Abstract
Objective: To develop an ALS respiratory symptom scale (ARES) and evaluate how ARES compares to Medical Research Council Modified Dyspnea Scale (MRC), Borg dyspnea scale, and respiratory subscores from ALSFRS-R (ALSFRS-Resp) in detecting respiratory symptoms, correlation with pulmonary function and ALSFRS-R, and deterioration of pulmonary function and ALSFRS-R over time.
Methods: The ARES scale consists of 9 questions addressing dyspnea during activities and 3 questions addressing symptoms of worsening pulmonary function. 153 subjects with ALS completed MRC, Borg, ALSFRS-R, and ARES questionnaires at baseline, 16, 32, and 48 weeks, and spirometry at baseline. 73 of these subjects had spirometry, maximum inspiratory (MIP) and expiratory pressures (MEP), nasal inspiratory pressure (SNIP), and maximum voluntary ventilation (MVV) measured at each visit. Sensitivity of each scale and correlations between symptom scores, pulmonary function, and ALSFRS-R were evaluated at baseline and over the study duration.
Results and conclusions: ARES was more sensitive than MRC, Borg and ALSFRS-Resp scales at baseline and for detecting changes at 16 and 32 weeks. ARES and ALSFRS-Resp correlated significantly with vital capacity at baseline, but Borg and MRC did not. Only ALSFRS-Resp correlated with respiratory pressures. Changes in ALSFRS-Resp and ARES both correlated with vital capacity decline; however, changes in ARES had superior correlation with respiratory pressure decline. Comparisons between telephone and in-person administration of ARES met criteria for satisfactory test-retest correlation in different settings one week apart. These findings suggest that the ARES may be more useful in monitoring symptom progression in ALS than other available scales.
Introduction
Presently, noninvasive ventilation (NIV) is initiated in ALS when the forced vital capacity (FVC) falls to 50%, MIP declines to less negative than −60cm H2O or the patient is dyspneic (Citation1,Citation2). While several respiratory scales measure symptoms of dyspnea in patients with pulmonary diseases (Medical Research Council Modified Dyspnea Scale (MRC) (Citation3) and the Borg Dyspnea scale (Citation4)), it is unclear if these scales are applicable to ALS patients. In addition, it is also not known if there is any correlation with these pulmonary disease scales and measured respiratory function in people with ALS. A simple respiratory scale that correlated with pulmonary function and that could also be administered remotely by telephone would be useful as adjunct for following decline and could serve as an indication to initiate NIV evaluation, especially in situations where formal PFTs are unavailable.
In this study, we designed a respiratory questionnaire specifically for use in ALS patients and administered the questionnaire to ALS patients along with the standard Borg and MRC questionnaires and the ALSFRS-R score. In addition, all patients had respiratory functions measured. In this way we could determine the correlations between standard dyspnea questionnaires, our respiratory symptom scale modified for use in ALS (ARES), and measures of pulmonary function.
Methods
This work was part of a multicenter pilot study of Nutrition and NIV previously described (Citation5). This pilot included 5 nutrition-emphasis sites and 7 pulmonary-emphasis sites. For the pulmonary-emphasis group, subjects were evaluated at baseline, 8, 16, 32, and 48 weeks. At each visit, participants performed spirometry with forced vital capacities obtained in sitting and supine positions, sitting and supine maximal inspiratory pressure (MIP), sniff nasal pressure (SNP), maximal expiratory pressure (MEP), and maximal voluntary ventilation (MVV). FVC and MVV were measured by spirometry (Respironics Renaissance). Pressure measurements were measured using a portable electronic pressure meter (MicroMedical). All measures except for MVV were performed in triplicate and the highest value for each measure was used for analysis. Vital capacities are reported as percent predicted normal; respiratory pressures reported as cm H2O, and MVV in liters/minute. Participants in the nutrition-emphasis arm had only spirometry with vital capacity measurements performed during the baseline visit.
Subjects in both the nutrition- and pulmonary- emphasis arms were also evaluated by the ALSFRS-R functional rating score, and were given a series of standardized respiratory questionnaires including the Medical Research Council Modified Dyspnea Scale (patient perception of dyspnea on a scale of 0 to 5 based on level of exertion)(Citation3), Borg Dyspnea Scale (general perception of dyspnea on a scale of 0 to 10) (Citation4), and a newly developed ALS Respiratory Symptom Scale (ARES) designed specifically for this study in order to validate an ALS specific respiratory scale. The ARES score consists of 12 questions, each scored on a 10 point scale with a potential score of 0 (no dyspnea) to 120 (severe dyspnea) (). These questions encompassed 9 questions addressing dyspnea perception at progressively increasing levels of activity and three questions that address potential effects of worsening pulmonary function. These included questions on morning headache, a symptom of hypercarbia, and on sleep disordered breathing, as both nocturnal hypoventilation and obstructive sleep apnea are commonly reported in patients with ALS.(Citation6) In the event that a subject was unable to perform an activity, for instance ambulation; the participant was asked to answer the question based on what they would project their symptoms would be if they could perform the activity. In addition to the in-person visits, the score was also administered to pulmonary group by telephone at week 15 and 47 and compared to the week 16 and week 48 study visit administration respectively, in order to validate test-retest agreement and the feasibility of using telephone assessment. The respiratory subscore from the ALSFRS-R, consisting of the respiratory symptom questions 10 through 12, was also calculated (ALSFRS-Resp).
Table 1 The ALS Respiratory Symptom Score (ARES).
Differences in sensitivity of detecting dyspnea between the ARES, Medical Research Dyspnea score, Borg dyspnea scales, and the ALSFRS-Resp subscore were determined for each visit by Pearson Chi Square, using a score of zero to indicate the absence of dyspnea using the BORG, MRC, and ARES scales; and a score of 12 to indicate the absence of dyspnea for the ALSFRS-Resp. Pearson correlation coefficients were calculated to assess the correlation between each of the dyspnea scales and total ALSFRS-R score, sitting and supine vital capacity, SNP, MEP, MIP, and MVV obtained at the baseline visit.
Differences in median dyspnea scores between successive visits were compared using Kruskal-Wallace test. For the ASLFDS and the ALSFRS-Resp, the rate of worsening in dyspnea was calculated by the slope of change in dyspnea scores among participants in whom data from at least 3 visits were available. These slopes were correlated to the changes in pulmonary function in the pulmonary emphasis group, as measured by the slope of change in median vital capacity, SNP, MEP, MIP, or MVV over the course of the 48 week study period, using Spearman correlation coefficients. Slopes were not calculated for MRC or Borg because there was minimal change in median scores over the 48 week study period
To evaluate test-retest reliability and determine whether telephone administration of the ARES score was feasible, telephone administration of the ARES score was performed at 15 and 47 weeks and compared to in-person administration during the follow-up visits at 16 and 48 weeks, respectively. Comparison between telephone and subsequent-week in-person administration was done by Pearson correlation and consistency tested using Cronbach’s alpha. A correlation of greater than 0.7 and p value of less than 0.05 was considered evidence of acceptable test-retest reliability. A Cronbach alpha score of greater than 0.7 was considered evidence of acceptable test-retest consistency.
Results
Seventy-three ALS participants were enrolled in the Pulmonary arm and eighty ALS participants in Nutrition arm of the study for a total of 153 subjects. The average time from onset to diagnosis was 12.6 ± 11.8 months (range: 0–90 months). Demographics and baseline pulmonary function results scores are shown in ; respiratory pressure measurements were only obtained in the Pulmonary arm.
Table 2 Demographics and baseline data.
At baseline, the ARES score correlated with sitting and supine vital capacity, but not to pressure measurements or MVV; the ALSFRS-Resp correlated with all vital capacity and respiratory pressure measurements but not to MVV. Borg and MRC scores did not correlate with any pulmonary function measure. All four dyspnea scores correlated significantly with the ALSFRS-R score (ARES: r = −0.53, p < 0.001; ALSFRS-Resp: r = 0.51, p < 0.001; MRC: r = −0.3, p = 0.009; BORG: r = −.27, p = 0.02). At the baseline visit, all but one participant (99.3%) reported dyspnea on the ARES scale, whereas 23.8% and 66.0% of subjects reported dyspnea on the Borg Rating of Perceived Exertion and MRC scoring scales respectively (as evidenced by scores greater than zero); whereas 60.3% of subjects reported dyspnea on the ALSFRS-Resp (as evidenced by scores less than 12), (; p < 0.001) indicating that the ARES was more sensitive at detecting the presence of dyspnea at baseline than the other three scales. At the follow up visits, there were increases in the percentages of subjects with positive MRC and Borg scores; however, at the time of the 48-week visit, 73.4% of Borg scores, and 24.4% of MRC scores remained at zero and thus still did not detect the presence of dyspnea despite disease progression, vs 1% zero scores for the ARES and 1.1% scores under 12 for the ALSFRS-Resp (p < 0.001).
Table 3 Correlation of baseline dyspnea scores to measures of pulmonary function and ALS-FRS score.
Progression of dyspnea scores from baseline through subsequent visits are shown in . Significant changes in median dyspnea scores between baseline and 16 week visits were seen for MRC, ARES, and ALSFRS-Resp scores, but not for Borg. Significant changes in median dyspnea scores between 16 and 32 week visits was seen only for the ARES score. None of the scores showed a significant change between 32 and 48 weeks ().
Table 4 Sensitivity of dyspnea scores.
Over the course of the study, the rate of rise in ARES score was significantly correlated with the rate of decrease in sitting (but not supine) vital capacity measurements, sitting and supine SNP, MIP, MEP, MVV, and ALSFRS-R score. The rate of decrease in the ALSFRS-Resp was significantly correlated with sitting and supine vital capacity measurements, sitting SNP, and MVV but not with MIP or supine SNP; MEP was borderline significant at just above 0.05 (). The correlation between ARES vs MEP was significantly higher than the correlation for ALSFRS-R vs MEP (z = −1.88, p = 0.03; absolute values of correlation coefficients were used for calculation).
Table 5 Change in Dyspnea and Respiratory Scores from baseline.
46 participants completed test-retest validation for the ARES score with telephone and in-office scoring at 15 and 16 weeks respectively, and 35 completed test-retest validation at 47 and 48 weeks respectively. ARES phone scores had strong positive correlations with corresponding in-office scores at 16 weeks (ρ = 0.72; p < 0.001), 48 weeks (ρ = 0.79; p < 0.001), and for all 81 paired measures (ρ = 0.78, p < 0.001). Cronbach’s alpha was 0.88 for all 81 paired measures, indicating acceptable consistency.
Table 6 Correlation of the rate of change in ARES and ALSFRS-Resp scores to the rate of change of pulmonary function and ALS-FRS-R score.
Discussion
We have found that the ALS specific ARES scale was more sensitive at detecting dyspnea at study entry in ALS subjects than the Medical Research Council Dyspnea score, the Borg Dyspnea scales, or the ALSFRS-Resp. The ARES detected dyspnea in over 99% of participants at study entry, whereas the MRC, Borg, and ALSFRS-Resp did not detect dyspnea in 66%, 23%, and 40% of participants respectively. The Borg score was particularly insensitive, with a median score of zero and a mean score of only 0.4 out of 10 at baseline. While detection rates increased with MRC and Borg scores over time, at the end of the study 63% of Borg scores and 24% of MRC scores remained at zero despite overall decline in pulmonary function. Similarly, median ARES scores rose significantly over the first 32 weeks of the study, whereas MRC and ALSFRS-Resp changed only between the baseline and 16 week visit, and the median Borg score did not change at all. The greater sensitivity of the ARES score may thus prove it to be a useful tool for initiating NIV, as the presence of dyspnea is a criterion for NIV initiation.
We also found that the baseline ARES and ALSFRS-Resp scores correlated with sitting and supine forced vital capacity at baseline, whereas MRC and Borg did not. Moreover, we found that the rate of rise in ARES correlated significantly with the rate of decline in sitting vital capacity and inspiratory and expiratory airway pressure measurements, thus making the scale a useful surrogate for pulmonary function to follow over the course of the disease. The rate of change of the ALSFRS-Resp showed similar correlation with sitting vital capacity measurements and with SNP; however, this measure did not correlate with MIP (which we have found to be the best predictor of the need for NIV), and also did not correlate as well with MEP (a measure reflective of the ability to clear secretions) as the ARES.
A strength of our scale is that it reflects quantitation of dyspnea scaling progressively from rest to more difficult functions (e.g. walking up a flight of stairs), and incorporates symptoms of fatigue, as well as findings suggestive of carbon dioxide retention (headache, daytime somnolence) which may occur as pulmonary function tests decline and respiratory insufficiency develops. The test is short and easily completed either in person or by telephone. Test-retest data at weeks 16 and 48 show satisfactory reproducibility and consistency; moreover, as the test and retest data were performed by telephone and in-person respectively, this also validates that the scale may be administered by telephone with the expectation that scores will be reasonably similar to in-person administration. This may provide caregivers and researchers an additional tool to measure pulmonary decline between clinic visits or during a remote telemedicine session.
Our findings are in contrast to a recent evaluation of the ALSFRS-R by Pinto et al, (Citation7) which showed an improvement in the dyspnea question despite decline in pulmonary function and gait function in 10% of patients, and improvement in other respiratory questions in 6% of patients who had started or increased use of noninvasive ventilation. We believe that pairing the wording of the questions in our scale with specific tasks and the ability to perform these tasks has led to a better correlation of clinical score with pulmonary function and overall functional capacity. The American Thoracic Society (ATS) position paper on dyspnea defines dyspnea as a subjective sensation with domains that include (a) sensation and severity, (b) affective distress, and (c) symptom impact or burden.(Citation8) Whereas ALSFRS-Resp, MRC, and Borg include only measures of severity, ARES also has a component of symptom impact by incorporating functional questions into the scale, similar to some scores used for COPD (Citation9). However, in contrast to COPD, in ALS the inability to perform an activity could be due to either breathlessness or (perhaps more commonly) due to motor weakness. The ARES questionnaire phrasing thus provides a method for the subject to separate the subjective sense of exertional dyspnea from the inability to perform the activity due to their skeletal muscle weakness. This is a potential limitation of the study as there is no way to objectively verify the degree of dyspnea during such activities, however this is also true of any measure of dyspnea, which per ATS definition “can only be perceived by the person experiencing it”.(Citation8)
Our participants were recruited from 12 sites across the United States and vary in disease severity and pulmonary function, thus adequately representing the population of patients with ALS typically seen clinically. Our study is limited by a relatively small number of subjects, which is inherent in the study of a rare disease. Further studies will be needed to establish a minimal clinically significant difference in scoring and to establish whether score cutoffs can predict the need for noninvasive or invasive ventilation.
In summary, we have found that advantages of the ARES over the Borg and MRC scales include higher sensitivity both at baseline and for detecting changes over the course of the disease, better correlation with pulmonary function, and better tracking of the decline of pulmonary function and respiratory muscle strength. Compared to the ALSFRS-Resp, we found the correlation to vital capacity measurements to be equivalent at baseline, but the ARES was better for detecting dyspnea at baseline (earlier in the disease course) and changes in respiratory pressures over the course of the disease, whereas ALSFRS-Resp had a better correlation to baseline respiratory pressure measurements. These findings suggest that the ARES scale may be more useful in monitoring progression of symptoms in ALS than other currently available scales. In addition, the incorporation of a broader array of respiratory symptoms including dyspnea, symptom burden, and other associated symptoms of worsening pulmonary function provides a more robust assessment of respiratory symptomatology that may be useful for clinical trials.
Declaration of interest
Dr. Heiman Patterson has received payment for serving on the medical advisory board for Mitsubishi Tanabe Pharma America, Biogen, Samus, Cytokinetics, and Orphazyme. She has received an honorarium from IQVA and received a consulting fee from Evidera.
Dr. Khazaal has no relevant disclosures
Dr. Sherman has no relevant disclosures. Content contributed by Dr. Sherman is through his affiliation with Drexel University.
Dr. Kasarskis has research support from: Alexion, AB Science, Neuraltus and collaborative research support from: Healey Platform trial, Amylyx, Kansas University, Columbia University
Dr. Jackson serves a consultant for Mitsubishi Tanabe Pharma America, Cytokinetics, and Brainstorm.
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References
- Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2009;73:1227–33.
- Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2009;73:1218–26.
- Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999;54:581–6.
- Burdon JG, Juniper EF, Killian KJ, Hargreave FE, Campbell EJ. The perception of breathlessness in asthma. Am Rev Respir Dis. 1982;126:825–8.
- Kasarskis EJ, Mendiondo MS, Wells S, Malguizo MS, Thompson M, Healey M, et al. The ALS Nutrition/NIV study: design, feasibility, and initial results. Amyotroph Lateral Scler.2011;12:17–25.
- Boentert M. Sleep and sleep disruption in amyotrophic lateral sclerosis. Curr Neurol Neurosci Rep. 2020;20:25–33.
- Pinto S, de Carvalho M. The R of ALSFRS-R: does it really mirror functional respiratory involvement in amyotrophic lateral sclerosis? Amyotroph Lateral Scler Frontotemporal Degener. 2015; 16:120–3.
- Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med. 2012;185:435–52.
- Garrod R, Bestall JC, Paul EA, Wedzicha JA, Jones PW. Development and validation of a standardized measure of activity of daily living in patients with severe COPD: the London Chest Activity of Daily Living scale (LCADL). Respir Med. 2000;94:589–96. Jun