Expiratory Muscle Strength Training in Multiple System Atrophy: A Pilot Study

ABSTRACT

Background

The effects of expiratory muscle strength training (EMST) has not yet been investigated in MSA patients.

Objective

The primary objective was to test the effects of EMST on expiratory muscle strength and voluntary peak cough flow (vPCF) in patients with multiple system atrophy (MSA). The secondary objective was to assess the suitability of the pulmonary dysfunction index as a tool for identifying MSA patients with expiratory muscle weakness and reduced voluntary peak cough flow.

Methods

This was an open label, non‐controlled study, with an 8‐week intensive home‐based EMST protocol. The outcome measures included: maximal expiratory pressure (MEP) and vPCF. The sensitivity and specificity of the index of pulmonary dysfunction in the respiratory diagnostic process were assessed using receiver operating characteristic (ROC) analysis.

Results

Fifteen MSA patients were enrolled in the study. Twelve MSA patients completed the training period. After the training period, MEP significantly increased (P = 0.006). Differences in vPCF were not significant (P = 0.845). ROC analysis indicated that the overall respiratory diagnostic accuracy of the index of pulmonary dysfunction had an outstanding capability to detect patients at risk of less effective coughing and an acceptable capability of detecting patients with decreased expiratory muscle strength.

Conclusions

These findings indicate non‐significant differences in vPCF after 8 weeks of EMST. The index of pulmonary dysfunction appears to be a promising prognostic screening tool for identifying altered cough efficacy in MSA patients. Test cut‐offs may be used to select an appropriate respiratory physiotherapy technique.

Multiple system atrophy (MSA) is an adult onset, rare neurodegenerative disorder characterized by progressive autonomic dysfunction, parkinsonian syndrome, cerebellar and pyramidal symptoms in various combinations. ¹ Respiratory disturbances are also common and are even included in the list of supportive non‐motor features in the Movement Disorders Society Criteria for the Diagnosis of Multiple System Atrophy. ² They reflect the spread of the neurodegenerative process to the pontomedullary respiratory nuclei. Common respiratory symptoms pathognomonic for MSA includes laryngeal stridor due to vocal cord abductor dysfunction ³ and impaired ventilatory responses to hypoxia due to malfunction of hypoxia sensitive carotid chemoreceptors and central chemoreceptive neurons. ⁴

Another respiratory problem which is usually ignored, is respiratory muscle weakness. ⁵ Similar to patients with Parkinson's disease, patients with MSA have significantly weakened respiratory muscles compared to healthy controls. ⁵ It seems that MSA and Parkinson's disease may share the same mechanism of respiratory muscle weakness: (1) poor posture restricting the chest; (2) rigidity decreasing thoracic wall compliance; and (3) disrupted respiratory muscle coordination. Respiratory muscles are crucial for generating adequate peak airflow during a cough, so their weakening may affect the effectiveness of a cough. ⁶ The disturbance of this protective mechanism increases the risk of aspiration pneumonia, which is one of the main causes of death in MSA patients. ¹ , ⁷ , ⁸

Expiratory muscle strength training (EMST) studies have reported significant improvements in maximum expiratory strength, ⁹ cough efficacy ¹⁰ and dysphagia ¹¹ in patients with Parkinson's disease. However, the efficacy of EMST has not yet been demonstrated in MSA patients. Combining the aforementioned assumption that Parkinson's disease and MSA share similar mechanisms of respiratory muscle weakness, and the already proven effect of EMST in Parkinson's disease, it can be hypothesized that the EMST should be effective for expiratory muscle strength in MSA patients.

Due to the rapid progression of the disease, it is crucial to recognize the risk of expiratory muscle weakness and reduced cough efficacy as early as possible. A potential solution would be to regularly assess all MSA patients’ expiratory muscle strength and cough efficacy in routine clinical practice. However, neurologists lack sufficient time and necessary equipment for this assessment. Therefore, an effective solution in terms of time and equipment costs could be the implementation of a screening test for respiratory functions such as the index of pulmonary dysfunction (IPD) used in multiple sclerosis. ¹² This index has correctly predicted the presence or absence of significant expiratory muscle weakness and has an acceptable validity and reliability. ¹³ Given that three of the four test items of the IPD assess cough efficacy, one can speculate that the test might also detect patients with a weak cough.

The primary aim of this study was to investigate the feasibility and impact of EMST on expiratory muscle strength and voluntary peak cough flow in patients with MSA. The second aim was to assess the suitability of IPD as a tool for identifying MSA patients with expiratory muscle weakness and reduced voluntary peak cough flow.

Materials and Methods

Participants

Patients were recruited from the Movement Disorders Centre, Department of Neurology, General University Hospital in Prague. Inclusion criteria were: (1) diagnosis of MSA according to the second consensus criteria ¹⁴ ; (2) age between 40 and 80 years; (3) range from I‐IV in the Global disability scale of Unified multiple system atrophy rating scale (UMSARS) ¹⁵ ; and (4) on a stable dose of medication during the last 4 weeks throughout the study. Exclusion criteria were (1) other concomitant neurological disorders relevant with respect to the aim of the study; (2) current smokers; (3) difficulties in maintaining a proper mouth seal and (3) history of cardiovascular or lung disease; (4) signs of current respiratory infection at the time of the assessment and (5) any changes in medications within the study period. Based on previous EMST studies in PD patients ¹⁰ , ¹⁶ a sufficient sample size of 15 participants was estimated. This study was approved by the Ethics Committee of the General University Hospital in Prague (No 89/18). Participants gave a written informed consent prior to participation.

Study Design

In this proof‐of‐concept study participants completed an assessment of maximum expiratory pressure (MEP) and voluntary peak cough flow (vPCF) at the baseline (pre‐training) and after 8 weeks of EMST (1–3 days post‐training). Two researchers with more than 2 years of experience with respiratory assessments were working together during the tests to ensure correct execution of respiratory maneuvers.

Respiratory Training Protocol

EMST was completed using a handheld, one‐way, spring‐loaded valve trainer. Participants were instructed to perform five sets of five forceful expirations for 5 days a week. Between each set, a 2 min rest period was prescribed. A typical training session lasted approximately 15 min. To encourage training compliance, participants and their caregivers were provided with a home therapy diary and were asked to track their daily therapy sessions by marking off each exercise set performed. The researchers in this study monitored and coached the participants every 2‐week via phone to increase training compliance. To accommodate individualized training loads, two devices were used, which functioned on the same physical principle and mechanical construction but provided different training resistances. For participants whose MEP values were <40 cm H₂O a low range pressure expiratory muscle trainer Phillips Threshold PEP (Respironics; Cedar Grove, NJ, USA; adjustable resistance 5–20 cm H₂O) was used. For participants with MEP values >40 cm H₂O a higher range pressure EMST150 (Aspire Products, LLC, United States; adjustable resistance 30–150 cm H₂O) was utilized. The training device was set at 75% of each participant's baseline MEP value. After 4 weeks of EMST, the MEP values were reassessed to readjust training difficulty to 75% of each participant's current MEP.

Maximum Expiratory Pressure

Maximum pressure assessments were performed using a flanged rubber mouthpiece connected to a pressure manometer (Micro RPM, Micro Medical). MEP assessments were performed in accordance with the American Thoracic Society/European Respiratory society statements on respiratory muscle testing. ¹⁷ Three values differing less than 10% from one another were required to achieve an average for the participants’ individualized MEP scores. Every assessment was performed at the same time of day throughout the study. Patients were investigated in their best ON medication state.

Voluntary Peak Cough Flow

The vPCF was detected using an oral Micro 1 Spirometer (CareFusion, UK). The Micro 1 Spirometer has met all the requirements of the ATS/ERS for accuracy of lung function testing. ¹⁸ Assessment was performed in accordance with the European Respiratory society statements on respiratory muscle testing. ¹⁹ Testing was performed with subjects seated. Participants were asked to “cough as if something went down the wrong pipe.” Three measurement values differing less than 5% from one another were required. The highest one was then selected as the voluntary peak cough flow value.

Index of Pulmonary Dysfunction

IPD comprises of four items (Table S1). The first two are direct questions asked to the patient about their difficulty in handling mucus/secretion and diminished cough strength. The third item–the subject's ability to generate a strong cough on demand. The last item tests their ability to count following a single maximal inspiration. The total score of the index ranges from 4 to 11. A higher score is associated with more disturbed pulmonary function test results. ¹³ Patients underwent an IPD assessment prior to the training period. In order to determine if the IPD scores could define the level of vPCF impairment, patients with vPCF below a normal level (<360 L/min) were divided according to guidelines for the physiotherapy of the spontaneously breathing patient ²⁰ into three groups: (1) patients at risk of less effective coughing (vPCF <360 L/min); (2) patients with less effective coughing (vPCF <270 L/min), and (3) patients with severely weak cough efficacy (vPCF <160 L/min). To investigate if the IPD scores could define patients with expiratory muscle weakness, patients were divided according to previous research ²¹ into two groups: (1) patients without expiratory muscle weakness (>70% normative value) and (2) patients with expiratory muscle weakness (<70% normative value). Normative values were selected according to Evans et al. ²²

Statistical Analysis

The effects of intervention was evaluated by the Wilcoxon's paired test using NCSS 12 statistical software from the Number Cruncher Statistical System (Kaysville, UT, USA). The statistical significance was set at P < 0.05. Adherence was calculated by comparing the total amount recorded in the patient training logs to the prescribed amount (1000 EMST maneuvers over the 8‐week study period). The discriminant validity of the IPD in MSA patients for vPCF and MEP prediction was evaluated using receiver operating characteristics (ROC). According to the ROC analysis, the AUC values were: 0.5 no discrimination, 0.7 to 0.8 acceptable discrimination, 0.8 to 0.9 excellent discrimination, and more than 0.9 outstanding discrimination capability. ²³

Results

Twenty MSA patients were identified as eligible after the initial screening by a movement disorders specialist. Out of these, 5 patients declined involvement due to the need to travel long distances to the hospital. A total of 15 patients entered the study. All participants that entered the study would also meet the revised MSA criteria published after the recruitment process. ² Over the 8‐week study period, 3 patients withdrew from the study. The reasons for withdrawal were: fall (n = 1), psychiatric decompensation requiring acute hospitalization (n = 1) and personal reasons (n = 1). A summary of demographic and clinical characteristics is provided in Table 1. According to normative values, pre‐training MEP ranged from 25% to 116% (median [IQR]: 77.4% [58.9–96.6]). Pre‐training vPCF ranged from 145 to 626 L/min (median [IQR]: 345 L/min [216–415]). Four out of 12 patients reported difficulty in handling mucus/secretion and diminished cough strength in the IPD. After EMST, one of these patients reported subjective improvement of cough effectiveness.

TABLE 1.

Demographic and clinical characteristics of MSA patients who completed the study period

Baseline characteristics
Age (years)	63 (55–68.5)
Gender (female/male)	3/9
Weight (kg)	89 (71–99)
Height (cm)	182 (167–187)
BMI	28.3 (24.6–29.4)
MIP predicted (%)	52 (36.3–71.6)
MEP predicted (%)	77 (58.9–96.6)
vPCF (l/min)	345 (216–415)
FVC predicted (%)	73 (59–82)
FEV1 predicted (%)	86 (56–92)
FEV1/FVC predicted (%)	107 (107–120)
Disease duration (years)	4 (2.5–6)
MSA‐P/C	9/3
Global disability scale of UMSARS	2 (2–3)
IPD	6 (5–7.5)

Note: Values are median (interquartile range).

Abbreviations: BMI, Body Mass Index; C, Cerebellar phenotype; FEV1, Forced expiratory volume in 1 s; FVC, Forced vital capacity; IPD, Index of pulmonary dysfunction; MEP, Maximum Expiratory Pressure; MIP, Maximum Inspiratory Pressure; MSA, Multiple System atrophy; P, Parkinsonian phenotype; UMSARS, Unified Multiple System Atrophy Rating Scale; vPCF, Voluntary Peak Cough Flow.

Effects of EMST

In weeks 1–4, the mean adherence to the prescribed exercises was 98% and in weeks 5–8 it was 88%. There were no adverse effects of the intervention. There was a significant increase (P = 0.006) in MEP from pre‐training to post‐training by 32%. Differences in vPCF were not significant (P = 0.845). MEP and vPCF variables from the pre‐ to the post‐training are provided in Table 2.

TABLE 2.

Median and interquartile range (IQR) of maximum expiratory pressure and voluntary peak cough flow values across pre‐ and post‐testing time points

Measure	Pre‐training W0	Post‐training W8	P‐value
MEP (cmH2O)	70 (62.5–87.3)	92.3 (81.4–128)	0.006
MEP (% normative values)	77.4 (58.9–96.6)	102 (79.1–112)	0.008
vPCF (L/min)	345 (216–415)	372 (315–466)	0.845

Abbreviations: MEP, Maximum Expiratory Pressure; vPCF, Voluntary Peak Cough Flow.

Index of Pulmonary Dysfunction

Baseline MEP and vPCF data from 15 MSA patients were analyzed for correlation analysis with IPD. The IPD negatively correlated with MEP (r = −0.58; P = 0.030) and vPCF (r = −0.87; P = 0.001). ROC analysis demonstrated an AUC of 0.991, 0.98 and 0.964 indicating an outstanding capability of detecting patients at risk of less effective coughing (vPCF <360 L/min; n = 7), patients with less effective coughing (<270 L/min; n = 5) and patients with severely weak cough efficacy (<160 L/min; n = 1) respectively. The AUC of 0.795 indicates an acceptable capability of the IPD to detect patients with decreased expiratory muscle strength (<70% of normative value; n = 7). Cut‐off scores, sensitivity and specificity are provided in Table 3.

TABLE 3.

The discriminant validity of IPD in MSA patients for vPCF and MEP determination

IPD	Cut‐off point	AUC (% 95 CI)	Sensitivity (95% CI)	Specificity (95% CI)
vPCF (L/min)
<360 L/min	≥6	0.991 (0.865, 0.999)	1 (0.631, 1)	0.857 (0.421, 0.996)
<270 L/min	≥7	0.98 (0.803, 0.998)	1 (0.478, 1)	0.8 (0.444, 0.975)
<160 L/min	≥9	0.964 (0.764, 0.995)	1 (0.025, 1)	0.929 (0.661, 0.998)
MEP (cmH2O)
<70% (normative value)	≥6	0.795 (0.339, 0.949)	0.727 (0.39, 0.94)	0.75 (0.194, 0.994)

Abbreviations: AUC, Area Under the Curve; IPD, Index of Pulmonary Disease; MEP, Maximum Expiratory Pressure; vPCF, Voluntary Peak Cough Flow.

Discussion

This was the first study to evaluate the effects of EMST in MSA patients. Our results indicate that EMST was feasible and led to significant improvements in MEP in our cohort of MSA patients. Differences in vPCF were not significant. In addition, IPD seems to be a promising screening tool for identifying MSA patients with decreased cough effectiveness and decreased expiratory muscle strength.

This 8‐week intensive EMST program led to significant expiratory muscles strength gains in MSA patients by 32%. Since the smallest detectable difference for expiratory pressure examination ranged from 18% to 22%, ²⁴ the 32% improvement in expiratory muscle strength in our cohort is considered as a real change. Therapy adherence was very high in both training months. After the training, MSA patients reached or even slightly exceeded their age‐ and sex‐matched normative MEP values. ²² The observed impact of EMST is similar to improvements reported in individuals with Parkinson's disease ¹⁰ , ¹⁶ or multiple sclerosis. ²⁵ This finding is important given the speed of MSA progression as compared to Parkinson's and multiple sclerosis.

After 8 weeks of EMST, the only statistically insignificant difference was observed in vPCF. This was somewhat unexpected as this type of training was effective for improving vPCF in PD patients. ¹⁰ This discordance may be due to the higher incidence of restrictive pulmonary dysfunction in MSA patients as compared to PD. ⁵ Indeed, 73% (11 out of 15) of our patients met the criteria ²⁶ for restrictive pulmonary dysfunction which contributes to the reduction in chest compliance, amplitude and lung expansion. ²⁷ Similar to expiratory muscle weakness, it also affects cough effectiveness. ²⁸ Also, a smaller effect of levodopa on restrictive pulmonary dysfunction can be expected in MSA as compared to PD. ²⁹ , ³⁰ Therefore, to improve vPCF, respiratory techniques addressing restrictive pulmonary dysfunction should presumably be implemented in MSA in addition to EMST. Reyes et al ¹⁶ showed that EMST plus a volume‐oriented technique was more beneficial than EMST alone for improving reflex and voluntary PCF in PD patients.

The results of this study indicate that IPD is highly accurate for detecting patients at risk of decreased expiratory strength and cough efficacy. Moreover, the cut‐off score can identify three groups of patients according to their vPCF values: (1) patients at risk of less effective coughing (cut‐off ≥6; vPCF <360 L/min; MEP < 70% normative value); (2) patients with less effective coughing (cut‐off ≥7; vPCF <270 L/min), and (3) patients with severely week cough efficacy (cut‐off ≥9; vPCF <160 L/min).

Bott et al ²⁰ recommends introducing strategies for assisted airway clearance when the PCF is less than 270 L/min in spontaneously breathing adults. However, we believe that the right time for initiating respiratory training in order to delay the onset of expiratory muscle weakness and reduced cough efficacy, begins ideally in patients with a subclinical vPCF decrease (270–360 l/min). These patients are likely to have sufficient capacity for improvement. Therefore, the IPD could serve as a useful screening tool for referring patients to a more detailed respiratory examination and early initiation of respiratory therapy. Further, when necessary, equipment for respiratory muscle strength and cough efficacy examination is missing (which is the case in clinical practice in many departments), the cut‐off scores may be used to select an appropriate respiratory physiotherapy technique. The respiratory physiotherapy algorithm in Parkinson's disease based on vPCF and MEP value can be an example for the selection of a proper respiratory physiotherapy technique in MSA patients. ³¹

The limitations of this study include a small sample size, the absence of a control arm and the fact that peak reflex cough flow was not measured. The low number of patients also did not allow for distinguishing the effect of EMST in patients with MSA‐C and MSA‐P. A blinded design may add further strength to the current evidence, that is, sham pressure sets for device‐aided therapy and blinded lung function assessments. From a clinical point of view, the relationship of EMST with clinical parameters, such as UMSARS and quality of life, is missing. Future research should investigate the effects of lung volume‐oriented training coupled with EMST to increase vPCF. Patients might experience difficulties with usability of EMTS through the course of their MSA disease progression. Therefore, additional studies with longer EMST training protocol and participants with more severe motor and cognitive problems are needed.

Conclusions

This was the first study to evaluate the effect of EMST in MSA patients. EMST training was well tolerated in MSA patients and resulted in significant improvements in MEP. However, no differences in vPCF were observed. The index of pulmonary dysfunction has been shown as a potentially useful instrument to detect MSA patients at risk of decreased cough efficacy and expiratory muscle weakness.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

M.S.: 1A, 1B, 1C, 2A, 2B, 2C, 3A

T.B: 1A, 1B, 1C, 2C

J.K.: 1A, 1B, 1C, 2C

R.L.: 1A, 1B, 1C, 2C

O.G.: 1A, 3A

T.L.: 1B, 1C

R.J.: 3B

E.R.: 1A, 2C, 3B

M.H.: 1A, 3B.

Disclosures

Ethical Compliance Statement: This study was approved by the Ethics Committee of the General University Hospital in Prague (No 89/18). All participants signed an informed consent. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: This work was supported by the project National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107)‐Funded by the European Union–Next Generation EU; Charles University: Cooperatio Program in Neuroscience; General University Hospital in Prague project MH CZ‐DRO‐VFN64165. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

Supporting information

Table S1. Index of pulmonary dysfunction.