ADVERTISEMENT

Issue Navigator

Volume 11 No. 05
Earn CME
Accepted Papers





Scientific Investigations

Noninvasive Ventilation Improves Sleep in Amyotrophic Lateral Sclerosis: A Prospective Polysomnographic Study

Bart Vrijsen, PT, MSc1,2; Bertien Buyse, MD, PhD1,2; Catharina Belge, MD, PhD1,2; Wim Robberecht, MD, PhD3,4; Philip Van Damme, MD, PhD3,4,5; Marc Decramer, MD, PhD2; Dries Testelmans, MD, PhD1,2
1Leuven University Centre for Sleep/Wake Disorders, Department of Pulmonology, University Hospitals Leuven, Belgium; 2Department of Pulmonology, University of Leuven, Belgium; 3Department of Neurology, University of Leuven, Belgium; 4Experimental Neurology (Department of Neurosciences) and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven (KU Leuven), Belgium; 5Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium

ABSTRACT

Study Objective:

To evaluate the effects of noninvasive ventilation (NIV) on sleep in patients with amyotrophic lateral sclerosis (ALS) after meticulous titration with polysomnography (PSG).

Methods:

In this prospective observational study, 24 ALS patients were admitted to the sleep laboratory during 4 nights for in-hospital NIV titration with PSG and nocturnal capnography. Questionnaires were used to assess subjective sleep quality and quality of life (QoL). Patients were readmitted after one month.

Results:

In the total group, slow wave sleep and REM sleep increased and the arousal-awakening index improved. The group without bulbar involvement (non-bulbar) showed the same improvements, together with an increase in sleep efficiency. Nocturnal oxygen and carbon dioxide levels improved in the total and non-bulbar group. Except for oxygen saturation during REM sleep, no improvement in respiratory function or sleep structure was found in bulbar patients. However, these patients showed less room for improvement. Patient-reported outcomes showed improvement in sleep quality and QoL for the total and non-bulbar group, while bulbar patients only reported improvements in very few subscores.

Conclusions:

This study shows an improvement of sleep architecture, carbon dioxide, and nocturnal oxygen saturation at the end of NIV titration and after one month of NIV in ALS patients. More studies are needed to identify the appropriate time to start NIV in bulbar patients. Our results suggest that accurate titration of NIV by PSG improves sleep quality.

Commentary:

A commentary on this article appears in this issue on page 511.

Citation:

Vrijsen B, Buyse B, Belge C, Robberecht W, Van Damme P, Decramer M, Testelmans D. Noninvasive ventilation improves sleep in amyotrophic lateral sclerosis: a prospective polysomnographic study. J Clin Sleep Med 2015;11(5):559–566.


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting the motor system and is characterized by progressive decrease in muscle strength. In addition to weakness of peripheral muscles, respiratory muscle weakness develops during the course of the disease, leading to reduced alveolar ventilation and respiratory failure, which is the main cause of death in ALS.1,2

A randomized controlled trial showed improvement in survival and quality of life (QoL) in ALS patients treated with noninvasive ventilation (NIV).3 Although survival in the subgroup of patients with severe bulbar impairment did not improve, small improvements in QoL were observed.

Sleep is often disturbed in ALS patients.47 In the presence of diaphragmatic dysfunction, REM sleep decreases.8 Furthermore, sleep disturbances and nocturnal desaturations have been observed in ALS patients with normal respiratory function and preserved diaphragmatic innervation.9

BRIEF SUMMARY

Current Knowledge/Study Rationale: Previous research has shown an improvement in survival and quality of life after initiation of NIV in ALS. Until now, no improvement in objective sleep parameters has been found; however, NIV was titrated during daytime. More detailed titration with polysomnography could perhaps improve quality of sleep.

Study Impact: This study shows that NIV titration with polysomnography improves objective sleep outcomes in ALS patients. Hence, meticulous titration of NIV has an important clinical impact in this patient group. Further research is necessary to create evidence to find the correct time to start NIV in bulbar ALS patients.

Although NIV is predominantly used at night, few studies have examined the effect on sleep in ALS. Nevertheless, NIV could have a negative impact on sleep: wearing a mask and having air blown into the nose and/or mouth do not seem to create the perfect circumstances for good sleep quality. In the presence of weakness of facial or bulbar muscles, application of the mask could create difficulties, resulting in non-intentional leaks. Furthermore, difficulties with swallowing and managing secretions could interfere with NIV during sleep.10 Conversely, improvement of oxygenation and carbon dioxide levels would have beneficial effects on sleep. Most studies dealing with sleep in ALS are based on patient-reported outcomes and reported improved sleep after NIV initiation.3,1114 Only two studies used polysomnography (PSG) to evaluate sleep during NIV and did not demonstrate improvement in sleep. Katzberg et al. showed an improved oxygenation but no improvement in sleep efficiency (SE), sleep arousals and sleep architecture during NIV.15 Atkeson et al. showed a high frequency of patient-ventilator asynchronies (PVA).16 Therefore, additional studies evaluating the effect of NIV on sleep are needed.17

The aim of this prospective study was to evaluate the influence of NIV on sleep in ALS by PSG with capnography before and after one month of NIV. Correlations were searched between therapeutic compliance with carbon dioxide measurement, improvement in patient-reported outcomes (total scores), and improvement in objective sleep parameters. Although a previous study shows no improvement in sleep structure,15 we hypothesized that improvement in sleep structure could be found with a more meticulous NIV titration.

METHODS

Patients

At University Hospitals Leuven, ALS patients are routinely followed at the Neuromuscular Reference Centre (NMRC) in collaboration with pulmonologists (BB, DT). Patients with decreased inspiratory muscle strength (maximal inspiratory mouth pressure [MIP] < 60 cm H2O), restrictive pulmonary function (vital capacity [VC] < 80% of the predicted value) and at least one of the following criteria were offered NIV: symptoms of nocturnal alveolar hypoventilation, increased daytime arterial carbon dioxide ([PaCO2] > 45 mm Hg) or an increase ≥ 10 mm Hg in transcutaneous carbon dioxide (PtcCO2) during sleep compared to their awake supine value (≥ 40 mm Hg). These inclusion criteria ensured that all patients in this study fulfilled the NIV criteria according to the guidelines of the American Academy of Neurology and the guidelines of the European Federation of Neurological Societies in ALS patients.18,19

Methods

Patients were admitted to the sleep lab for 5 days and 4 nights. Diagnostic PSG was performed on the first night. The next morning, NIV was started (Trilogy 100, Philips Respironics, Murrysville, PA, USA) with a nasal mask. Patients were accustomed to NIV in spontaneous (S) mode with an inspiratory positive airway pressure (IPAP) of 8 cm H2O and an expiratory positive airway pressure (EPAP) of 4 cm H2O. In the afternoon, IPAP was titrated in S mode during a nap to reach a tidal volume of 6 mL/min/kg ideal body weight. In the morning of days 3, 4, and 5, PSG was analyzed and NIV settings were adjusted according to nocturnal PtcCO2, oxygen saturation (SpO2%), and occurrence of respiratory events. Each afternoon the patient napped for 1 hour to get accustomed to the new settings. In the presence of mouth leaks, a chin strap or oronasal mask was applied. After 1 month of NIV, patients were readmitted for PSG.

PSG (Medatec, Brainnet II, Brussels, Belgium) was used to record sleep and respiratory parameters. Sleep was scored and calculated after visual inspection of the tracings, according to the guidelines of the American Academy of Sleep Medicine (AASM) by 2 physicians with large experience in PSG analysis.20 During diagnostic PSG, airflow was detected by a thermistor (Braebon, NY, USA) and nasal pressure cannula system (Teleflex Medical, NC, USA). A pneumotachograph (Hamilton Medical, Bonaduz, Switzerland) was used to record flow during NIV titration. Apnea and hypopnea were scored according to the AASM 2012 guidelines.21 PtcCO2 was continuously monitored by a Tosca 500 monitor (Radiometer Ltd., Bronshoj, Denmark). The PtcCO2 and pneumotachograph data were incorporated in the PSG software and continuously followed.

Before and after 1 month of NIV, patients performed a VC measurement in sitting and (if possible) supine position according to the guidelines of the European Respiratory Society,22 with prediction equations as proposed by Quanjer.23 Daytime arterial blood gas (ABG) analysis was carried out in sitting position without ventilatory support. Measurements of MIP and sniff nasal inspiratory pressure (SNIP) were performed (MicroRPM, Micro Medical, Brooklyn, NY, USA).24,25 Patients completed questionnaires concerning sleep, QoL, and functionality. The Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) were used to measure sleep quality and daytime sleepiness, respectively.26,27 Apart from the short-form 36 health questionnaire (SF-36), a generic measurement searching for health-related QoL,28 we employed the McGill Quality of Life questionnaire (MQoL) measuring QoL specifically in patients with a life-threatening disease.29 Functionality was measured by the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).30 Bulbar function was based on the first 3 questions of the ALSFRS-R, and patients were classified as bulbar when this score was ≤ 9.31

This study was registered at clinicaltrials.gov (NCT01889043) and approved by the local ethical committee (ML7674). Written informed consent was obtained from all participants.

Statistical Analysis

Statistical analyses were performed with SAS 9.0 (SAS Institute Inc., Cary, NC, USA). Data are reported as mean ± standard deviation or as median and interquartile range. Comparisons between pre and post measurements were performed by paired t-test or Wilcoxon signed-rank test, depending whether data were normally distributed or not. Between-group comparisons were performed by unpaired t-test or Mann-Whitney test. Spearman rho and Pearson were used to test correlations. Results were considered significant when p < 0.05. Figures were made by GraphPad Prism 5.01 (GraphPad Software Inc., La Jolla, CA, USA).

RESULTS

From January 2012 to April 2013, 63 patients were referred to our unit by the NMRC. Twenty-four patients (60 ± 10 years, 21 males) were started on NIV (Figure 1). Demographic data and baseline measurements of inspiratory muscle strength, VC, and ABG are shown in Table 1. Measurement of supine VC could not be performed in 7 patients because of severe orthopnea. Three patients refused ABG analysis, and 2 patients had problems performing MIP/SNIP measurement. The most prevalent symptoms of alveolar hypoventilation were orthopnea (20 patients), increased daytime sleepiness (17 patients), frequent awakenings (15 patients), and exertional dyspnea (12 patients). In our group, 10 patients showed important bulbar involvement and were classified as “bulbar”; 14 patients were classified as “non-bulbar.”

Flow chart of patient inclusion.

NMRC, neuromuscular reference centre; NIV, noninvasive ventilation; LUCS, Leuven University Centre For Sleep/Wake Disorders.

jcsm.11.5.559a.jpg

jcsm.11.5.559a.jpg
Figure 1

Flow chart of patient inclusion. NMRC, neuromuscular reference centre; NIV, noninvasive ventilation; LUCS, Leuven University Centre For Sleep/Wake Disorders.

(more ...)

Demographic data and baseline measurements of arterial blood gases, vital capacity, and inspiratory muscle strength.

jcsm.11.5.559.t01.jpg

table icon
Table 1

Demographic data and baseline measurements of arterial blood gases, vital capacity, and inspiratory muscle strength.

(more ...)

Seventeen patients were discharged from the hospital on spontaneous/timed (S/T) mode and 7 patients on S mode, due to intolerance of S/T mode (5 of these patients had bulbar involvement with residual saliva and swallowing problems which aggravated with the S/T mode and thereby influencing their subjective and objective sleep quality). Nineteen patients were ventilated by nasal mask and 5 patients by oronasal mask. IPAP was set at 14 ± 2 cm H2O and EPAP was set at 4 ± 1 cm H2O. Patients on S/T mode had a back-up frequency of 16 ± 2/ min. One non-bulbar male patient died of pneumonia before follow-up, and one bulbar male patient could not be tested with NIV after one month because of intolerance (1.8 h/day use, only during daytime). These 2 patients were excluded from further analysis.

After one month (38 ± 9 days), ALSFRS-R was significantly decreased (p < 0.01 for all patients; p < 0.05 for non-bulbar patients or bulbar patients). Daytime PaCO2 decreased significantly in the total group (46 ± 6 vs. 43 ± 5 mm Hg, p < 0.05) and non-bulbar patients (48 ± 6 vs. 43 ± 5 mm Hg, p < 0.05).

Sleep Architecture

At baseline, PSG revealed poor sleep quality (Table 2). A low SE, with low percentages of slow wave sleep (N3) and REM sleep, and an increased arousal-awakening index (AAI) were present.32 Sleep quality of bulbar patients was better than sleep quality of non-bulbar patients, with less stage 1 sleep (N1), more REM sleep, and a lower AAI. Except for one patient who had no N3, all sleep stages were present in bulbar patients, while N3 and REM sleep were absent in 8 and 5 nonbulbar patients, respectively.

Sleep structure in all, non-bulbar and bulbar patients before and after one month of NIV use.

jcsm.11.5.559.t02.jpg

table icon
Table 2

Sleep structure in all, non-bulbar and bulbar patients before and after one month of NIV use.

(more ...)

After one month, several changes in sleep architecture were present. AAI and percentage of N1 sleep were significantly reduced and percentages of N3 and REM sleep were significantly increased (while total sleep time was not significantly higher) in all patients. The same observations were made in the group of non-bulbar patients, with even a significant increase in SE. In the non-bulbar group all sleep stages were now present in all patients but one. In the bulbar patients, no improvement in SE, sleep stages, or AAI was found (Table 2).

Analyzing PSG of the night with the final settings during the start-up procedure already found improvements in sleep structure compared to diagnostic PSG. The total group showed improvement in AAI (17 [12–21] per hour of sleep; p < 0.01) and the amount of N1 (4 [2–9] %; p < 0.01), N3 (19 [8–30] %; p < 0.01) and REM (21 [14–26] %; p < 0.05) sleep, while the non-bulbar group showed improvement in SE (81 [67–84] %; p < 0.01), AAI (18 [13–22] per hour of sleep; p < 0.01), and N1 (3 [2–9] %; p < 0.01), N3 (19 [4–30] %; p < 0.05), and REM (25 [20–29] %; p < 0.01) sleep. Bulbar patients showed no improvement at discharge.

Sleep Respiratory Parameters

At diagnostic PSG, patients showed few obstructive events (0.0 [0.0–0.3] obstructive apneas per hour of sleep; 0.1 [0.0–6.3] obstructive hypopneas per hour of sleep). Table 3 shows improvements in SpO2% and PtcCO2. In the total group the time spent with SpO2% < 90% improved during the total night as well as in REM and N1 and stage 2 (N2) sleep. Time spent with PtcCO2 > 55 mm Hg improved during the total night measurement, N1, N2, and N3 sleep. Non-bulbar patients showed significant changes in the same parameters as the total group. Additionally, a trend to improvement was found for time spent with SpO2% < 90% in N3 (p = 0.0579). Bulbar patients only improved in time spent with SpO2% < 90% in REM sleep. In the bulbar group, no changes were found in PtcCO2 measurement.

Measurements of oxygen saturation and transcutaneous carbon dioxide measurements at baseline and after one month of NIV treatment.

jcsm.11.5.559.t03.jpg

table icon
Table 3

Measurements of oxygen saturation and transcutaneous carbon dioxide measurements at baseline and after one month of NIV treatment.

(more ...)

Analyzing the data of SpO2% and PtcCO2 of the night with the final settings during titration showed improvements in comparison with the diagnostic PSG. The total group improved in the time spent with SpO2% < 90% during the total night (4 [0–49] %; p < 0.01), N1+N2 (3 [0–48] %; p < 0.01), and REM (1 [0–50] %; p < 0.01) sleep, and also in time spent with PtcCO2 > 55 mm Hg during the total night (0 [0–21] %; p < 0.01) and N1+N2 sleep (20 [0–16] %; p < 0.05). The non-bulbar patients improved in time spent with SpO2% < 90% during the total night (5 [1–61] %; p < 0.05), N1+N2 (4 [0–72] %; p < 0.05) and REM (2 [0–60] %; p < 0.05) sleep and time spent with PtcCO2 > 55 mm Hg during the total night (0 [0–17] %; p < 0.01) and N1+N2 (0 [0–14] %; p < 0.05) sleep, while bulbar patients only improved in the time spent with SpO2% < 90% during REM sleep (1 [0–18] %; p < 0.05).

Questionnaires

Table 4 shows the data of the ESS, PSQI, and MQoL before and after one month of NIV. Non-bulbar patients showed improvements in daytime sleepiness (8.0 [3.5–11.5] vs 4.0 [3.0–7.0]; p < 0.05), the PSQI total score (8.0 [6.5–14.5] vs 5.0 [2.5–7.5]; p < 0.01), MQoL total score (5.0 [4.2–6.0] vs 6.8 [5.4–7.9]; p < 0.01), and several subscales. In contrast, bulbar patients only reported an improved PSQI total score (9.0 [6.5–12.5] vs 5.0 [4.0–9.0]; p < 0.01) and sleep duration (1.0 [0.0–2.0] vs 0.0 [0.0–0.5]; p < 0.01). Improvements were found in the SF-36 emotional health subscale for the total (50 [28–77] vs 62 [56–81]; p < 0.0001), non-bulbar (50 [29–84] vs 68 [54–90]; p < 0.01), and bulbar group (50 [25–67] vs 60 [56–77]; p < 0.01). Vitality changed only for the total (35 [10–50] vs 50 [29–60]; p < 0.05) and non-bulbar groups (25 [10–49] vs 48 [26–60]; p < 0.01).

Measurements of Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality index (PSQI), and McGill quality of life questionnaire (McGill) at baseline and after one month.

jcsm.11.5.559.t04.jpg

table icon
Table 4

Measurements of Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality index (PSQI), and McGill quality of life questionnaire (McGill) at baseline and after one month.

(more ...)

Compliance

Therapeutic compliance was significantly correlated with initial daytime PaCO2 (Figure 2A). Furthermore, NIV use was correlated with baseline nocturnal PtcCO2 and changes in PtcCO2 measurements over 1 month (Table 5). Figure 2B shows a statistical significant relationship between compliance and change in MQoL total score in the total group and nonbulbar group. No correlation was found between therapeutic compliance and change in any objective sleep parameter.

Correlation between therapeutic compliance and daytime arterial carbon dioxide before NIV and change in quality of life.

(A) Correlation between daytime arterial carbon dioxide (n = 19) before NIV initiation and use hours: r = 0.54, p < 0.05. (B) Correlation between change in the total score of the McGill questionnaire (ΔMQoLtot) and use hours in the total group (r = 0.56, p < 0.01) and non-bulbar group (gray dots) (r = 0.63, p < 0.05). PaCO2, partial pressure of carbon dioxide in arterial blood; ΔMQoLtot, change in the total score of the McGill Quality of Life questionnaire.

jcsm.11.5.559b.jpg

jcsm.11.5.559b.jpg
Figure 2

Correlation between therapeutic compliance and daytime arterial carbon dioxide before NIV and change in quality of life. (A) Correlation between daytime arterial carbon dioxide (n = 19) before NIV initiation and use hours: r = 0.54, p

(more ...)

Correlations of therapeutic compliance (use hours) with baseline measurements of time of transcutaneous carbon dioxide spent > 55 mm Hg and changes over one month in time of transcutaneous carbon dioxide spent > 55 mm Hg.

jcsm.11.5.559.t05.jpg

table icon
Table 5

Correlations of therapeutic compliance (use hours) with baseline measurements of time of transcutaneous carbon dioxide spent > 55 mm Hg and changes over one month in time of transcutaneous carbon dioxide spent > 55 mm Hg.

(more ...)

DISCUSSION

This is the first study demonstrating improvements in sleep architecture and respiratory parameters in ALS patients during treatment with nocturnal NIV, measured by PSG. The total group and subgroup of non-bulbar patients showed improvements in SE, amount of N3 and REM sleep, AAI, and oxygenation and carbon dioxide levels present at the end of the titration procedure; these improvements remained after one month of NIV use. In addition, patients also reported better sleep with less somnolence during daytime and improvement in QoL. In bulbar patients, improvements were limited, with no change in sleep architecture, small improvement in nocturnal SpO2%, and few subjective improvements.

In our study, NIV improved (apart from gas exchange) PSG-recorded and patient-reported sleep and QoL. Few studies showed improvement in sleep by patient-reported outcomes in ALS. Lyall et al. did not make a distinction between bulbar and non-bulbar patients, but VC in their patients was similar to our group. Without specifying time of follow-up, they found a significant improvement in ESS score.12 Butz et al. showed a long-term improvement of sleep quality by using the PSQI, also without distinction between bulbar and non-bulbar involvement.11 In the randomized controlled trial, Bourke et al. used the symptom subscale of the Sleep Apnea Quality of Life Index (SAQLI) and found an improvement of symptoms in the total group and in patients with good bulbar function.3 Patients with poor bulbar function had no improvement, except for the time-weighted mean of the SAQLI symptom score. Although our bulbar patients used NIV 6.4 h/day, compared to 3.8 h/ day in the study of Bourke et al., we also found no significant changes in our bulbar group (PSG or patient-reported), except for the total PSQI score and its subscale of sleep duration.

To our knowledge, only one study evaluated PSG recorded sleep architecture in ALS patients on NIV.15 Our results are in contrast with this study as it showed no change in SE, sleep arousals, or sleep architecture. Several factors could explain these differences. In Katzberg's study, NIV was titrated during daytime according to the patient's comfort. In our study, NIV was titrated by PSG guidance; hence, sleep structure was taken into account during titration. Furthermore, the NIV device itself could influence sleep due to possible differences in triggering. In our study, the Trilogy 100 was used with the AutoTrak setting. Katzberg et al. did not mention their trigger modality, but fixed trigger sensitivity could influence the number of PVAs and AAI, as trigger sensitivity could possibly differ between sleep stages.3336 Another difference is the use of average volume-assured pressure support (AVAPS) in Katzberg's study. Until now, no randomized controlled trial with AVAPS has been performed in ALS. Impact of self-changing pressures on leaks, PVA, and sleep is therefore unknown. Although in a heterogenic group of neuromuscular patients, volume-targeted ventilation has shown to cause more PVA than pressure support ventilation.37 Katzberg et al. already suggested that an additional night of PSG to titrate NIV would have been helpful to optimize treatment in their cohort.15 In stable neuromuscular patients, with at least 3 months of NIV use, 66% still showed a PSQI score ≥ 5 (mean score 6.98 ± 3.2).38 In that study, NIV was established following evaluation of diurnal comfort, respiratory function, and gas exchange, and of nocturnal in-hospital cardiorespiratory polygraphic monitoring, but without any sleep study. As most patients still showed poor sleep quality, the authors stated that great care should be paid to an effective and optimal NIV setting. Indeed, as the median (interquartile range) PSQI score in our study before NIV was 8.5 (6.8–13.3) and decreased to 5.0 (3.0–8.3), with even a significant improvement in the bulbar patients, it seems that PSG could be of major importance to improve sleep quality in patients starting with NIV.

The most striking result of this study is that NIV improved PSG-recorded and patient-reported sleep, QoL, nocturnal SpO2%, and carbon dioxide in the total and non-bulbar group of patients, but that almost no improvements were found in the group of bulbar patients. An explanation could be compiled from the data before NIV initiation; PSG recorded sleep quality, SpO2%, and carbon dioxide measurements were better in the bulbar group and therefore, there is less room for improvement. The question then arises whether NIV is started too soon in bulbar patients, as also PaCO2 was lower and SNIP was slightly higher. These patients frequently complain of orthopnea but this sensation is probably partly induced by breathing difficulties due to accumulation of secretions and/or excessive saliva. On the other hand, postponing NIV in bulbar patients could impede NIV titration and adjustment to a mask secondary to advanced bulbar symptoms. This point of discussion becomes even more complicated if we consider our bulbar patients individually. Indeed, sleep and QoL did not improve in patients with a very low score on the bulbar questions of the ALSFRS-R, but patients with a score of 8 and 9 had variable results. It could be suggested that NIV should be initiated in patients with bulbar involvement when decreased sleep quality is reported by the patient or PSG, but certainly more research on when to start NIV in bulbar ALS patients is necessary.

Correlation was found between therapeutic compliance and nocturnal time spent above 55 mm Hg PtcCO2 at baseline. This is in agreement with Kim et al. who showed that duration of nocturnal hypercapnia, measured by end-tidal capnography, was predictive for good compliance.39 This finding could promote early measurement of nocturnal PtcCO2, even in normocapnic patients during daytime, and together with the correlation between compliance and change of nocturnal PtcCO2, encourage good compliance. Even a simple daytime PaCO2 measurement was correlated with future compliance. Apparently, patients with high PaCO2 need less encouragement on their compliance, but patients with mild hypercapnia should be well observed to increase compliance. Our results show a positive correlation between change in QoL and therapeutic compliance in the total and non-bulbar groups. Bourke et al. also showed a strong relationship between QoL and NIV compliance, even over the long term.13

One limitation of our study is that patients during diagnostic PSG are exposed for the first time to PSG measurement, and that this could influence sleep negatively. However, after one month of sleeping with NIV at home, it will still be an adaptation when full PSG is carried out again, especially taking into account the increased functional disability. Another limitation is the limitation of our data to results after one month. Butz et al. showed that patient-reported improvements in sleep emerge after one month of NIV treatment and could last for up to 10 months.11 As the goal of NIV is improving sleep and QoL and simultaneously increasing survival, longitudinal studies on the effect of NIV on sleep and the effect of improved sleep quality on survival are definitely needed. We know that PSG is not routinely used during NIV titration in most countries. Probably, three nights of titration with PSG (as performed in this study) will not be necessary in most patients; however, the findings of this study underline the importance of PSG during NIV titration in patients with ALS.

CONCLUSIONS

This is the first prospective study showing objective improvement in different sleep parameters after one month of NIV in ALS. Increased amounts of N3 and REM sleep with a decreased AAI and improved gas exchange were observed, especially in patients with none or mild bulbar involvement. Furthermore, patients reported better sleep and QoL. In patients with severe bulbar involvement, almost no improvement was found, and additional research is needed on when NIV should be started in these patients. This study suggests that meticulous titration of NIV by PSG could improve sleep in patients with ALS.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.

ABBREVIATIONS

AAI

arousal-awakening index

ABG

arterial blood gas

ALS

amyotrophic lateral sclerosis

EPAP

expiratory positive airway pressure

MIP

maximal inspiratory mouth pressure

MQoL

McGill Quality of Life questionnaire

NIV

non-invasive ventilation

PSG

polysomnography

PSQI

Pittsburgh Sleep Quality Index

PVA

patient-ventilator asynchronies

QoL

quality of life

REM

rapid eye movement

SAQLI

Sleep Apnea Quality of Life Index

SE

sleep efficiency

SNIP

sniff nasal inspiratory pressure

VC

vital capacity

ACKNOWLEDGMENTS

The authors thank the team members of the Neuromuscular Reference Centre Leuven (University Hospitals Leuven, Belgium) and the Leuven University Centre for Sleep/Wake Disorders (University Hospitals Leuven, Belgium) for their assistance in data collection. Bart Vrijsen thanks the Clinical Research Foundation, UZ Leuven, Belgium and ABMM-Téléthon for their financial support.

REFERENCES

1 

Vitacca M, Clini E, Facchetti D, et al., authors. Breathing pattern and respiratory mechanics in patients with amyotrophic lateral sclerosis. Eur Respir J. 1997;10:1614–21. [PubMed]

2 

Gordon PH, Corcia P, Lacomblez L, et al., authors. Defining survival as an outcome measure in amyotrophic lateral sclerosis. Arch Neurol. 2009;66:758–61. [PubMed]

3 

Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ, authors. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 2006;5:140–7. [PubMed]

4 

Hetta J, Jansson I, authors. Sleep in patients with amyotrophic lateral sclerosis. J Neurol. 1997;244 4 Suppl 1:S7–9. [PubMed]

5 

Kimura K, Tachibana N, Kimura J, Shibasaki H, authors. Sleep-disordered breathing at an early stage of amyotrophic lateral sclerosis. J Neurol Sci. 1999;164:37–43. [PubMed]

6 

Santos C, Braghiroli A, Mazzini L, Pratesi R, Oliveira LV, Mora G, authors. Sleep-related breathing disorders in amyotrophic lateral sclerosis. Monaldi Arch Chest Dis. 2003;59:160–5. [PubMed]

7 

Lo Coco D, Mattaliano P, Spataro R, Mattaliano A, La Bella V, authors. Sleep-wake disturbances in patients with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2011;82:839–42. [PubMed]

8 

Arnulf I, Similowski T, Salachas F, et al., authors. Sleep disorders and diaphragmatic function in patients with amyotrophic lateral sclerosis. Am J Respir Crit Care Med. 2000;161:849–56. [PubMed]

9 

Atalaia A, De Carvalho M, Evangelista T, Pinto A, authors. Sleep characteristics of amyotrophic lateral sclerosis in patients with preserved diaphragmatic function. Amyotroph Lateral Scler. 2007;8:101–5. [PubMed]

10 

Vandenberghe N, Vallet AE, Petitjean T, et al., authors. Absence of airway secretion accumulation predicts tolerance of noninvasive ventilation in subjects with amyotrophic lateral sclerosis. Respir Care. 2013;58:1424–32. [PubMed]

11 

Butz M, Wollinsky KH, Wiedemuth-Catrinescu U, et al., authors. Longitudinal effects of noninvasive positive-pressure ventilation in patients with amyotrophic lateral sclerosis. Am J Phys Med Rehabil. 2003;82:597–604. [PubMed]

12 

Lyall RA, Donaldson N, Fleming T, et al., authors. A prospective study of quality of life in ALS patients treated with noninvasive ventilation. Neurology. 2001;57:153–6. [PubMed]

13 

Bourke SC, Bullock RE, Williams TL, Shaw PJ, Gibson GJ, authors. Noninvasive ventilation in ALS. Indications and effect on quality of life. Neurology. 2003;61:171–7. [PubMed]

14 

Mustfa N, Walsh E, Bryant V, Lyall RA, et al., authors. The effect of noninvasive ventilation on ALS patients and their caregivers. Neurology. 2006;66:1211–7. [PubMed]

15 

Katzberg HD, Selegiman A, Guion L, et al., authors. Effects of noninvasive ventilation on sleep outcomes in amyotrophic lateral sclerosis. J Clin Sleep Med. 2013;9:345–51. [PubMed Central][PubMed]

16 

Atkeson AD, Roy-Choudhury A, Harrington-Moroney G, Shah B, Mitsumoto H, Basner RC, authors. Patient-ventilator asynchrony with nocturnal noninvasive ventilation in ALS. Neurology. 2011;77:549–55. [PubMed]

17 

Vrijsen B, Testelmans D, Belge C, Robberecht W, Van Damme P, Buyse B, authors. Non-invasive ventilation in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14:85–95. [PubMed]

18 

Miller RG, Jackson CE, Kasarskis EJ, et al., authors; for the Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review). Neurology. 2009;73:1218–26. [PubMed Central][PubMed]

19 

Andersen PM, Abrahams S, Borasio GD, et al., authors; on behalf of the EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS): revised report of an EFNS task force. Eur J Neurol. 2012;19:360–75. [PubMed]

20 

Iber C, Ancoli-Israel S, Chesson AL, Quan SF, authors; for the American Academy of Sleep Medicine. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.

21 

Berry RB, Budhiraja R, Gottlieb DJ, et al., authors; for the American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012;8:597–619. [PubMed Central][PubMed]

22 

Miller MR, Crapo R, Hankinson J, et al., authors; for the ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005;26:153–61. [PubMed]

23 

Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC, authors. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J. 1993;16:5–40

24 

Black LF, Hyatt RE, authors. Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis. 1969;99:696–702. [PubMed]

25 

Héritier F, Rahm F, Pasche P, Fitting JW, authors. Sniff nasal inspiratory pressure. A noninvasive assessment of inspiratory muscle strength. Am J Respir Crit Care Med. 1994;150:1678–83. [PubMed]

26 

Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ, authors. The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatric Res. 1989;28:193–213

27 

Johns MW, author. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14:540–5. [PubMed]

28 

Ware JE, Snow KK, Kosinski M, Gandek B, authors. SF-36 health survey: manual and interpretation guide. Boston: MA: The Health Institute, New England Medical Center, 1993.

29 

Cohen SR, Mount BM, Strobel MG, Bui F, authors. The McGill Quality of Life questionnaire: a measure of quality of life appropriate for people with advanced disease. A preliminary study of validity and acceptability. Palliat Med. 1995;9:207–19. [PubMed]

30 

Cedarbaum JM, Stambler N, Malta E, et al., authors. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. J Neurol Sci. 1999;169:13–21. [PubMed]

31 

Fattori B, Grosso M, Bongioanni P, et al., authors. Assessment of swallowing by oropharyngoesophageal scintigraphy in patients with amyotrophic lateral sclerosis. Dysphagia. 2006;21:280–6. [PubMed]

32 

Walsleben JA, Kapur VK, Newman AB, et al., authors. Sleep and reported daytime sleepiness in normal subjects: the Sleep Heart Health Study. Sleep. 2004;27:293–8. [PubMed]

33 

Douglas NJ, White DP, Pickett CK, Well JV, Zwillich CW, authors. Respiration during sleep in normal man. Thorax. 1982;37:840–4. [PubMed Central][PubMed]

34 

Fraigne JJ, Orem JM, authors. Phasic motor activity of respiratory and non-respiratory muscles in REM sleep. Sleep. 2011;34:425–34. [PubMed Central][PubMed]

35 

White JE, Drinnan MJ, Smithson AJ, Griffiths CJ, Gibson GJ, authors. Respiratory muscle activity and oxygenation during sleep in patients with muscle weakness. Eur Respir J. 1995;8:807–14. [PubMed]

36 

Crescimanno G, Canino M, Marronne O, authors. Asynchronies and sleep disruption in neuromuscular patients under home noninvasive ventilation. Respir Med. 2012;106:1478–85. [PubMed]

37 

Crescimanno G, Marrone O, Vianello A, authors. Efficacy and comfort of volume-guaranteed pressure support in patients with chronic ventilatory failure of neuromuscular origin. Respirology. 2011;16:672–9. [PubMed]

38 

Crescimanno G, Misuraca A, Purrazzella G, Greco F, Marronne O, authors. Subjective sleep quality in stable neuromuscular patients under non-invasive ventilation. Sleep Med. 2014;15:1259–63. [PubMed]

39 

Kim S, Park KS, Nam H, et al., authors. Capnography for assessing nocturnal hypoventilation and predicting compliance with subsequent noninvasive ventilation in patients with ALS. PLoS One. 2011;6:e17893. [PubMed Central][PubMed]