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
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   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 )00210-5
14                                 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]. The
16                            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                                                     0.71
J.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 likelihood
18                                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 of
20                               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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Fries, University of Vermont College of Medicine, Bur-                       [4]   Stambler N, Charatan M, Cedarbaum JM et al. Prognostic factors of
lington, VT; L Phillips, University of Virginia Medical                            survival in ALS. Neurology 1998;50:66–72.
Center, Charlottesville, VA; BR Brooks, University of                        [5]   ALS CNTF Treatment Study (ACTS) Group. A double-blind,
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