Pourmand, MD. Maimonides Medical Center, Brooklyn, NY:
A. Miller, MD; M. Brodbari; K. Bruining, MD; E. Drexler, MD; H. Elinzano,
MD; M. Keilson, MD; T. LaRocca, RN, BSN; L. Morgante, RN, MSN; L. Sciarra,
RN, MSN; R. Wolintz, MD. University of California at Los
Angeles MS Center: L. Myers, MD; R. Baumhefner, MD; S. Craig, RN; R.
Klutch; N. Sicotte, MD. Ohio State University, Columbus: K. Rammohan, MD; D. Higgens, MD; J. Kissel, MD; D. Lynn, MD; A. Sifford,
RN; A. Slivka, MD; J. Warner. Vanderbilt University MS Center,
Nashville, Tenn: S. Sriram, MD; S. Hunter, MD, PhD; H. Moses, Jr, MD;
F. Niaz, MD; J. Simmons, RN; K. Reece, RN. MS Center at
Shepherd Center, Atlanta, Ga: W. Stuart, MD; E. Awad, MD; D. Court,
RN; R. Gilbert, MD; E. Hedaya, MD; S. Morgan; D. Stuart, MD. Washington University, St Louis, Mo: J. Trotter, MD; D. Cross, MD;
D. Derrington, MD; J. Lauber, RN; C. Martinez, LPN. University
of California at Irvine: S. Van den Noort, MD; R. Babcock, RN; P. Fotinakes,
MD; Y. Qin; G. Thai, MD. Yale University, New Haven:
T. Vollmer, MD; G. Blanco; J. Guarnaccia, MD; T. Halverson; E. Kane; S. Markovic-Plese,
MD; L. Marshall; S. Novella, MD; H. Patwa, MD; G. Richerson, MD; M. Rizzo,
MD. University of Alabama at Birmingham: J. Whitaker,
MD; K. Bashir, MD; B. Layton, RN; L. Nabors III, MD; A. Nicholas, MD, PhD;
R. Slaughter, MD; K. Whikehart. University of Texas at Houston
Health Science Center: J. Wolinsky, MD; S. Brod, MD; E. Cerreta, RN;
W. Lindsey, MD; C. Weisbrodt, RN. Hopital Notre-Dame, Montreal,
Quebec: P. Duquette, MD; G. Bernier, MD; P. Cossette, MD; R. Dubois,
RN; J. Poirier. Ottawa General Hospital, Ottawa, Ontario: M. Freedman, MD; S. Christie, MD; C. Freedman, BMT (PT); R. Nelson,
MD; H. Rabinovitch, MD; U. Webb, RN. University of Toronto
MS Clinic, St Michael's Hospital, Toronto, Ontario: P. O'Connor, MD;
J. Fleming; P. Fleming, RN; T. Gray, MD; M. Hohol, MD; P. Marchotti, MD. University of Western Ontario Hospital, London, Ontario:
G. Rice, MD; T. Bentall, RN; G. Ebers, MD, DPhil; M. Hopkins; P. Mandolfino,
MD; M. Nicolle, MD; D. Wingerchuk, MD. Neurological Center
Quellenhof, Bad Wildbad, Germany: A. Foit, MD; R. Ascheron; A. Fauser,
MD; J. Fernholtz; A. Immesberger; M. Riexinger; R. Roth. Stadtisch Kliniken Osnabruck, Germany: P. Haller, PhD, MD; D. Lammers;
S. Stove, MD; A. Terwey, MD; S. Windhagen. Medizinische
Hoschule, Hannover, Germany: F. Heidenreich, MD; H. Becker; K. Fricke,
MD; R. Hilse, MD; N. Kohler, MD; A. Kracke, MD; R. Lindert, MD; S. Maniak,
MD; S. Marckmann, MD. Athens University, Athens, Greece: M. Dalakas, MD; C. Kilidreas, MD; A. Rombos, MD; C. Taskanikas, MD;
C. Voumvourakis, MD. Haddassah Hebrew National University,
Jerusalem, Israel: O. Abramsky, MD; A. Askenazi, MD; A. Karmi, MD;
D. Karussis, MD; A. Linitsky, MD; M. Mor, MD. VU Ziekenhuis,
Amsterdam, the Netherlands: C. Polman, MD, PhD; J Castelijns, MD; B.
Jelles, MD; N. Kalkers, MD; J. Killestein, MD; T. Schweigmann; B. Uitdehaag,
MD. Chefarzt der Marinanne-Strauß-Klinik, Milchberg, Germany: N. Konig, MD; H. Albrecht, MD; W. Feneberg,
MD; C. Kutschker, MD; W. Pollmann, MD; M. Stark, MD. (For each site, the principal
investigator is listed first.)
Accepted for publication November 27, 2000.
This study and the development of the MSFC manual (a manual describing
MSFC testing and scoring procedures, which is available through the National
MS Society) were supported by Biogen, Inc, Cambridge, Mass.
Presented at the annual meeting of the American Academy of Neurology,
Toronto, Ontario, April 22, 1999.
We thank Richard A. Rudick, MD, for reviewing the manuscript.
From the Mellen Center for Multiple Sclerosis Treatment and Research
and the Department of Neurology, The Cleveland Clinic Foundation, Cleveland,
Ohio (Drs Cohen and Fischer and Mss Jak and Kniker); the Center for Research
Methodology and Biometrics, AMC Cancer Center, Lakewood, Colo (Dr Cutter);
the Departments of Neurology, University of Rochester, Rochester, NY (Dr Goodman),
Hannover Medical School, Hannover, Germany (Dr Heidenreich), and the University
of Alabama at Birmingham (Dr Whitaker); Biogen, Inc, Cambridge, Mass (Drs
Kooijmans, Sandrock, and Simonian and Ms Lull); and the Department of Radiology,
University of Colorado, Denver (Dr Simon). Drs Kooijmans, Sandrock, and Simonian
and Ms Lull are full-time employees of Biogen, Inc. None of the other authors
has a personal financial investment, ownership, equity, or other financial
holdings with Biogen, Inc. Dr Fischer and Mss Jak and Kniker supervised the
training of examining technicians and were reimbursed through a contract with
Biogen, Inc, which was paid to The Cleveland Clinic. Drs Cohen, Cutter, Goodman,
Heidenreich, Simon, and Whitaker have served as consultants for, received
honoraria from, or received research support from Biogen, Inc.
Corresponding author and reprints: Jeffrey A. Cohen, MD, The Mellen
Center-U10, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH
44195 (e-mail: cohenj{at}ccf.org).
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