Management of respiratory problems in people with neurodegenerative conditions: a narrative review

Jones, U.; Enright, S.; Busse, M.

doi:10.1016/j.physio.2011.03.002

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Volume 98, Issue 1 , Pages 1-12, March 2012

Management of respiratory problems in people with neurodegenerative conditions: a narrative review

School of Healthcare Studies, Cardiff University, Heath Park, Cardiff CF14 4XN, UK

published online 09 May 2011.

Article Outline

Abstract

Background

Respiratory failure and dysfunction are common problems in many neurodegenerative conditions. Although physiotherapists manage these problems, it is not known which treatments have been studied and their efficacy.

Objective

To review evidence on the management of respiratory problems in people with neurodegenerative conditions using the PRISMA approach.

Data sources

Comprehensive searches were conducted using the following electronic databases from inception to May 2010: HUGEnet, SIGLE, British Library Direct, CINAHL, Medline, AMED and Web of Knowledge. Bibliographies of all studies and systematic reviews were searched by hand.

Study selection

Studies were selected based on: self-ventilating participants with neurodegenerative conditions; interventions aimed at improving respiratory function; and any valid and reliable measures of respiratory function as outcomes.

Study appraisal

Studies were appraised by one reviewer using the Critical Appraisal Skills Programme. Data were synthesised using a narrative approach.

Results

Thirty-five studies were included in the review. The strongest evidence was for the use of non-invasive ventilation for people with amyotrophic lateral sclerosis, although this was weak. The evidence for the use of respiratory muscle training and methods to increase peak cough flow showed a positive effect, but was also weak.

Conclusion

There is weak evidence for the positive effects of physiotherapeutic interventions for respiratory problems in people with neurodegenerative conditions. Further work is necessary in specific neurodegenerative conditions to identify why respiratory problems occur, and larger scale studies should be undertaken to investigate management of these problems.

Keywords: Neurodegenerative conditions, Respiratory insufficiency, Physiotherapy

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Introduction

Rationale

Respiratory dysfunction is common in neurodegenerative conditions, such as multiple sclerosis [1], amyotrophic lateral sclerosis (ALS) [2] and Huntington's disease [3]. Physiotherapeutic management of respiratory problems is often supportive rather than preventative, only taking place in the middle and late stages of the condition [4]. With the exception of national guidelines for the use of non-invasive ventilation in patients with motor neurone disease [5], there are no national guidelines for the management of respiratory problems in people with Parkinson's disease, Huntington's disease or multiple sclerosis. The British Thoracic Society/Association of Chartered Physiotherapists in Respiratory Care guidelines for the adult, spontaneously breathing patient [6] focus on people with neuromuscular disease but do not provide sufficient detail for neurodegenerative conditions. Neurodegenerative conditions differ from neuromuscular diseases in that the former refers to central neurological disorders, and the latter refers to post-neuromuscular junction disorders. Multiple sclerosis, Parkinson's disease, Huntington's disease and ALS/motor neurone disease are neurodegenerative conditions with central nervous system processing problems and peripheral weakness.

People with neurodegenerative conditions have difficulty clearing secretions for a number of reasons, including respiratory muscle weakness and bulbar insufficiency [7]. Ineffective gas exchange may occur due to retained secretions, compounded by respiratory muscle weakness influencing the effectiveness of cough. Decreased inspiratory muscle strength may lead to alveolar hypoventilation, ventilation–perfusion mismatch, and further respiratory muscle fatigue due to altered biomechanics [8]. There is a gap in our knowledge about the physiotherapeutic management of respiratory problems in people with neurodegenerative conditions, despite the fact that respiratory problems are the leading cause of death in this population [7].

Objective

The aim of this paper was to review evidence on the management of respiratory problems in people with neurodegenerative conditions using the PRISMA statement [9].

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Methods

Search process

A population, intervention, comparison and outcome (PICO) approach was used [10], [11]. The population was defined as people with neurodegenerative conditions. The intervention was any physiotherapy-based intervention influencing the respiratory system. No set comparisons were made or follow-up times set. Outcome was any reliable and valid measure of respiratory function, and not respiratory failure alone.

Comprehensive searches were conducted using the following electronic databases from inception to May 2010 (number of studies identified in brackets): HUGEnet (161), SIGLE (624), British Library Direct (192), CINAHL (130), Medline, EMBASE and AMED (4307). Bibliographies of all studies and systematic reviews were searched by hand. Keywords were structured using PICO. Population keywords included ‘neuro*’, ‘Parkinson's disease’, ‘amyotrophic lateral sclerosis’, ‘motor neurone disease’, ‘multiple sclerosis’ and ‘Huntington's disease’. Intervention keywords included ‘physiotherapy’ and ‘respiratory’, and outcome keywords included ‘lung’. Subsequent to the initial search and analysis of the categories of evidence found, two further search terms were used: ‘respiratory muscle strength’ and ‘retained secretions’. Box 1 shows the search strategy used in CINAHL, Medline, AMED and EMBASE databases.

Box 1. Search strategy.

physiother*

neuro*

respir*

lung

respiratory muscle strength

retained secretions

3 OR 4 OR 5 OR 6

1 AND 2 AND 7

motor neurone disease

amyotrophic lateral sclerosis

multiple sclerosis

Huntington's disease

Parkinsonism disease

7 OR 8 OR 9 OR 10 OR 11

12 AND 7

Eligibility criteria, identification and selection of studies

Full-text, English-language randomised controlled trials, experimental studies, and prospective and retrospective observational studies which investigated changes in respiratory function following a physiotherapy-based intervention were included. One reviewer identified and reviewed all titles and abstracts followed by the full text of each article. Exclusion criteria were: the population consisted entirely of patients with neuromuscular conditions such as myesthenia gravis and muscular dystrophies, all members of the population were aged <18 years, the subjects were not breathing spontaneously, the intervention did not influence respiratory function, only one subject was studied, or respiratory failure was the sole outcome measure.

Critical appraisal

Critical appraisal was carried out by one reviewer using the Critical Appraisal Skills Programme (CASP) appraisal tool [12].

Data analysis

Analysis was completed by one reviewer. Due to heterogeneity of populations, interventions and outcome measures, it was not possible to carry out a meta-analysis. A narrative review of all included studies was undertaken.

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Results

Study selection

In total, 5414 studies were retrieved; 5368 studies were excluded by the title, abstract or method (Fig. 1), and 11 studies were excluded by the full text (available from authors on request). Descriptive analysis of the remaining 35 studies highlighted three main themes: the problem of retained secretions, the problem of decreased muscle strength, and the influence of exercise on respiratory function. Studies were grouped into these themes for the narrative review.

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Fig. 1.
Study selection process.

Critical appraisal

A summary of the critical appraisal, following the CASP approach [12], of all selected studies (n=35) is shown in Table 1. Populations were defined clearly in all studies; only two studies carried out power calculations. In those studies (n=6) that required allocation to groups, this was defined. Random allocation was defined in the seven randomised controlled trials. Reproducibility of interventions was variable (14/35 not reproducible), reasons included retrospective studies and inadequate information. All outcome measures were defined, reliable and valid, but different outcome measures were used in comparable studies. Generalisability of the findings was low for the majority of studies due to lack of power and non-reproducible interventions.

Table 1. Summary of critical appraisal of all selected studies.

Study	Study design	Focused question	Appropriate design	Population defined	Sample size calculation	Allocation defined	Intervention reproducible	Outcome measures defined	Data analysis defined	Inferential analysis employed	Appropriate interpretation	Generalisability	Clinical relevance discussed
Annane 2007 [23]	EBR	Yes	Yes	Yes	N/A	N/A	N/A	Yes	Yes	N/A	Yes	Yes	Yes
Aboussouan 2001 [28]	Obs (P)	Yes	Yes	Yes	No	N/A	No	Yes	Yes	Yes	Yes	No	Yes
Bach 1993 [14]	Exp	Yes	Yes	Yes	No	N/A	No	Yes	No	Yes	Yes	No	Yes
Bourke 2003 [24]	Obs (P)	Yes	Yes	Yes	No	N/A	Yes	Yes	No	Yes	Yes	No	Yes
Butz 2003 [29]	Obs (P)	Yes	Yes	Yes	No	N/A	No	Yes	Yes	Yes	Yes	No	Yes
Carratu 2009 [25]	Obs (R)	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Chaisson 2006 [21]	Exp	Yes	Yes	Yes	No	Yes	No	Yes	Yes	Yes	Yes	No	Yes
Chatwin 2003 [15]	Exp	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Cheah 2009 [37]	RCT	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes
Chiara 2006 [39]	Exp	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Fry 2007 [34]	RCT	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes
Gosselink 2000 [1]	RCT	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Goldstein 1991 [30]	Exp	Yes	Yes	Yes	No	N/A	No	Yes	Yes	Yes	Yes	No	Yes
Inzelberg 2005 [36]	Exp	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes
Jackson 2006 [22]	Obs (R)	Yes	No	Yes	No	N/A	No	Yes	Yes	Yes	Yes	No	Yes
Kleopa 1999 [26]	Obs (R)	Yes	Yes	Yes	No	N/A	No	Yes	Yes	Yes	Yes	No	Yes
Klefbeck 2003 [35]	RCT	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes
Koseoglu 1997 [45]	Exp	Yes	Yes	Yes	No	N/A	No	Yes	Yes	Yes	Yes	No	Yes
Lange 2006 [20]	RCT	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Lechtzin 2006 [8]	Exp	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Lo Coco 2006 [27]	Obs (P)	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Mostert 2002 [42]	Exp	Yes	Yes	Yes	No	Yes	No	Yes	Yes	Yes	Yes	No	Yes
Mustfa 2003 [16]	Exp	No	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Mutluay 2007 [47]	RCT	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Nardin 2008 [46]	Exp	Yes	Yes	Yes	Yes	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Nauffal 2002 [31]	Obs (P)	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Olgiati 1989 [41]	Exp	Yes	Yes	Yes	No	N/A	No	Yes	No	Yes	Yes	No	Yes
Pitts 2009 [40]	Exp	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Rampello 2007 [44]	Exp	Yes	Yes	Yes	No	Yes	No	Yes	Yes	Yes	Yes	No	Yes
Rasova 2006 [43]	Exp	No	Yes	Yes	No	Yes	No	Yes	Yes	Yes	Yes	No	Yes
Sancho 2004 [17]	Exp	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Smeltzer 1996 [38]	RCT	Yes	Yes	Yes	No	Yes	No	Yes	Yes	Yes	Yes	No	Yes
Suleman 2004 [19]	Exp	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Trebbia 2005 [18]	Exp	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes
Winck 2004 [13]	Exp	Yes	Yes	Yes	No	N/A	Yes	Yes	Yes	Yes	Yes	No	Yes

EBR, evidence-based review; Exp, experimental; Obs (P), observational (prospective) study; Obs (R), observational (retrospective) study; RCT, randomised controlled trial; N/A, not applicable.

Study characteristics and synthesis of results

Based on descriptive analysis of selected studies, three main themes were identified: the problem of retained secretions (n=10), the problem of decreased respiratory muscle strength (n=19), and the influence of exercise on respiratory function (n=6). The theme of retained secretions was subdivided into interventions to improve the effectiveness of cough (n=7) and interventions to mobilise secretions (n=3). The theme of decreased respiratory muscle strength was subdivided into non-invasive ventilation (n=10) and respiratory muscle training (n=9). The third theme included studies related to exercise. Details of the study characteristics are summarised in Table 2, Table 3, Table 4, Table 5.

Table 2. Details of studies on retained secretions.

Study	Population	Intervention and method	Relevant outcome measure	Key significant findings
Bach 1993 [14]	21 patients with neurodegenerative conditions	MIC, MIC and MAC, MIE Single group, repeated measures from each intervention MIE: several five-cycle applications at comfortable pressures	PCF	MIE better than MIC and MAC, which was better than MIC at ↑ PCF
Chatwin 2003 [15]	21 adults and children with neurodegenerative conditions	Unassisted cough, physiotherapy-assisted cough, non-invasive-ventilator-assisted cough, exsufflation-assisted cough, insufflation/exsufflation-assisted cough Single group, repeated measures from each intervention	PCF	Exsufflation-assisted cough and insufflation/exsufflation-assisted cough better than unassisted cough
Chaisson 2006 [21]	Nine patients with ALS	HFCWO, standard treatment Two groups: Group 1, standard care plus HFCWO applied for 15minutes, twice daily; Group 2, standard care. Both groups received instruction on cough augmentation manoeuvres	FVC	No difference in rate of decline in FVC between HFCWO and standard treatment
Jackson 2006 [22]	18 patients with ALS	HFCWO Retrospective study, HFCWO applied twice daily for 10 to 20minutes or more frequently if needed. Frequency 10 to 14Hz, pressures 30 to 40cmH₂O	PCF	No significant changes
Lange 2006 [20]	46 patients with ALS	HFCWO, no treatment Randomised controlled trial HFCWO: twice daily for 10 to 15minutes for 12 weeks. Frequency 10 to 12Hz, pressures 1 to 4 (linear scale no units) Control group: no treatment	PEFR, dyspnoea, FVC	↓ Dyspnoea; FVC decreased in control group but not in HFCWO group
Mustfa 2003 [16]	47 patients with ALS	Cough, MAC, maximal exsufflation, maximal insufflation, MIE Single group, repeated measures from each intervention	PCF	Exsufflation and MIE ↑ PCF
Sancho 2004 [17]	26 patients with ALS	MAC, MIE and MAC Single group, repeated measures from each intervention MIE: pressure 40 to −40cmH₂O, I/E ratio 2:3 with 1-second pause	PCF	MIE can increase PCF in stable patients with ALS with 4l/s<PCF_MIC>2.7l/s
Suleman 2004 [19]	10 patients with motor neurone disease	Mechanical glottis, cough Single group, repeated measures from each intervention	PEFR	↑ PEFR with mechanical glottis PEFR with mechanical glottis>PEFR with cough
Trebbia 2005 [18]	10 patients with neurodegenerative conditions	Manual hyperinflation, manually assisted cough, manual hyperinflation and manually assisted cough Single group, repeated measures from each intervention	PCF	PCF higher during manual hyperinflation and manually assisted cough than manual hyperinflation and manually assisted cough alone
Winck 2004 [13]	13 patients with ALS, seven patients with neurodegenerative conditions	MIE Single group, measures taken before and after MIE. MIE: six I/E cycles at each of 15 to −15cmH₂O, 30 to −30cmH₂O, 40 to −40cmH₂O; I/E ratio 3:4 with 4-second pause between each cycle	PCF, SaO₂, dyspnoea	↑ PCF, SaO₂ ↓ Dyspnoea

MIC, maximal insufflation capacity; MAC, manually assisted cough; MIE, mechanical insufflation–exsufflation; I/E, insufflation/exsufflation; PCF, peak cough flow; ALS, amyotrophic lateral sclerosis; HFCWO, high-frequency chest wall oscillation; FVC, forced vital capacity; PEFR, peak expiratory flow rate; SaO₂, oxygen saturation.

Table 3. Details of studies on non-invasive ventilation (NIV) for decreased respiratory muscle strength.

Study	Population	Intervention and method	Relevant outcome measure	Key significant findings
Annane 2007 [23]	Neuromuscular or chest wall disorders	Nocturnal mechanical ventilation Cochrane review	FVC, SNIP, SaO₂	Current evidence weak but consistent that nocturnal mechanical ventilation alleviates chronic hypoventilation in the short term
Aboussouan 2001 [28]	60 patients with ALS	NIV Single group, repeated measures over time NIV: volume controlled or BiPAP; pressures for patient comfort; for as long as tolerated during night and, as necessary, in daytime	FVC, FEV₁, MIP, MEP	No significant change in outcomes over time
Bourke 2003 [24]	17 patients with ALS	BiPAP Single group, repeated measures over time. BiPAP: pressures dependent on arterial blood gases, oxygen saturation and compliance; timing adjusted for patient comfort	FVC	Rate of decline in FVC slower post treatment
Butz 2003 [29]	30 patients with ALS	NIV Single group, repeated measures over time NIV: pressure cycled; pressures 8 to 22mbar dependent upon arterial blood gases, oxygen saturation and relief of symptoms	FVC, SaO₂, PaO₂, PaCO₂	SaO₂ and PaO₂ ↑ over time
Carratu 2009 [25]	72 patients with ALS	NIV Retrospective comparing three groups according to FVC and NIV use NIV: volume controlled or BiPAP; pressures 8cmH₂O IPAP, 3cmH₂O EPAP; volume/pressure dependent upon chest rise, leaks and comfort; used nightly as tolerated and, as necessary, in daytime	FVC, FEV₁, PaO₂, PaCO₂	FVC decline slower in survivors who tolerated NIPPV
Goldstein 1991 [30]	Six including two patients with neurodegenerative conditions	NIV Single group, repeated measures over time. NIPPV: volume cycled	TLim	TLim ↑ at 3 months post intervention
Kleopa 1999 [26]	122 patients with ALS	BiPAP Retrospective comparing three groups – those who tolerated BiPAP for >4hours, those who tolerated BiPAP for <4hours and those who refused	%FVC predicted	Decline of %FVC slower in those who could tolerate NIPPV
Lechtzin 2006 [8]	19 patients with ALS, four healthy controls	BiPAP Two groups, measured before and after BiPAP. BiPAP: 5minutes; pressure dependent upon lung compliance	FEV₁, FVC, FER, MIP, MEP, static lung compliance	Lung compliance ↑ with BiPaP in patients with ALS, no change in control group
Lo Coco 2006 [27]	71 patients with ALS	BiPAP Single group, repeated measures over time. BiPAP: pressures adjusted to patient comfort, leaks and efficiency of ventilation; for as long as tolerated nightly and, as necessary, in daytime	FVC	Decline of FVC slower in those who could tolerate NIPPV
Nauffal 2002 [31]	62 including 27 patients with neurodegenerative conditions	BiPAP Single group, repeated measures over time BiPAP nightly; pressures dependent on ABG	FEV₁, FVC, FER, MIP, MEP, ABG	SaO₂ ↑ after 3 months FEV₁, FVC ↓ after 12 months

FVC, forced vital capacity; SNIP, sniff nasal inspiratory pressure; SaO₂, oxygen saturation; BiPAP, bilevel positive airway pressure. FEV₁, forced expiratory volume in 1second; MIP, maximal inspiratory pressure; MEP, maximal expiratory pressure; PaO₂, partial pressure of oxygen; PaCO₂, partial pressure of carbon dioxide; TLim, respiratory muscle endurance time; FER, forced expiratory ratio; ALS, amyotrophic lateral sclerosis; ABG, arterial blood gases; IPAP, inspiratory positive airway pressure; EPEP, expiratory positive airway pressure; NIPPV, non-invasive positive pressure ventilation.

Table 4. Details of studies on respiratory muscle training for decreased respiratory muscle strength.

Study	Population	Intervention	Relevant outcome measure	Key significant findings
Cheah 2009 [37]	19 patients with ALS	IMT group vs sham group IMT: 10minutes, three times daily for 12 weeks Resistance increased weekly from 15% to 60% SNIP, then sustained at 60% SNIP Sham device had no resistance	FVC, MIP, SNIP, MEP	FVC, MIP, SNIP ↑ trend
Chiara 2006 [39]	17 patients with multiple sclerosis, 14 healthy controls	EMT Repeated measures pre EMT, post EMT and 4 weeks after no training EMT: four sets of six repetitions, 5 days/week for 8 weeks Resistance increased weekly from 40% to 80% MEP then sustained at 80% MEP	FVC, FEV₁, MEP, PEFR	MEP, PEF ↑ after 8 weeks of training. No difference between patients with multiple sclerosis and healthy controls
Fry 2007 [34]	46 patients with multiple sclerosis	Home IMT group vs control group IMT: three sets of 15 repetitions, daily for 10 weeks. Resistance increased from 30% MIP according to Borg RPE and symptoms Control: no intervention	MIP, MEP, MVV	MIP ↑
Gosselink 2000 [1]	28 patients with multiple sclerosis	EMT group vs breathing exercises group EMT: three sets of 15 repetitions, twice daily for 3 months Resistance 60% MEP Breathing exercises to enhance maximal inspiration	FVC, MIP, MEP	MIP ↑ after 3 months of training, no difference between EMT and breathing exercises groups MEP ↑ after 3 months of training, significant compared with breathing exercises
Inzelberg 2005 [36]	20 patients with Parkinson's disease	IMT group vs control group IMT: 30minutes, 6 days/week for 12 weeks. Resistance increased from 15% to 60% MIP and sustained at 60% MIP Control: frequency as IMT. Resistance 7cmH₂O	FVC, MIP, inspiratory muscle endurance	MIP and endurance ↑, no change in FVC, no change in control group
Klefbeck 2003 [35]	15 patients with multiple sclerosis	IMT group vs control group IMT: three sets of 10 repetitions, twice every other day for 10 weeks Resistance: 40% to 60% MIP, dependent upon Borg RPE<17 Control: deep breathing exercises as part of physiotherapy treatment	FVC, FEV₁, MIP, MEP, PEFR	MIP and MEP ↑ from baseline MIP ↑ significantly compared with control group
Olgiati 1988 [41]	Eight patients with multiple sclerosis	IMT/EMT dependent upon %MIP/MEP Training: 6 to 10minutes, twice daily, 5 days/week for 4±1 weeks Resistance dependent upon %MIP/MEP and increased progressively	MIP, MEP, MVV	MIP, MEP, MVV ↑
Pitts 2009 [40]	10 patients with Parkinson's disease	EMT Repeated measures over time Training: five sets of five breaths, once daily, 5 days/week for 4 weeks. Resistance 75% of MEP	MEP, PCF	MEP ↑
Smeltzer 1996 [38]	20 patients with multiple sclerosis	EMT group vs control group EMT: three sets of 15 repetitions, twice daily for 3 months Resistance based on MEP and increased based on ability to perform exercises Control frequency as EMT, with IMT at resistances too low to affect inspiratory muscle strength	MIP, MEP	MEP ↑

ALS, amyotrophic lateral sclerosis; IMT, inspiratory muscle training; FVC, forced vital capacity; MIP, maximal inspiratory pressure; SNIP, sniff nasal inspiratory pressure; MEP, maximal expiratory pressure; EMT, expiratory muscle training; FEV₁, forced expiratory volume in 1second; PEFR, peak expiratory flow rate; MVV, maximal voluntary ventilation RPE, rate of perceived exertion.

Table 5. Details of studies on exercise and its influence on respiratory function.

Study	Population	Intervention	Relevant outcome measure	Key significant findings
Koseoglu 1997 [45]	Nine patients with Parkinson's disease	Pulmonary rehabilitation Single group compared before and after intervention Pulmonary rehabilitation: 60minutes, three times per week for 5 weeks	FVC, FEV₁, PEFR, MVV	No significant changes
Mostert 2002 [42]	37 patients with multiple sclerosis, 26 healthy controls	Multiple sclerosis exercise training (bike) group vs multiple sclerosis control group vs healthy control group vs healthy exercise training group Training: 30minutes, five times per week for 3 to 4 weeks, individualised intensity Multiple sclerosis control group: normal physiotherapy Healthy control group: no physical exercise that could improve aerobic fitness	FVC, FEV₁, FER, PEFR, MVV, aerobic capacity	FVC, PEFR ↑ in exercise group; no change in aerobic capacity
Mutluay 2007 [47]	62 patients with multiple sclerosis	Breathing enhanced upper extremity exercises group vs control group Breathing exercises programme: 30minutes, once daily for 6 weeks	FVC, FEV₁, FER, MIP, MEP	FEV₁, FER ↑ compared with control MEP ↑ trend compared with control
Nardin 2008 [46]	Eight patients with ALS	Diaphragmatic training Single group measured before and after intervention Training: five sets of 10minutes daily for 12 weeks	FVC, hypercapnic ventilatory response	No change
Rampello 2007 [44]	19 patients with multiple sclerosis	Aerobic training (cycle ergometer) vs neurological rehabilitation Randomised crossover study Training: 55minutes, three times per week for 8 weeks. Intensity dependent on work rate and increased to 80% maximum work rate Rehabilitation: 60minutes, three times per week for 8 weeks	FVC, FEV₁, MIP, MEP	No difference in lung function
Rasova 2006 [43]	112 patients with multiple sclerosis	Neurophysiological physiotherapy vs aerobic bike training vs mixed training vs control Physiotherapy: 1hour, twice per week for 2 months Bike training: twice per week, intensity 60% maximal oxygen uptake, time dependent on disability score range 10 to 30minutes Mixed training: 1hour, twice per week physiotherapy and bike training as above Control: no intervention	FVC, FEV₁, PEFR	PEFR ↑ in intervention groups, no difference between groups

FVC, forced vital capacity; FEV₁, forced expiratory volume in 1second; PEFR, peak expiratory flow rate; MVV, maximal voluntary ventilation; MIP, maximal inspiratory pressure; MEP, maximal expiratory pressure; ALS, amyotrophic lateral sclerosis; FER, forced expiratory ratio.

The problem of retained secretions

Ten studies (see Table 2) described interventions for retained secretions due to ineffective cough. All studies were small, and populations contained patients with ALS/motor neurone disease (n=6) and other neurodegenerative conditions (n=4). Six studies compared combinations of increasing maximal insufflation capacity, mechanical insufflation–exsufflation (MIE) and manually assisted cough. Three studies used high-frequency chest wall oscillation (HFCWO) to mobilise secretions, and one study investigated the use of a mechanical glottis to enhance cough. The primary outcome measure for most studies (7/10) was peak cough flow (PCF), with two studies using peak expiratory flow rate (PEFR), and one study using forced vital capacity (FVC) and oxygen saturation (SaO₂).

Studies relating to improvement in the effectiveness of cough

Winck et al. [13] investigated the effects of MIE on parameters including PCF, SaO₂ and dyspnoea. The sample contained 13 patients with ALS and seven patients with other neurodegenerative conditions. PCF and SaO₂ were measured at baseline and after MIE ±40cmH₂O, and showed a significant improvement in patients with ALS (PCF and SaO₂: P<0.005) and other neurodegenerative conditions (PCF: P<0.05, SaO₂: P<0.005). Dyspnoea was measured in the patients with neurodegenerative conditions, and was found to decrease significantly from baseline to ±40cmH₂O (P<0.05). Median PCF increased from 180 to 220l/min in the patients with ALS, and from 170 to 200l/min in the patients with neurodegenerative conditions.

Bach [14], Chatwin et al. [15], Mustfa et al. [16] and Sancho et al. [17] compared the combinations of MIE, manually assisted cough and breath stacking in patients with ALS and other neurodegenerative conditions, using PCF as an outcome. For patients with ALS (n=73, [16], [17]), MIE was more effective than manually assisted cough in those without bulbar involvement and who were stable. MIE was not effective in patients with bulbar dysfunction and those with little impairment of lung function. The specific issue of bulbar involvement highlights the importance of impaired cough due to upper airway weakness which may not be overcome by these interventions [16]. In people with other neurodegenerative conditions, Bach [14] found that MIE was more effective than manually assisted cough with breath stacking; cough with insufflations and unassisted cough. Chatwin et al. [15] found that although MIE and exsufflation alone were better than unassisted cough, they were not significantly better than assisted cough in a mixed adult and child sample. In a small study of 10 patients with neurodegenerative conditions, Trebbia et al. [18] found that a combination of manually assisted cough and manual hyperinflation improved PCF significantly.

An alternative aid to cough may be a mechanical glottis device that imitates glottis closure. Suleman et al. [19] investigated the mechanical glottis in healthy controls and people with bulbar problems, and demonstrated that the device created a PEFR significantly higher than that of both a straightforward PEFR manoeuvre and a cough manoeuvre in people with bulbar problems.

Physiotherapy-based interventions to improve the effectiveness of cough by increasing PCF have some efficacy for people with neurodegenerative conditions. MIE and manually assisted cough appear to be more effective than unassisted cough. The choice of intervention depends upon the patient's vital capacity and whether there is bulbar involvement. The heterogeneous populations used, including neurodegenerative and neuromuscular disorders, make it difficult to draw conclusions for specific disease populations.

Intervention to mobilise secretions

The above interventions focused on increasing flows necessary to expectorate secretions, whereas HFCWO aims to mobilise secretions. In three studies with a total of 62 patients with ALS, HFCWO was applied twice per day for 10 to 30minutes per session [20], [21], [22]. Although there were no significant changes in respiratory function (SaO₂, FVC, PCF), breathlessness decreased significantly [20], and 92% of patients felt better after treatment [22]. Based on this, HFCWO may enhance the mobilisation of secretions in people with neurodegenerative conditions, but large-scale studies are necessary to provide conclusive findings.

Summary of the problem of retained secretions

Studies on the management of retained secretions have focused on increasing lung volumes to create flow rates sufficient to mobilise and expectorate secretions. Evidence suggests that improvements in PCF may be gained through MIE and manually assisted cough; further research into their effectiveness in different subgroups of people is needed. PCF was used consistently as an outcome measure, yet there is little evidence for its reliability.

The problem of decreased respiratory muscle strength

Two main therapies were identified to address the problem of respiratory muscle weakness: non-invasive ventilation and respiratory muscle training. Non-invasive ventilation aims to reduce the work of breathing and conserve energy, whilst respiratory muscle training aims to strengthen inspiratory and expiratory muscles, and improve endurance. Studies of the effectiveness of these interventions include a systematic review of eight randomised controlled trials, five randomised controlled trials, five prospective observational studies, two retrospective observational studies and five experimental studies (see Table 3, Table 4 for details).

Non-invasive ventilation

Ten studies (see Table 3) used non-invasive ventilation as an intervention. The systematic review was specific to ALS. Other studies included 391 patients with ALS and 68 mixed population studies. Studies were mainly prospective observational studies (n=5), with two retrospective studies and two experimental studies. Interventions included bilevel positive airway pressure, volume-cycled non-invasive ventilation and pressure-cycled non-invasive ventilation. Outcome measures included FVC, sniff nasal inspiratory pressure, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), respiratory muscle endurance and lung compliance.

A systematic review [23] identified eight randomised controlled trials investigating the efficacy of nocturnal mechanical ventilation in relieving hypoventilation-related symptoms in patients with neuromuscular and chest wall disorders. In this review, neuromuscular disorders included ALS. The primary outcome measure was reversal of daytime hypoventilation symptoms, with few studies reporting lung function measurements. The findings of the review suggest that non-invasive ventilation is beneficial in the short term, but the evidence is weak.

Seven studies, not included in the above review, investigated the effect of non-invasive ventilation on lung function in patients with ALS (n=391). Four studies (n=282) demonstrated a slower decline in FVC in patients who could tolerate non-invasive ventilation [24], [25], [26], [27]. Non-invasive ventilation was individualised to each patient by mode and length of intervention. The evidence is weakened by the fact that two of these studies were retrospective [25], [26].

Inconclusive evidence exists for other measures of lung function. Aboussouan et al. [28] found no change in FVC, forced expiratory volume in 1second, MIP or MEP; Butz et al. [29] reported increased oxygenation (SaO₂ and partial pressure of oxygen); and Lechtzin et al. [8] showed increased lung compliance following non-invasive ventilation. Two studies including 29 patients with a range of neurodegenerative conditions reported increased respiratory muscle endurance [30] and improved oxygenation [31] following non-invasive ventilation.

Summary of findings on non-invasive ventilation

Studies have found that non-invasive ventilation may influence lung function in patients with ALS/motor neurone disease, and it is recommended to improve quality of life and survival as well as alleviating breathlessness. The role of non-invasive ventilation in the management of other neurodegenerative conditions needs to be explored.

Respiratory muscle training

Respiratory muscle training techniques using the same principles as those for skeletal muscle training (i.e. overload, specificity and reversibility) have been shown to improve respiratory strength and endurance in healthy subjects [32] and in patients with chronic respiratory disease [33]. Training may also influence respiratory muscle endurance, dependent upon the training protocol. Outcome measures include MIP, MEP and 12-second maximal voluntary ventilation.

Nine studies, including four randomised controlled studies (see Table 4), assessed the effect of respiratory muscle training in people with neurodegenerative conditions. Two randomised controlled studies of 61 patients with multiple sclerosis [34], [35] and one study of 20 patients with Parkinson's disease [36] identified significant increases in MIP following inspiratory muscle training. The trial by Cheah et al. [37] only demonstrated an increasing trend in inspiratory pressure measured by MIP and sniff nasal inspiratory pressure compared with sham inspiratory muscle training in 19 patients with ALS. Studies lasted between 10 and 12 weeks, with training ranging from daily to every other day. Although Fry et al. [34] did not observe a change in maximal voluntary ventilation, Inzelberg et al. [36] reported a significant increase in inspiratory muscle endurance as measured by the peak pressure obtained on breathing against progressive loads to fatigue.

The efficacy of expiratory muscle training is less clear than that of inspiratory muscle training. Two randomised controlled trials demonstrated significant increases in MEP in 48 patients with multiple sclerosis compared with breathing exercises [1] and a control group [38]. Chiara et al. [39] also reported a significant increase in MEP in 17 patients with multiple sclerosis after 8 weeks of training. A 4-week study by Pitts et al. [40] of expiratory muscle training in patients with Parkinson's disease showed a significant increase in MEP but no difference in PCF. Differences in the length of training (daily for 3 months [1], [38]; daily for 8 weeks [39]; and 5 days/week for 4 weeks [40]) and stage of disease (mild [38], mild/moderate [39], [40] and severe [1]) may explain the different results.

In a pilot study by Olgiati et al. [41], eight patients with multiple sclerosis were assigned to either inspiratory muscle training or expiratory muscle training, dependent upon whether their MIP or MEP was <70% predicted. Although training only lasted for 4 weeks, significant increases were observed in MIP, MEP and maximal voluntary ventilation for the whole group.

Summary of studies on respiratory muscle training

There is some evidence that respiratory muscle training does increase strength and endurance. The majority of studies included patients with multiple sclerosis, and therefore results may be specific to this population. Although a number of studies were randomised controlled trials, the interventions and outcomes differed, limiting firm conclusions. Further research is needed to investigate pathophysiological changes occurring in respiratory muscles of people with neurodegenerative conditions, and the physiological and clinical effects of respiratory muscle training.

The influence of exercise on respiratory function

Six studies investigated the influence of different types of exercise in people with neurodegenerative conditions (see Table 5). Three studies (n=168 patients with multiple sclerosis [42], [43], [44]) compared exercise (bike) training with neurological rehabilitation, and only one of these studies [42] found a significant difference in FVC and PEFR in the exercise group. A specific pulmonary rehabilitation programme in nine patients with Parkinson's disease [45] and diaphragmatic training in eight patients with ALS [46] did not show any significant changes in respiratory function. In contrast, breathing enhanced upper extremity exercise in 40 patients with multiple sclerosis demonstrated an increasing trend for FVC and MEP compared with the control group [47]. The lack of significant changes in respiratory function may be due to the length of the training programmes which ranged from 3 to 8 weeks.

Further research is needed to determine the effects of general exercise in people with neurodegenerative conditions, and how this is influenced by and influences respiratory function.

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Discussion

Summary of evidence

This review selected 35 studies of physiotherapy-based interventions for respiratory function. Interventions were summarised as those aiming to: improve the effectiveness of cough; mobilise secretions; decrease the work of breathing; increase the strength of the respiratory muscles; and influence respiratory function through exercise. The evidence selected was weak due to lack of power and reproducibility of interventions, as highlighted in Table 2. Synthesis of evidence through a meta-analysis was not possible due to heterogeneous populations, interventions and outcome measures; as such, a narrative review was undertaken.

The effectiveness of cough may be improved using MIE and manually assisted cough. HFCWO to mobilise secretions did not influence respiratory function but may reduce breathlessness. The evidence for these positive effects is weak. Non-invasive ventilation to reduce the work of breathing may have an influence on lung function in the short term. Respiratory muscle strength and endurance may be improved using specific training programmes. The evidence for exercise as an intervention to improve lung function was inconclusive.

This weak evidence base and anecdotal evidence from discussions with the European Huntington's Disease Network Physiotherapy Working Group (http://www.euro-hd.net/html/network/groups/physio) indicates that further research is needed in people with neurodegenerative conditions. Knowledge gaps exist in a number of specific areas. Firstly, the mechanisms underlying respiratory problems in people with neurodegenerative conditions such as multiple sclerosis, Parkinson's disease, Huntington's disease and motor neurone disease are unknown. Respiratory function throughout disease progression needs to be explored in order to identify when changes occur, and therefore when physiotherapeutic interventions, both preventative and restorative, should be implemented. The effectiveness of physiotherapeutic interventions can be explored through studies with larger sample sizes, which could be achieved through multicentre trials, using PCF, MIP and MEP as outcome measures. The overarching aim of further research would be to provide evidence-based guidelines for the management of respiratory problems specific to people with neurodegenerative conditions.

Limitations

This review is limited by the number and quality of studies, and consequently a meta-analysis was not feasible. Studies had heterogeneous populations, were underpowered, were often non-randomised, and were of insufficient number to provide guidelines for management of the different stages of progressive conditions. Interventions and outcome measures were not standardised between studies.

The review process was limited by having one reviewer rather than two, thus introducing potential bias. This was minimised by using the PICO structure [10] for searching and the CASP appraisal tool [12].

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Conclusions

The evidence to support the use of methods to increase the effectiveness of cough, respiratory muscle strength and endurance in people with neurodegenerative conditions is weak but does indicate a positive effect. The strongest evidence is for the use of non-invasive ventilation in patients with ALS to alleviate symptoms of chronic hypoventilation. Further research must be focused on developing guidelines for the effective management of respiratory problems in people with neurodegenerative conditions, with consideration given to the pathophysiological similarities and differences in those conditions.

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Acknowledgements

The authors wish to thank Mrs E. Gillen, Librarian, School of Nursing and Healthcare Studies Library at Cardiff University for her advice in the development of the review; and Professor A. Rosser, Professor of Clinical Neurosciences at Cardiff University for her support and advice.

Funding: This study forms part of a PhD undertaken at Cardiff University by Una Jones, which was partly funded by Physiotherapy Research Foundation and Research Capacity Building Collaboration Wales.

Conflict of interest: None declared.

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