The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function
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Journal of the Neurological Sciences 169 (1999) 13–21
www.elsevier.com / locate / jns
The ALSFRS-R: a revised ALS functional rating scale that incorporates
assessments of respiratory function
a, a b b b
Jesse M. Cedarbaum *, Nancy Stambler , Errol Malta , Cynthia Fuller , Dana Hilt ,
Barbara Thurmond b , Arline Nakanishi b , BDNF ALS Study Group (Phase III)1
a
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Rd., Tarrytown, NY 10591, USA
b
Amgen, Inc., Amgen Center, Thousand Oaks, CA 91320, USA
Abstract
The ALS Functional Rating Scale (ALSFRS) is a validated rating instrument for monitoring the progression of disability in patients
with amyotrophic lateral sclerosis (ALS). One weakness of the ALSFRS as originally designed was that it granted disproportionate
weighting to limb and bulbar, as compared to respiratory, dysfunction. We have now validated a revised version of the ALSFRS, which
incorporates additional assessments of dyspnea, orthopnea, and the need for ventilatory support. The Revised ALSFRS (ALSFRS-R)
retains the properties of the original scale and shows strong internal consistency and construct validity. ALSFRS-R scores correlate
significantly with quality of life as measured by the Sickness Impact Profile, indicating that the quality of function is a strong determinant
of quality of life in ALS. 1999 Elsevier Science B.V. All rights reserved.
Keywords: Amyotrophic lateral sclerosis; Rating scales; Pulmonary function
1. Introduction dysfunction in ALS. In this report, we investigate the
impact of adding three of these evaluation items to replace
The Amyotrophic Lateral Sclerosis Functional Rating the breathing scale of the ALSFRS (Table 1). We tested
Scale (ALSFRS) is a validated questionnaire-based scale the ability of the revised scale to assess respiratory
that measures physical function in carrying out activities of function without altering the overall properties, utility, or
daily living (ADL) of patients with ALS [1–4]. It has been validity of the original instrument. The addition of the
used in clinical trials [5,6] as well as in clinical practice respiratory symptom ratings resulted in an improved scale
because of its ease of use and its correlation with both that is more sensitive to change and has better ability to
objective measures of disease status and levels of disabili- predict survival than the original ALSFRS. This report is a
ty. The components of the scale group into four factors or retrospective validation of the revised scale.
domains that encompass gross motor tasks, fine motor
tasks, bulbar functions and respiratory function [1]. The
components of the scale, however, are not equally weight-
2. Patients and methods
ed. Where three questions each rate the motor and bulbar
abilities only one question rates breathing ability.
The 387 placebo-treated patients who were followed as
In the course of conducting a clinical trial with brain-
part of the BDNF Phase II–III treatment study sponsored
derived neurotrophic factor (BDNF), a series of queries
by Amgen–Regeneron Partners constitute the population
were developed to evaluate the progression of respiratory
for this evaluation. The demographic characteristics and
the pretreatment measures of ALS status of these patients
are summarized in Table 2.
*Corresponding author. Tel.: 11-914-347-2113; fax: 11-914-347-
7000. The patients were evaluated monthly for 9 months as
1
A complete listing of the BDNF Study Group (Phase III) members is part of a therapeutic treatment trial. Monthly evaluations
given in Appendix A. performed during the trial included the ALSFRS, percent
0022-510X / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved.
PII: S0022-510X( 99 )00210-514 J.M. Cedarbaum et al. / Journal of the Neurological Sciences 169 (1999) 13 – 21 Table 1 The ALS Functional Rating Scale — Revised (ALSFRS-R) 1. Speech 4 Normal speech processes 3 Detectable speech disturbance 2 Intelligible with repeating 1 Speech combined with nonvocal communication 0 Loss of useful speech 2. Salivation 4 Normal 3 Slight but definite excess of saliva in mouth; may have nighttime drooling 2 Moderately excessive saliva; may have minimal drooling 1 Marked excess of saliva with some drooling 0 Marked drooling; requires constant tissue or handkerchief 3. Swallowing 4 Normal eating habits 3 Early eating problems — occasional choking 2 Dietary consistency changes 1 Needs supplemental tube feeding 0 NPO (exclusively parenteral or enteral feeding) 4. Handwriting 4 Normal 3 Slow or sloppy: all words are legible 2 Not all words are legible 1 Able to grip pen but unable to write 0 Unable to grip pen 5 a. Cutting food and handling utensils ( patients without gastrostomy)? 4 Normal 3 Somewhat slow and clumsy, but no help needed 2 Can cut most foods, although clumsy and slow; some help needed 1 Food must be cut by someone, but can still feed slowly 0 Needs to be fed 5 b. Cutting food and handling utensils (alternate scale for patients with gastrostomy)? 4 Normal 3 Clumsy but able to perform all manipulations independently 2 Some help needed with closures and fasteners 1 Provides minimal assistance to caregiver 0 Unable to perform any aspect of task 6. Dressing and hygiene 4 Normal function 3 Independent and complete self-care with effort or decreased efficiency 2 Intermittent assistance or substitute methods 1 Needs attendant for self-care 0 Total dependence 7. Turning in bed and adjusting bed clothes 4 Normal 3 Somewhat slow and clumsy, but no help needed 2 Can turn alone or adjust sheets, but with great difficulty 1 Can initiate, but not turn or adjust sheets alone 0 Helpless 8. Walking 4 Normal 3 Early ambulation difficulties 2 Walks with assistance 1 Nonambulatory functional movement 0 No purposeful leg movement 9. Climbing stairs 4 Normal 3 Slow 2 Mild unsteadiness or fatigue 1 Needs assistance 0 Cannot do
J.M. Cedarbaum et al. / Journal of the Neurological Sciences 169 (1999) 13 – 21 15
Table 1. (Continued)
10. Dyspnea (new)
4 None
3 Occurs when walking
2 Occurs with one or more of the following: eating, bathing, dressing (ADL)
1 Occurs at rest, difficulty breathing when either sitting or lying
0 Significant difficulty, considering using mechanical respiratory support
11. Orthopnea (new)
4 None
3 Some difficulty sleeping at night due to shortness of breath,
does not routinely use more than two pillows
2 Needs extra pillows in order to sleep (more than two)
1 Can only sleep sitting up
0 Unable to sleep
12. Respiratory insufficiency (new)
4 None
3 Intermittent use of BiPAP
2 Continuous use of BiPAP during the night
1 Continuous use of BiPAP during the night and day
0 Invasive mechanical ventilation by intubation or tracheostomy
predicted forced vital capacity or FVC% (adjusted for each of pulmonary function (FVC%) and the SIP. Pairwise
patient’s gender, age, and height), assessment of respirato- Pearson or Spearman correlation coefficients are reported
ry events associated with ALS (including ventilatory for each respective cross-sectional comparison. Prospective
support), and the Sickness Impact Profile (SIP) [7]. The comparison of the ALSFRS-R with muscle strength testing
SIP was measured every 3 months. and the Schwab and England rating scale [1] will be done
in a future evaluation.
2.1. Analytical methods Longitudinal change in the ALSFRS-R was compared
with changes in the SIP and pulmonary function (FVC%).
The internal consistency of the revised scale was Pairwise Pearson correlation coefficients are presented for
assessed by Cronbach’s alpha [8] and by factor analysis each respective longitudinal comparison.
with varimax (variance maximization) rotation [9]. Survival data were analyzed using Cox’s Proportional
Construct validity is demonstrated by comparison of the Hazards Model [10]. Survival prediction is presented as
novel rating instrument to an established one. The the fitted values from a logistic regression of survival
ALSFRS was originally validated against measures of outcome at 9 months as a function of baseline ALSFRS-R.
isometric muscle strength, two other subjective rating Test–retest reliability could not be assessed in this study
scales, and milestones of disease progression [1,2]. None because monthly intervals were too far apart to assume no
of these measures was performed in the BDNF clinical change in the measures. Test–retest evaluation should be
trial. Hence, the ALSFRS and ALSFRS-R were compared done with visits timed closer, ideally within 1 week, to
with FVC% [1,2] the SIP, an accepted quality-of-life confirm that a measure does not change in a time frame
measure. Construct validity was tested by comparing the when the disease is assumed not to be changing at a
pretreatment value of the ALSFRS-R and its subscores, as detectable level. Test–retest reliability will be evaluated in
well as 9-month change scores, with independent measures a future, prospective study.
Cronbach’s alpha was calculated using SAS, version
Table 2 6.12 (SAS Institute, Cary, NC, USA). All other analyses
Demographics and baseline measures were performed using JMP version 3.1.5 (SAS Institute).
Measurement Number of Mean Std err
patients (%) mean
Age (years) 387 55.9 0.6 3. Results
Gender
Male 259 (66.9) 3.1. Factor analysis: internal structure of the ALSFRS-R
Female 128 (33.1)
Symptom duration (years) 387 2.1 0.1 Factor analysis of the revised scale revealed that the
ALSFRS 387 30.1 0.3 evaluation items cluster into four factors that account for
ALSFRS-R 384 38.0 0.3 73% of the total variance, as shown in Table 3. As in the
FVC (%) 387 87.5 1.0 original ALSFRS, these factors correspond to fine motor,
SIP 321 16.0 0.6
gross motor, bulbar, and respiratory function [1]. The16 J.M. Cedarbaum et al. / Journal of the Neurological Sciences 169 (1999) 13 – 21
Table 3
Rotated factor loadings
Item Fine motor Bulbar Gross motor Respiratory
Speech 0 0.9 0 0
Salivation 0 0.8 0 0
Swallowing 0 0.8 0 0.2
Writing 0.9 0 0 0
Feeding 0.9 0 0 0
Dressing 0.8 0 0.3 0
Turning 0.6 0 0.5 0
Walking 0 0 0.9 0
Climbing 0 0 0.9 0
Dsypnea 0 0 0.2 0.6
Orthopnea 0 0.2 0 0.7
Respiratory insufficiency 0 0 0 0.8
Percent of total variance 28.9 20.2 13.3 10.4
rotated factor loadings of the revised scale correspond well demonstrating that adding the additional respiratory func-
to those previously reported for the original scale as tion evaluations has no impact on the internal consistency
applied to other ALS patients enrolled in earlier trials. The of the rest of the scale. These measures are consistent with
new questions relating to respiratory function group to- those previously reported for the ALSFRS [1], indicating
gether into a new ‘respiratory’ factor; this factor was good reliability for the revised scale and its components.
previously represented by the ALSFRS breathing scale
alone. The addition of these new questions has thus only 3.3. Construct validity
affected the evaluation of respiratory function, leaving the
remainder of the scale unaltered. Table 5 presents the correlations between the ALSFRS,
the ALSFRS-R, subscales of the ALSFRS-R, and two
3.2. Internal consistency measures of status, FVC% and SIP. The associations
between both the ALSFRS and the ALSFRS-R with the
Both the ALSFRS and the ALSFRS-R are internally SIP are nearly identical in magnitude, with respective
consistent. Values of Cronbach’s a (Table 4) were greater correlation coefficients of 20.72 and 20.71. The correla-
than 0.67 for all individual ratings; the value for the tions between the ALSFRS and the ALSFRS-R with the
ALSFRS was 0.74 raw and 0.73 standardized; the respec- SIP Physical Dimension score were similar to those for the
tive values for the ALSFRS-R were 0.73 and 0.71. Thus entire SIP (data not shown). SIP scores corresponded best
for any particular component of the ALSFRS the corre- with arm and leg function, as shown by the stronger
sponding values of Cronbach’s a are almost identical, correlations with either the upper or lower subscales than
Table 4
Internal consistency of ALSFRS and ALSFRS-R
Measure Cronbach’s alpha
Raw values Standardized values
ALSFRS ALSFRS-R ALSFRS ALSFRS-R
Speech 0.73 0.72 0.81 0.78
Salivation 0.73 0.72 0.81 0.78
Swallowing 0.73 0.72 0.81 0.78
Writing 0.70 0.69 0.78 0.76
Feeding 0.69 0.68 0.77 0.75
Dressing 0.69 0.68 0.77 0.75
Turning 0.70 0.69 0.77 0.75
Walking 0.71 0.70 0.80 0.77
Climbing 0.70 0.69 0.79 0.76
Breathing 0.73 0.80
Total ALSFRS 0.74 0.73
Dyspnea 0.71 0.78
Orthopnea 0.72 0.78
Respiratory insufficiency 0.73 0.79
Total ALSFRS-R 0.73 0.71J.M. Cedarbaum et al. / Journal of the Neurological Sciences 169 (1999) 13 – 21 17
Table 5
Association between ALSFRS-R and subscales with independent assessments of physical status
ALSFRS-R Respiratory Subscale FVC% SIP b ALSFRS
a a
Total Upper Lower Respiratory Dyspnea Orthopnea Respiratory Total Breathing a
insufficiency a
ALSFRS-R
Total 1 0.77 0.61 0.41 0.34 0.26 0.09 0.41 20.72 0.99 0.36
Upper 1 0.30 0.10 0.11 0.03 20.02 0.27 20.57 0.78 0.14
Lower 1 0.15 0.15 0.07 0 0.12 20.58 0.61 0.08
Respiratory 1 0.89 0.55 0.26 0.33 20.28 0.28 0.56
Dyspnea 1 0.28 20.27 0.26 0.55
Orthopnea 1 0.21 20.16 0.19 0.28
Respiratory 1
insufficiency 0.18 20.01 0.05 0.24
FVC% 1 20.32 0.40 0.36
SIP 1 20.71 20.28
ALSFRS
Total 1 0.37
Breathing 1
a
Spearman correlation coefficient.
b
Negative correlation coefficients are reported because a higher value on FVC and ALSFRS-R components denotes a better function but a lower SIP
corresponds to a better function.
with the respiratory subscale. Further examination of the 3.4. Survival
associations of each of the respiratory questions of the
revised ALSFRS and the SIP show that the majority of the The ALSFRS previously has been shown to be a
associations between the respiratory subscale and the SIP predictor of survival in ALS [2]. The ALSFRS and the
can be explained by the dyspnea score. This association is ALSFRS-R were both evaluated as prospective predictors
not surprising since dyspnea is associated with difficulty in of 9-month survival for this sample of placebo-treated
walking and climbing. In fact, there is a small contribution patients. As shown before, the patient’s age and prestudy
of dyspnea to the gross motor factor of the ALSFRS-R. FVC% were the strongest predictors of survival.
Although total ALSFRS and ALSFRS-R scores both Both the original and revised scales were divided into
correlate cross-sectionally with FVC% to about the same quartiles of their respective pretreatment distributions.
degree (Table 5), adding ratings of different aspects of Kaplan–Meier plots of the percent survival at 9 months by
respiratory function did not affect the scale’s corre- baseline ALSFRS-R quartile are presented in Fig. 2. Nine-
spondence with FVC%. In fact, the three individual ratings month survival differed for patients depending on whether
only have weak to moderate magnitudes of association their baseline ALSFRS-R was above or below the median
with FVC%, as shown by their respective Spearman of the distribution of ALSFRS scores for the study
correlation coefficients. This would suggest that subjective population (Fig. 2A). The median prestudy FVC% in this
reports of degree of dyspnea and orthopnea, as well as the group of patients was approximately 90%, a value associ-
need for ventilatory support, capture functional abilities ated with a 90% probability of 9-month survival [4].
that are not assessed by the FVC maneuver and are Adding the respiratory symptom ratings makes this scale
complementary to it. Not surprisingly, the component with more sensitive to predicting the outcome of patients who
the strongest association to vital capacity is the rating for are beginning to show some level of disability but are for
shortness of breath. the most part not in the terminal stage of the disease. Fig.
The decline in each of the functional domains of the 2B illustrates that, if a patient had an ALSFRS-R score in
ALSFRS-R is shown in Fig. 1. Table 6 presents the the top two quartiles, 9-month survival probability is still
pairwise correlations observed between change in over 90%. But those in the third quartile of ALSFRS
ALSFRS-R score and its respiratory function component, scores have a distinct and better probability of surviving 9
and the original ALSFRS, FVC%, and the SIP. Again, the months than those with ALSFRS-R scores in the bottom
respiratory subscale of the ALSFRS correlates less well 25%, a property not shared by the original ALSFRS.
with FVC% than the other measures. In addition, the good Both the ALSFRS and the revised scale were statistical-
correlation between change in the SIP and the ALSFRS or ly significant prognostic factors in addition to age and
the ALSFRS-R, suggests that these two rating scales assess FVC% (data not shown). The ALSFRS-R was a stronger
many of the same aspects of the ALS disease process. predictor than the original scale, with a larger likelihood18 J.M. Cedarbaum et al. / Journal of the Neurological Sciences 169 (1999) 13 – 21
Fig. 1. Cross-sectional mean (6SEM) change from baseline to 9 months for each of the four factors of the ALSFRS-R.
ratio chi-square than for the ALSFRS, 5.3 for the 4. Discussion
ALSFRS-R compared with 4.0 for the ALSFRS in a model
that also included baseline FVC% and the patient’s age. The ALSFRS is a validated clinical rating scale that has
Fig. 3 shows the predicted values of the logistic regression been shown to accurately track progression of patients’
model for 9-month survival based on the baseline disability in ALS [1–4]. Inclusion of assessments of ADL
ALSFRS-R score. function such as the ALSFRS is an essential element of the
design of ALS clinical trials [11]. One weakness of the
original ALSFRS was that it did not weight respiratory
dysfunction equally to limb and bulbar function. In the
Table 6 course of a large multicenter clinical trial, we developed a
Correlation of changes in measures to month 9 new questionnaire-based instrument to evaluate aspects of
Measure Number Correlation P value respiratory difficulty in ALS. Integration of information on
of patients subjective dyspnea, orthopnea, and documentation of the
ALSFRS vs. need for mechanical ventilatory assistance have been
FVC% 304 0.56 0.0001 added to the original scale. The ALSFRS-R retains the
SIP 210 20.56 a 0.0001 properties of the original ALSFRS, and incorporation of a
ALSFRS-R vs. more extensive assessment of respiratory function has
FVC% 304 0.58 0.0001 expanded the scope of the scale and increased its general
SIP 210 20.58 a 0.0001 applicability as a rating instrument without affecting
ALSFRS 304 0.97 0.0001
overall performance and validity. The sensitivity of the
Respiratory subscale vs. scale has perhaps been increased, as reflected by the
FVC% 304 0.32 0.0001
difference in survival outcome amongst patients in the
SIP 210 20.28 a 0.0001
ALSFRS 304 0.34 0.0001 lower two quartiles of ALSFRS-R score distribution.
ALSFRS-R 304 0.53 0.0001 Patient scores on the various subscales of the ALSFRS
a
Negative correlations between ALSFRS and SIP occur because higher have been correlated with changes in isometric muscle
scores on the ALSFRS reflect better function, whereas higher scores on strength [1,2,13,14], muscle mass [12–14], and, to the
the SIP represent worsening. bulbar subscale, abnormalities observed by magnetic inso-J.M. Cedarbaum et al. / Journal of the Neurological Sciences 169 (1999) 13 – 21 19
Therefore, objective measurements of pulmonary function
still have a place in the clinical evaluation of ALS.
Finally, we have demonstrated that ALSFRS scores
correlate strongly with the SIP, both cross-sectionally and
longitudinally. Thus, assessment of level of disability in
ALS patients yields a strong measure of quality of life as
well.
Acknowledgements
This study was sponsored and funded by Amgen–
Regeneron Partners.
Appendix A. Members of the BDNF Study Group
(Phase III)
EJ Kasarskis, Albert Chandler Medical Center, Lexington,
KY; JM Shefner, Brigham and Women’s Hospital, Boston,
MA; R Miller, California Pacific Medical Center, San
Francisco, CA; RA Smith, Center for Neurologic Study,
San Diego, CA; J Licht, Center for Neurologic Study, San
Diego, CA; H Mitsumoto, Cleveland Clinic Foundation,
Cleveland, OH; LC Hopkins, Emory Clinic, Atlanta, GA; J
Rosenfeld, Emory Clinic, Atlanta, GA; R Pascuzzi, Indiana
University School of Medicine, Indianapolis, IN; DR
Cornblath, Johns Hopkins University, Baltimore, MD; C
Armon, Loma Linda University, Loma Linda, CA; MJ
Strong, London Health Services Centre, London, Ontario,
Canada; R Kula, Long Island College Hospital, Brooklyn,
NY; A Windebank, Mayo Clinic, Rochester MN; EP
Bosch, Mayo Clinic Scottsdale, Scottsdale, AZ; BE Smith,
Mayo Clinic Scottsdale, Scottsdale, AZ; N Cashman,
Montreal Neurological Institution, Montreal, Quebec,
Fig. 2. Nine-month Kaplan–Meier survival curves by quartile of baseline Canada; M Sivak, Mount Sinai School of Medicine, New
ALSFRS (A) and ALSFRS-R (B). York, NY; S Sergay, Neurology Associates, Tampa, FL; T
Siddique, RL Sufit, Northwestern University Medical
School, Chicago, IL; W Johnston, Oregon Health Science
Center, Portland, OR; T Heiman-Patterson, Thomas Jeffer-
nance spectroscopy of the brainstem [15]. The lack of son University, Philadelphia, PA; MB Brooke, University
strong association between the respiratory subscale of the of Alberta, Edmonton, Alberta, Canada; MC Graves,
ALSFRS-R and percent predicted forced vital capacity is UCLA School of Medicine, Los Angeles, CA; RK Olney,
at first puzzling. We interpret this result to indicate that UCSF Medical Center, San Francisco, CA; RP Roos,
dyspnea, which may be experienced by patients with near- University of Chicago, Chicago, IL; H Neville, University
normal values of FVC% [16], and orthopnea, the cardinal of Colorado, Denver, CO; SP Ringel, University of
sign of diaphragmatic weakness in ALS [17], are not Colorado, Denver, CO; M Ross, University of Iowa
entirely the result of diminished bellows function of the Hospitals, Iowa City, IA; WG Bradley, University of
respiratory musculature. Perhaps additional factors, such as Miami School of Medicine, Miami, FL; KR Sharma,
deconditioning or the increased effort and fatigue that University of Miami School of Medicine, Miami, FL; G
accompany activity in ALS patients, contribute to sensa- Parry, University of Minnesota, Minneapolis, MN; R
tions of breathlessness. Alternatively, there may be suffi- Mandler, University of New Mexico, Albuquerque, NM;
cient reserve in the system to permit patients to exert a M Giuliani, University of Pittsburgh School of Medicine,
brief, maximal effort during a pulmonary function test, Pittsburgh, PA; CA Thornton, University of Rochester,
whereas fatiguability of the respiratory muscles during Rochester, NY; C Jackson, University of Texas Health
ongoing activity underlies the patients’ subjective reports. Science Center, San Antonio, TX; W Bryan, University of20 J.M. Cedarbaum et al. / Journal of the Neurological Sciences 169 (1999) 13 – 21
Fig. 3. Predicted 9-month survival probability as a function of baseline ALSFRS-R.
Texas Southwestern Medical Center, Dallas, TX; M Brom- guidelines for administration and scoring. In: Herndon R, editor,
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