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Abstract

Background: Ambulatory patients with Amyotrophic Lateral Sclerosis (ALS) show a decreased aerobic capacity which may hamper the ability to perform activities of daily living. A standardized measure, however, for assessing aerobic capacity in patients with ALS during the disease course, is lacking.

Objective: To examine the feasibility of the Åstrand-Ryhming (ÅR) test protocol longitudinally in ambulatory patients with amyotrophic lateral sclerosis (ALS).

Methods: Seven ambulatory male patients with spinal ALS onset were assessed at baseline and at 4, 7 and 10 months’ follow-up. Feasibility of the ÅR test protocol was analysed using percentage of: a) completed ÅR tests; b) achieved steady states; and c) predefined heart rates.

Results: Test completion decreased from 7/7 at baseline to 10/21 at follow-up due to ALS-related symptoms as fatigue, muscle weakness and cramps. Steady states and predefined heart rates were achieved in 12/17 and 17/17 of the completed tests, respectively. Overall, the feasibility of the ÅR test protocol declines from 5/7 at baseline to 7/21 at follow-up.

Conclusions: The results suggest that changes in aerobic capacity in ambulatory patients with ALS could not be successfully monitored due to a diminished feasibility of the ÅR test protocol.

Keywords

Amyotrophic Lateral Sclerosis exercise test physical fitness aerobic capacity outcome measure

INTRODUCTION

Early-stage ambulatory patients with Amyotrophic Lateral Sclerosis (ALS) show a skeletal muscle mass (SM) similar to healthy subjects, but with a reduced peak oxygen uptake per kilo SM (VO2/kg SM), most likely caused by deconditioning due to a reduction in habitual activities [1]. Sustained deconditioning due to physical inactivity can induce further reduction in aerobic capacity [2]. Just as in able-bodied individuals, a decreased aerobic capacity in patients with ALS may hamper the ability to perform activities of daily living that require sustained aerobic metabolism. This supports the importance of monitoring aerobic capacity as well as activities in daily living during the disease course in ambulatory patients with ALS.

For establishing aerobic capacity, the cardiopulmonary exercise test (CPET) is considered the gold standard. It directly measures maximal oxygen uptake (VO_2max), which reflects the ability of the cardiopulmonary system to deliver oxygen to the skeletal muscles [3]. In neuromuscular diseases like ALS, maximal exercise testing is not feasible for two important reasons. First, it may provoke muscle complaints and excessive fatigue with a prolonged recovery and should, therefore, be avoided [4]. Second, maximal exercise testing is often symptom-limited, and, therefore, not feasible for measuring aerobic capacity [5]. Mezzani et al. [1] showed that the CPET could be completed by only 24 out of 47 mildly impaired patients with early stage and upper limb onset ALS. A submaximal exercise test to predict the maximal aerobic capacity (VO_2max) might be a more feasible measure to evaluate the course of aerobic capacity in patients with ALS. The Åstrand-Ryhming (ÅR) test, a submaximal test that can be used to predict VO_2max [6], is often applied and has demonstrated moderate to good psychometric properties in other chronic diseases. Good test-retest reliability was reported in patients with chronic low back pain [7] and moderate concurrent validity in patients with musculoskeletal pain disorders [8]. Moreover, compared to maximal exercise testing, submaximal exercise testing is easier to perform, requires less equipment and is subsequently less expensive [5].

To date, no research has been carried out into the longitudinal assessment of aerobic capacity as functional outcome measure in the disease course of ambulatory patients with ALS. The present study reports a case series to examine the feasibility of the ÅR test protocol longitudinally in ambulatory patients with ALS.

MATERIALS AND METHODS

This study was part of a larger multi-center study on quality of life in ALS that took place in five centres in The Netherlands. The methods used have been published elsewhere [9]. Patients with a probable or definite ALS, diagnosed according to the “revised El Escorial World Federation of Neurology (WFN) criteria” [10], were consecutively recruited from the outpatient rehabilitation clinic at UMC Utrecht in The Netherlands. Informed consent was obtained from all included patients, according to the Declaration of Helsinki. The inclusion criteria include a.o. walking ability (ankle-foot orthosis or crutch/stick allowed) and cycling ability (on a cycle ergometer), and having a predicted forced vital capacity (FVC) of at least 80%. All participants gave informed consent and the study was approved by a university institutional review board.

Measurements were performed at baseline (T0) and at 4 (T1), 7 (T2), and 10 (T3) months’ follow-up. Disease severity was assessed using the ALS Functional Rating Scale (Revised) (ALS-FRS(-R)) [11]. Lung capacity was assessed by percent-predicted forced vital capacity (FVC%) measured with a spirometer (MicroRPM, Pt Medical, The Netherlands) adjusted for age, gender, race, weight and height. The highest value of two attempts was used. Muscle strength, defined as the maximum voluntary force that patients were able to exert in Newton (N), was measured with isometric “make” tests, using a MicroFET hand-held dynamometer (Jamar). Knee extension was assessed, because knee extension dominates power production during submaximal cycling [12]. Knee extension testing was performed in upright position, with hips and knees flexed 90° and the dynamometer just placed proximal to malleoli. Subjects were asked to build their force to maximum over a 3-second period of time; the higher value of two attempts was used.

Aerobic capacity, defined as the estimated maximal oxygen uptake (VO_2max), was obtained using the ÅR cycle ergometer protocol (appendix I) and the Åstrand-nomogram using mean steady-state heart rate with corrections for age and gender [6]. The initial cycle workload was estimated and set between 25 and 100 Watt, based on the muscle strength of the weakest hip flexion or knee extension assessed using hand-held dynamometry prior to the test. To examine the feasibility of the ÅR test protocol, we looked at (a) the completion of a 6-minute cycling test and reasons for premature termination or not starting the test; (b) the achievement of the steady state (i.e. no more than a 5 bpm change in heart rate in the last two minutes of the test); (c) a heart rate >120 bpm in the last two minutes of the test. Safety of the test was described in terms of adverseevents.

RESULTS

Seven ambulatory male patients with spinal onset type ALS were enrolled, including five patients without a walking aid, one patient with an ankle foot orthosis (AFO) and one with a stick or crutch. At baseline, participants were mildly impaired (ALS Functional Rating Score – Revised (ALSRFS-R) score≥38); their median age was 65.7 years (range 43.7–69.7) and median time since diagnosis, 4 months (range 2–22). The median predicted forced vital capacity (FVC) was 97% (range 90–105%) and the median estimated VO_2max at baseline was 31.3 ml/min/kg (range 19.8–45.7) (n = 5). The median muscle strength of the knee extensors, right and left, was 226N (range 59–392) and 244N (range 137–372), respectively. The median heart rate at the end of the test was 136 beats per minute (range 126–160); none of the participants used beta blockers. The median maximal workload was 150 watt (range 70–175). Baseline and follow-up outcomes are reported in Table 1.

The feasibility of the test protocol

Completion: At baseline, completion of 6 minutes’ cycling was established in all cases: 7/7. At follow-up, the completion of 6 minutes’ cycling decreased over time: 4/7 (T1); 4/7 (T2); 2/7 (T3). Steady state: A steady-state heart rate at the end of the test (i.e.≤5-beat per minute variance) was reached in 12 of the 17 completed tests, but not achieved in 2 out of 7 cases at T0, and 3 out of 10 cases at follow-up (T1-T3). Heart rate: Of the 17 completed tests (T0-T3), all 17 achieved the predefined heart rate (>120 bpm) in the last two minutes of the test. Safety: No adverse events occurred during testing and no complications or subsequent complaints were reported. Reasons for premature termination or not starting: muscle weakness of the lower extremities (n = 4), total body weakness (n = 1), fatigue (n = 3); muscle cramps in the abdominal region (n = 1) and death (n = 2). Decreased lung capacity (70% of the Force Vital Capacity (FVC) percent predicted) and complete paralysis of both upper extremities (not shownin table) were not restrictive factors for performing the test; on the other hand, having a walking ability was not a guarantee for a successful performance of the ÅR test protocol. Overall, the feasibility of the ÅR test protocol declines from 5 out of 7 tests (71%) at baseline to 7 out of 21 tests (33%) at follow-up (2/7 (T1); 3/7 (T2); 2/7 (T3)). Consequently, aerobic capacity during the course of the disease could be estimated in only one-third of the follow-up assessments.

DISCUSSION

Our results suggest that the ÅR test protocol was feasible in a small sample of ambulatory, mildly impaired, male patients with a spinal ALS onset. For longitudinal follow-up, however, the feasibility of the ÅR test protocol was symptom-limited. Consequently, changes in aerobic capacity could not be successfully assessed at follow-up, thereby limiting the use of the ÅR test protocol as functional outcome measure in the disease course of patients with ALS.

Our baseline findings are in line with an earlier, cross-sectional study [13], in which all of the 35 ambulatory patients, with less severe disease, were able to complete a discontinuous progressive submaximal exercise test [14]. As stated, no serial data of aerobic capacity are available for patients with ALS. This is the first reported study to evaluate the feasibility of a submaximal exercise test protocol in patients with ALS over time. We believe that the results of the present study contain relevant information about the reasons for the diminishing feasibility of the ÅR test protocol. The sample size was, however, small and homogenous in terms of gender and disease onset type, which limits the ability to generalize the results to all patients with ALS. Our results do, however, suggest that the assessment of changes in aerobic capacity using the ÅR test is not feasible at longitudinal follow-up in a relatively good patient group. It, therefore, seems meaningless to burden (more severely affected) patients with more cycle tests for purposes of further research into other psychometric qualities of the ÅR test.

One might question whether aerobic capacity can be considered a useful outcome among patients with a rapidly progressive disease such as ALS. Taking account of the vicious cycle described in the introduction (physical inactivity can induce further reduction in aerobic capacity), we suggest a shift towards physical activity measures. It is challenging to recommend an alternative, feasible test to evaluate activities longitudinally. Performance-based measures like the Timed Up & Go (TUG) or the 6-minute walk test (6MWT) are submaximal tests used to assess ALS patients’ ability to perform a standardized physical activity that is typically encountered in everyday life. A potential limitation of these performance tests is, again, a lack of feasibility as disability progresses and patients lose their ability to walk [15, 16]. Accelerometers might remain a more feasible measure over time, as they might also assess minimal daily physical activity. Most commonly used questionnaires in patients with ALS, such as the ALSFRS-R, are the most feasible option during the disease course as they do not exhibit a floor effect. The ALSFRS-R shows a high inter- and intra-rater reliability, has good internal consistency and test-retest reliability. Moreover, ALSFRS-R correlates with measures of muscle strength and survival [17].

Because of the diminished feasibility at follow-up measurements, we would not recommend the ÅR test as a follow-up measure in ambulatory patients with ALS. In the absence of a feasible test able to evaluate changes in aerobic capacity during the disease course of ALS, we recommend alternative measures to assess physical activity.

FUNDING

Funded by Prinses Beatrix SpierFonds (PBF) (The Dutch Public Fund for Neuromuscular Disorders), the Netherlands Organisation for Health Research and Development (ID: ZonMW 89000003).

CONFLICTS OF INTEREST

The authors have no conflict of interest to report.

Footnotes

ACKNOWLEDGMENTS

The authors are grateful to the patients for their time and efforts.

Appendix I

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