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Outcome Measures for Pediatric Spinal Muscular Atrophy
Susan T. Iannaccone, MD;
and the American Spinal Muscular Atrophy Randomized Trials (AmSMART)
Group
Arch Neurol. 2002;59:1445-1450.
ABSTRACT
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Background Spinal muscular atrophy (SMA) is a genetic disease of the anterior horn
cell with a frequency of 8 per 100 000 live births and a high rate of
mortality during infancy. The American Spinal Muscular Atrophy Randomized
Trials (AmSMART) Group is an organization of 5 centers formed to perform clinical
trials in children with SMA.
Objective To devise reliable methods to measure strength, motor function, lung
function, and quality of life for use as outcome measures in children with
SMA.
Setting Tertiary referral center, pediatric neurology department.
Patients and Methods Twelve children with SMA aged 2 to 14 years were enrolled in a reliability
study of 4 outcome measures: quantitative muscle testing (in children >5 years),
gross motor function measure, pulmonary function tests, and quality of life.
The Richmond Quantitative Measurement System was used to test grip, knee flexion
and extension, and elbow flexion. Gross motor function measure was performed
as described, and pulmonary function tests were measured using the KoKo system.
Quality of life was assessed via the PedsQL and the PedsQL Neuromuscular Module
for patients and parents.
Results Ten children fulfilled the inclusion criteria and completed at least
3 visits with 3 evaluators in 6 months. Using a weighted  , the gross
motor function measure showed high interrater reliability. Quantitative muscle
testing showed greater variability among the weakest children; the findings
for pulmonary function tests and quality of life were inconclusive. The PedsQL
Neuromuscular Module for parents had moderately high reliability.
Conclusion A tool for motor function may be more useful in clinical trials of childhood
SMA than one for quantitative muscle strength.
INTRODUCTION
SPINAL MUSCULAR atrophy (SMA) (OMIM 253300) is a genetic disease of
the anterior horn cell with a frequency of 8 per 100 000 live births.1-3 It has been classified
into 3 types according to age at onset, severity of disease, and motor milestones
achieved. Spinal muscular atrophy type I begins before age 6 months and has
a high rate of mortality during infancy. The prevalence rate is greatest for
SMA types II and III, which are associated with later onset and lower mortality
rates during middle and late childhood.4-5
Death almost always is secondary to severe restrictive lung disease that is
progressive, although muscle strength may be stable for decades.6
There is no known treatment for SMA. Until recently, no therapeutic trials
have been attempted. The disease is caused by mutation of the SMN1 gene, the product of which is called SMN protein.7-9
New information regarding the nature and function of SMN protein in SMA and
the availability of new pharmacologic agents now make it possible to consider
clinical trials in this disease.10 Our goal
is to devise reliable methods to measure lung function, strength, motor function,
and quality of life in children with SMA.
PATIENTS AND METHODS
The American Spinal Muscular Atrophy Randomized Trials (AmSMART) Group
is an organization of 5 pediatric medical centers formed to perform clinical
trials in children with SMA (Figure 1).
The 3-year project was organized as follows: part 1, interrater reliability
study; part 2, intrarater reliability study; and part 3, pilot drug trial.
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Figure 1. Organizational chart for the American
Spinal Muscular Atrophy Randomized Trials (AmSMART) Group. QMT indicates quantitative
muscle testing; TSRHC, Texas Scottish Rite Hospital for Children; and CRC,
Clinical Research Coordinator.
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For part 1, 12 children with SMA aged 2 to 14 years were enrolled between
August 1, 2000, and January 31, 2001. The outcome measures were (1) pulmonary
function tests (PFTs) in children older than 5 years, (2) quantitative muscle
testing (QMT) in children older than 5 years, (3) gross motor function measure
(GMFM), and (4) quality of life (QOL).
Patients were recruited from the Pediatric Neuromuscular Clinic at Texas
Scottish Rite Hospital for Children and were screened for inclusion and exclusion
criteria. Inclusion criteria were as follows: 2 to 18 years old, weakness
and a clinical diagnosis of SMA confirmed by mutation analysis of the SMN1 gene, forced vital capacity greater than 20% of predicted
for age, less than 15% variance on test-retest using QMT after instruction,
and informed consent. Exclusion criteria were as follows: no clinically significant
evidence of renal dysfunction, central nervous system damage, or neurodegenerative
or neuromuscular disease other than SMA and no mechanical ventilation of any
type for more than 16 h/d.
The evaluation room was located in the physical therapy department and
contained all equipment used for an evaluation session, including the examining
table (Figure 2), the Richmond Quantitative
Measurement System for QMT, items for use in the GMFM, and chairs for parents.
Sessions for individual patients were scheduled at the same time of day (eg,
morning or afternoon), with at least 48 hours between sessions. Individual
parts of the evaluation session were performed in the same order for all patients.
Positioning for PFTs and QMT was consistent for all patients. Rest periods
during the evaluation session were as follows: 30 to 60 seconds between attempts,
15 minutes between PFTs and QMT, and 15 minutes between QMT and the GMFM.
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Figure 2. Examining table used for quantitative
muscle testing.
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Pulmonary function tests were performed according to American Thoracic
Society standards and included maximum inspiratory pressure, maximum expiratory
pressure, cough pressure (peak cough flow), forced vital capacity, and forced
expiratory volume in the first second. Lung volumes were measured using the
KoKo spirometer system (Pulmonary Data Services, Inc, Louisville, Colo), which
calculates percentage predicted based on height and age.
The Richmond Quantitative Measurement System was used to test (1) right
and left grip, (2) right and left knee extension, (3) right and left knee
flexion, and (4) right and left elbow flexion. Each patient had 3 attempts
for each muscle group, and the computer recorded the best of 3 test results
on prompting from the evaluator. Strength was recorded in pounds. Patients
sat during testing of muscle groups 1, 2, and 3 and were supine for testing
of group 4.
The GMFM contained 88 items in 5 dimensions: lying and rolling (A),
sitting (B), crawling and kneeling (C), standing (D), and walking, running,
and jumping (E). Each patient continued through all dimensions according to
his or her abilities. Each item was scored individually and weighted equally.
Ten QOL forms were administered by the study coordinator (K.R.) at the
beginning of the first and last visits. The generic PedsQL11
included a parent questionnaire for each of 4 age groups: 2 to 4, 5 to 7,
8 to 12, and 13 to 18 years. In addition, there was a child questionnaire
for each of 3 age groups: 5 to 7, 8 to 12, and 13 to 18 years. The AmSMART
child psychologists developed a specific questionnaire, the PedsQL Neuromuscular
Module, with one version for parents and 2 for children aged 5 to 7 and 8
to 18 years. All procedures were approved by the institutional review board
of The University of Texas Southwestern Medical Center, Dallas.
TRAINING
All evaluators were licensed physical therapists with pediatric experience.
Two evaluators in Dallas (D.C. and J.G.) were responsible for training evaluators
from other centers. One consultant evaluator from Dallas (L.H.) and the evaluator
from Richmond, Va (J.M.), who had previous experience with QMT methods provided
additional training. The respiratory therapist from Dallas (K.H.) provided
training in the performance of PFTs. The Dallas group developed and distributed
a training videotape and a manual for QMT and PFTs. From March 4 to 9, 2001,
all evaluators met in Dallas for 1 week, during which they trained using the
Richmond Quantitative Measurement System equipment and conducted evaluation
sessions 3 and 4 for patients in phase 1.
DATA MANAGEMENT
All data were transcribed by evaluators onto case report forms (CRFs)
developed in the Department of Academic Computing Services at The University
of Texas Southwestern Medical Center. The CRFs were organized in a binder
for each patient. The CRFs were checked carefully by the study coordinator
(K.R.) and the principal investigator (S.T.I.), and a checklist was completed
for each CRF before it was sent to the Department of Academic Computing Services
for data entry and verification. Unique identifiers for a CRF were site number,
patient number, patient initials, and visit number. The Department of Academic
Computing Services developed and distributed a variance calculator program
to assist in determining whether the patient passed the inclusion criteria
of less than 15% variance between visits 1 and 2 on QMT.
DATA ANALYSIS
Analysis for PFTs and QMT was performed by calculating percentage change
measure across the last 3 visits; the proportion of measures that were within
the 10% or 15% criterion was reported. A commercial software program (Microsoft
Excel 2000; Microsoft Corp, Redmond, Wash) was used to prepare the data for
analysis, and 3 statistical packages (SPSS version 10 [SPSS Inc, Chicago,
Ill], StatXact version 4.0 [Cytel Software Corp, Cambridge, Mass], and SAS
version 8 [SAS Institute Inc, Cary, NC]) were used for analysis. Interrater
reliability for the GMFM was assessed by performing a weighted statistic
on dimensions A and B and a nonparametric Friedman test for repeated measurement
for dimensions A and B and the total GMFM. Cronbach coefficient  was
calculated for the parent version of the PedsQL Neuromuscular Module, and
test-retest reliability was performed for the first and last visits.
RESULTS
Ten children (4 girls and 6 boys) fulfilled the inclusion criteria and
completed at least 3 visits with 3 of the 6 evaluators in 6 months. The children
were aged 2 to 14 years (mean, 7.4 years). There was 1 walker and 9 nonwalkers.
PULMONARY FUNCTION TESTS
Six patients completed PFTs; 1 patient did not complete the peak cough
flow measure. Analyses using the percentage change measure for all 5 measures
of PFT (percent forced vital capacity, percent forced expiratory volume in
the first second, maximum inspiratory pressure, maximum expiratory pressure,
and peak cough flow) showed that 53% of measurements were within 10% and 73%
were within 15% of each other across 3 evaluators (Table 1). Review of individual test results showed that there was
consistency for individual patients in any given visit, but patients' results
sometimes varied between visits secondary to reactive airway disease or illness.
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Table 1. Summary Data for Pulmonary Function Tests in 6 Patients With
Spinal Muscular Atrophy
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QUANTITATIVE MUSCLE TESTING
Six patients completed QMT; 1 patient was missing data for right and
left grip. The percentage change measure for 8 muscle groups showed that 18%
of measurements were within 10% and 22% were within 15% of each other across
3 evaluators (Table 2).
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Table 2. Summary Data for Quantitative Muscle Testing by Muscle Group
in Patients With Spinal Muscular Atrophy
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GROSS MOTOR FUNCTION MEASURE
Preliminary analyses of the GMFM data showed that all patients could
complete the items from dimensions A (lying and rolling) and B (sitting),
but many were too weak to attempt dimensions C, D, and E. The average interrater
reliability (weighted statistic) for the 37 items from dimensions
A and B using data from visits 2, 3, and 4 was excellent ( = 0.72).
The 88 items of the GMFM were analyzed individually; items found to have 2
or more levels of discrepancy across the last 3 measurements were those in
dimensions C, D, and E. The Friedman test for repeated measurements found
dimensions A and B and the total GMFM to be nonsignificant, indicating that
measurements were consistent.
QUALITY OF LIFE
Of the forms administered, only one had enough data for analysis, the
PedsQL Neuromuscular Module for Parents. Using Cronbach coefficient ,
for the first visit = .69 and for the last visit = .57. Both
of these levels are considered good for a newly constructed instrument.
The test-retest reliability was 0.81.
COMMENT
Spinal muscular atrophy was first recognized as a distinct entity 110
years ago, with the nearly simultaneous publication of the clinicopathologic
descriptions of Werdnig and Hoffman.12-14
Children with SMA are among the weakest cared for in any muscle clinic. Most
are never able to roll from supine or to pull to sitting. In the 1960s, Byers
and Banker2 correlated severity of disease
with age at onset and mortality. This classification is consistent with there
being a clinical spectrum extending from the most severely affected with rapid
mortality (SMA type I) to those who have relatively preserved strength and
a normal life expectancy (SMA type III).15
Survival into the eighth decade is possible but rare.
The gene product of SMN1 is thought to be a
protein in complex with spliceosomes.16-18
The SMN protein was absent from motor neurons of SMA type I infants. Although
protein was found in patients with SMA type II or III, the amount of protein
was decreased compared with that in controls.19-20
These findings suggest that severity of disease is inversely proportional
to amount of SMN protein.21
A mouse model shows a phenotype similar to infantile SMA and has only
2 copies of the human SMN2 gene and no copies of
the mouse SMN gene.22 Therefore, the animal
has defective SMN protein similar to that present in people with SMA. In vitro
manipulation of motor neurons from these mice may reveal compounds that are
capable of up-regulating or modifying the SMN2 gene
to produce more protein or more normal protein. Using the technique of "high
throughput screening," researchers estimate that they can test as many as
100 000 compounds in a year.10 As soon
as safety testing can be completed, candidate compounds could be ready for
clinical trials. Thus, there may be improved rationale for drug treatment
of SMA within 2 years.
Objective and reliable measures of disease state in childhood SMA have
not yet been defined. All prospective and retrospective studies to date depend
on measurement of strength, assumed to reflect the pathophysiologic process
of motor neuron death. Standard methods of strength testing, such as the manual
muscle test, are not useful in this population because patients are so weak
that most muscle groups will not register more than 1 or 2 of a possible 5.
Moreover, the scale is ordinal so that statistical analysis is problematic
and small changes in strength cannot be measured. Thus, several groups have
attempted to use QMT with devices that are sensitive to very weak force, including
the handheld dynamometer and the fixed myometer, the Chatillon (AMETEK, Inc,
Paoli, Pa), both of which showed varying degrees of reliability and sensitivity.
One such study, the DCN/SMA study,6 was
conducted by 3 of the researchers involved in the present project. Between
1988 and 1994, 73 patients with SMA (41 girls and 32 boys; mean age, 17.3
years) were evaluated.6 Of the 14 muscle groups
that underwent QMT, results from 6 (3 on each side) were considered unreliable.
Thus, measures of shoulder abduction, shoulder adduction, and elbow extension
were eliminated from the total muscle score.
There was an increment in the total muscle score for patients younger
than 15 years that was statistically significant. Patients with SMA overall
showed an increase of 2.2 kg in a mean of 4 years, or an increment of approximately
0.5 kg/y. A similar suggestion of improved motor function was seen in a cohort
of patients with SMA younger than 6 years who were evaluated using a motor
function scale.23 Such improvement during early
childhood may be attributed to growth and development but remains way below
what is expected for healthy children. For patients older than 15 years, there
was no increment or decrement in the total muscle score.
Most important, no patient showed loss of strength during the observation.
Based on our data, we suggested several options to obtain statistically reliable
results in a clinical trial: (1) monitor motor function for at least 12 months
using a sensitive tool yet to be developed, (2) monitor for an increase in
QMT, (3) develop a strength measurement that is more sensitive and more reliable
than QMT, (4) increase the sample size, or (5) increase the duration of the
study. Because the number of patients and the length of the study affect the
feasibility and cost of completing a study, it would be practical to develop
sensitive methods of monitoring strength and motor function.24-26
Until recently, there were few valid or reliable tools for measure of
motor function in children. Those were of no use for nonambulatory children
and offered no discriminatory increments for small changes in strength. The
GMFM27 has been tested for validity and reliability
but only in patients with cerebral palsy and not in those with neuromuscular
disease. The GMFM contains 88 items, each of which has a graded score. The
items are grouped according to body region, such as upper extremities, and
some items reportedly may be omitted without affecting its validity. The GMFM
seems to be excellent for evaluating very weak children, such as those with
SMA. Our results showed good consistency for interrater and intrarater testing.
However, the number of patients for part 1 was small, and we have no data
yet to indicate how sensitive to change this measure might be.
Pulmonary function may better reflect disease state than muscle strength
because most patients with SMA die of respiratory failure. However, PFTs in
children are difficult to perform in a consistent way and rarely have been
used as outcome measures for clinical trials. Furthermore, all lung volume
variables must be compared with age-matched controls as percentage predicted
for age, which is always calculated on the basis of height. Height measures
in patients with SMA are notoriously inaccurate because of orthopedic deformities
such as scoliosis and flexion contractures.
A new requirement for clinical trials is measurement of the patient's
perception of disease state, the QOL. Defined as the degree of satisfaction
or dissatisfaction felt by people with various aspects of their lives, QOL
may be measured for individuals and for families.28-29
Health-related QOL depends on concurrent lifestyles, past experiences, hopes
for the future, dreams, and ambitions,30 with
objective and subjective components.31 The
pediatric health-related QOL may include functional performance and patients'
evaluations of their own experiences.30, 32-33
Testa and Simonson31 described 3 primary domains
in pediatric health-related QOL: physical, psychological, and social.31, 34-35
In addition to more general surveys of information, QOL instruments
have been designed around specific childhood diseases, such as cancer and
arthritis.36-37 These measures
are commonly used in clinical trials.38-40
The PedsQL11, 30 incorporates associated
modules for work in oncology, asthma, or diabetes mellitus. The PedsQL includes
subdomains assessing physical, emotional, school, and social functioning.
Reliability, validity, and specificity were established,41
and it allowed the addition of disease-specific questions. We do not yet have
enough data to determine whether this tool will be useful for SMA.
The AmSMART Group has made a first attempt to develop valid and reliable
outcome measures for children with SMA aged 2 to 18 years, whether ambulatory
or nonambulatory. Reliability results depended on the patients' and the evaluators'
familiarity with the procedures. As in previous studies,6
we found the patients' learning curve to be 2 to 3 visits. Evaluators were
especially uncomfortable with measuring PFTs. They lacked the judgment for
recognizing less than full effort and did not recognize abnormal flow loops
indicating that the patient had reactive airways. Therefore, we incorporated
a follow-up training session of 2 days that included extensive discussion
of normal lung physiology following American Thoracic Society guidelines.
We concluded, moreover, that training sessions should be conducted at a time
when data were not being collected so that evaluators could concentrate on
learning technique without feeling pressure to collect data.
In conclusion, after reliability testing with a small number of patients,
the GMFM seems to be the most reliable outcome measure used. A tool that measures
motor function may be more useful in clinical trials of childhood SMA than
one that measures quantitative muscle strength. Performance of PFTs in children
requires special training. Evaluator training sessions should be separated
in time and space from sessions used for collection of reliability data. Inconsistency
of outcome measures may be secondary to patient, evaluator, or tool factors.
AUTHOR INFORMATION
Accepted for publication April 10, 2002.
Author contributions: Study
concept and design (Drs Iannaccone, Morton, Reisch, Schochet, Luckett,
Samaha, Russman, and Leshner); acquisition of data
(Drs Iannaccone, Morton, Schochet, and Wong; Mss Rabb, Carman, Gordon, Harris,
J. Smith, Fritch, Zilke, Mayhew, and Stout; and Mr Webster); analysis and interpretation of data (Drs Iannaccone, Hynan, Schochet,
Samaha, and S. Smith); drafting of the manuscript
(Drs Iannaccone and Morton and Mss Rabb, Carman, Gordon, Harris, Fritch, Zilke,
and Stout); critical revision of the manuscript for important
intellectual content (Drs Iannaccone, Hynan, Reisch, Schochet, Luckett,
Wong, Samaha, Russman, Leshner, and S. Smith and Ms J. Smith); statistical expertise (Dr Hynan); obtained funding (Dr Iannaccone); administrative, technical, and
material support (Drs Iannaccone, Morton, Schochet, Luckett, Leshner,
and S. Smith; Mss Rabb, Carman, Gordon, Harris, J. Smith, Zilke, and Mayhew;
and Mr Webster); study supervision (Drs Iannaccone,
Reisch, Schochet, Luckett, and Samaha and Mss Rabb and J. Smith).
This study was supported by grant 1-RO1-NS 39327-01A1 from the National
Institutes of Health, Bethesda, Md, and by the Muscular Dystrophy Association,
Tucson, Ariz.
Members of the American Spinal Muscular Atrophy Randomized Trials Group:
Texas Scottish Rite Hospital for Children: Susan T. Iannaccone,
MD; Karen Rabb, RN; Deanna Carman, BS, PT; Jennifer Gordon, MS, PT; Kathalene
Harris, BS, RRT; and Anne Morton, PhD. The University of Texas Southwestern
Medical Center: Linda Hynan, PhD; Joan Reisch, PhD; Janet
Smith, BA; Joe C. Webster, BA; Peter Schochet, MD; Peter Luckett, MD; and
Laura Herbelin. Children's Hospital Medical Center, Cincinnati, Ohio: Brenda Wong, MD; Fred Samaha, MD; and Ann Fritch, MS, PT.
Shriner's Hospital for Children, Portland, Ore: Barry Russman,
MD, and Kirsten Zilke, BS, PT. Children's Hospital, Richmond, Va: Robert Leshner, MD, and Jill Mayhew, BS, PT. Gillette Children's
Specialty Health Care, St Paul, Minn: Stephen Smith, MD,
and Jean Louis Stout, MS, PT.
Corresponding author and reprints: Susan T. Iannaccone, MD, Texas
Scottish Rite Hospital for Children, 2222 Welborn St, Dallas, TX 75219 (e-mail: susan.iannaccone{at}tsrh.org).
From the Department of Neurology, Texas Scottish Rite Hospital for
Children, Dallas.
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