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Safety and efficacy of short- and long-term inspiratory muscle training in late-onset Pompe disease (LOPD): a pilot study

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Abstract

Background

In patients with late-onset Pompe disease, progressive respiratory muscle weakness with predominantly diaphragmatic involvement is a frequent finding at later stages of the disease. Respiratory muscle training (RMT) is an established therapy option for patients with several neuromuscular disorders including Duchenne muscular dystrophy. Forced voluntary muscle contractions of inspiration and/or expiration muscles enhance ventilation by increasing respiratory coordination, endurance, and strength. Efficacy of RMT in LOPD is rarely examined, and the clinical studies performed are difficult to compare because of different training programs and protocols. This impedes a useful statement and recommendation about the safety and efficacy of respiratory muscle training.

Methods

We conducted a monocentric unblinded single-arm pilot study in patients with LOPD to evaluate the safety and efficacy of inspiratory muscle training (IMT). The primary objective was to determine the efficacy of a 6-week repetitive IMT with a gradual increase of inspiratory resistance, measured by MIP (maximum inspiratory pressure) in the upright position. For statistical analysis, we used an A–B–C single subject design. The 6-week training-period A was followed by a 6-week non-training period B and an optional training period of 40 weeks in period C. The total study duration for the periods A, B and C was 52 weeks. Throughout the study, spirometry assessments (FCV, FEV1) and measurements of respiratory strength (MIP, MEP) were performed at defined time points, as well as capillary oximetry and capnometry, motor function test and patient’s questionnaires for quality of life and dyspnea, measured by St. George’s Respiratory Questionnaire (SGRQ) and MMRC-Dyspnea scale. For the cross-sectional comparison, a paired two-sided t test, and for the longitudinal comparison, a two-sample, two-sided t test were used. When data were not normally distributed, a Wilcoxon–Mann–Whitney test was added. Finally, the annual decline in FVC and FEV1 before and after IMT was compared.

Findings

11 subjects were included in this pilot study. Overall, IMT was well tolerated. In four subjects, a total of six adverse events related to the study procedures were noticed. Training compliance was excellent in the first weeks of training, but declined continuously in the extension period. There was a significant increase in our primary outcome measure MIP within the 6-week period of frequent IMT with a mean of 15.7% (p =0.024; d =0.402). A significant increase was also seen after week 52 by a mean of + 26.4% (mean + 13.4 cmH2O, p =0.001, d =0.636). In the 6-week non-training interim-period (period B), the values remained stable, and there was no clinically meaningful decline in secondary outcome measures. The increase in MIP did not have any effect on secondary outcome measures like spirometry tests (FVC, FEV1), capillary blood gas analysis, motor function tests, patient’s perceived quality of life or any significant change in dyspnea score.

Conclusions

Frequent IMT improves MIP and thereby stabilizes and decelerates the decline of the diaphragm strength. The gradual increase of inspiratory resistance is well tolerated without any increase of side effects, as long as IMT is supervised and resistance is individually adjusted to the patient’s perceived grade of exhaustion. Although we could not detect a significant impact on secondary outcome measures, IMT should be offered to all LOPD patients, especially to those who demonstrate a progressive decline in respiratory muscle function or are unable to receive ERT.

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Acknowledgements

We thank Vivisol Germany GmbH, Home Care Services, Neufahrn, Germany, for the free of charge provision of the IMT training devices Repsifit S®. We also want to thank the participants for their commitment and performance in this study.

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Authors and Affiliations

  1. Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians University Munich, Ziemssenstr. 1a, 80336, Munich, Germany

    Stephan Wenninger, Eva Greckl, Haris Babačić, Kristina Stahl & Benedikt Schoser

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  1. Stephan Wenninger
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  2. Eva Greckl
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  3. Haris Babačić
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  4. Kristina Stahl
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  5. Benedikt Schoser
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Correspondence to Stephan Wenninger.

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Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics committee of the Ludwig-Maximilians-University Munich, Germany (vote no. 689/16).

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Wenninger, S., Greckl, E., Babačić, H. et al. Safety and efficacy of short- and long-term inspiratory muscle training in late-onset Pompe disease (LOPD): a pilot study. J Neurol 266, 133–147 (2019). https://doi.org/10.1007/s00415-018-9112-4

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