Objective To evaluate the frequency, severity and determinants of sleep disturbances in patients with amyotrophic lateral sclerosis (ALS).
Methods Information about night-time complaints was collected using a standardised questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS) in a group of 100 patients with ALS and in 100 control subjects matched for age and sex. Functional disability was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R). Sleep was studied by overnight polysomnography in 12 patients.
Results Fifty-nine patients with ALS and 36 controls reported sleep disturbances. The mean global PSQI score of patients with ALS was significantly higher than the control participants (6.82±4.0 vs 4.86±3.2), and three of the seven components of PSQI in patients with ALS were significantly different from controls: ‘sleep latency,’ ‘habitual sleep efficiency’ and ‘sleep disturbances.’ The most commonly reported night-time complaints by patients with ALS were nocturia (54%), sleep fragmentation (48%) and nocturnal cramps (45%). Poor sleep was associated with decreased ALSFRS-R score, highest depression and ESS score. After a multivariate analysis, patients' disability and daytime somnolence remained significantly associated with sleep quality. Polysomnographic studies showed decreased sleep efficiency and fragmented sleep architecture.
Conclusion This study demonstrated that patients with ALS have a significant poor quality of sleep, and this correlated with the severity of ALS and daytime somnolence. Increased awareness for sleep–wake problems in patients with ALS is important, as effective intervention could lead to a better management of these patients.
- Amyotrophic lateral sclerosis
- daytime sleepiness
- motor neuron disease, sleep
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by progressive degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord, leading to muscle atrophy, paralysis and death because of respiratory failure within 2–5 years.1
Although it is well known that patients with ALS frequently report sleep-related complaints (such as insomnia, disturbed sleep, frequent nocturnal awakenings, nightmares, morning headaches and daytime sleepiness), these symptoms have been usually ascribed to disturbed nocturnal gas exchange and hypoventilation,2 3 and so far, they have received limited attention.
We recently found an increased frequency of restless legs syndrome (RLS) in a population of patients with ALS, and these patients frequently reported insomnia complaints and showed increased functional disability.4 Moreover, irrespective of the presence of RLS symptoms, many patients complained about reduced subjective sleep quality and increased daytime somnolence in the absence of respiratory dysfunction.4
We therefore decided to investigate the frequency, characteristics and determinants of sleep problems in a group of 100 consecutive patients with ALS.
Patients and methods
We collected detailed clinical data on 100 consecutive patients with ALS during their routine visit to our ALS Center between February 2008 and April 2010. Patients were diagnosed as definite or probable ALS according to the El-Escorial WFN revised criteria.5 The control group was composed of 100 healthy subjects, enrolled among the spouses or friends of patients attending the neurology department for disorders other than ALS, matched for age and sex to the ALS group. Apart from sleeping medications, all control subjects did not require any other pharmacological treatment.
All subjects underwent a standardised face-to-face interview with a neurologist and expert in sleep medicine (DLC), board-certified by the Italian Association of Sleep Medicine. The structured interview collected data on sleep problems (‘yes’ or ‘no’ type of answer). Subjects had to specify whether they had: (1) persistent initial insomnia (difficulty falling asleep within 30 min or more); (2) difficulties staying asleep (more than two ≥30 min nocturnal awakenings independently of the need to use the bathroom, or undesirable early morning awakening with inability to fall asleep again); (3) unrefreshing sleep (feeling tired and sleepy after waking in the morning). Symptoms should have lasted at least for 1 month and had an impact on the subject's daily life. Information was also sought on whether patients snored or had nocturia, postural discomfort, pain or muscle cramps.
In addition, the Pittsburgh Sleep Quality Index (PSQI)6 was administered to all the study participants. PSQI is a standardised questionnaire including 19 individual items regarding the quality of sleep patterns over the past month. It consists of seven components, namely, ‘subjective sleep quality,’ ‘sleep latency,’ ‘sleep duration,’ ‘habitual sleep efficiency,’ ‘sleep disturbances,’ ‘use of sleep medication,’ and ‘daytime dysfunction.’ Each of the seven component scores is weighted equally on a scale of 0 (no difficulty) to 3 (severe difficulty). The seven component scores are then summed to yield a global PSQI score, ranging from 0 to 21, with a higher score indicating poorer sleep quality. A PSQI score >5 was taken to indicate poor sleep.6
The diagnosis of RLS was made using the four standard diagnostic criteria proposed by the International RLS Study Group.7 Daytime somnolence was evaluated using the Epworth Sleepiness Scale (ESS).8 Excessive daytime sleepiness (EDS) was defined by an ESS score of ≥10.
We also collected the following parameters for each patient with ALS included in the study: date and area of ALS onset, medical and drug history, forced vital capacity (FVC), use of nocturnal ventilation. Functional impairment owing to ALS was evaluated using the ALS-Functional Rating Scale—Revised (ALSFRS-R),9 a 12-item, 48-point scale that measures bulbar, upper-extremity, lower-extremity and respiratory functions. Scores range from 0 (severe impairment) to 48 (normal functioning). Bulbar involvement was quantified using the bulbar section of the ALSFRS-R ranging from 0 (markedly impaired) to 12 (normal).
Depression was evaluated using the Beck Depression Inventory (BDI),10 a self-reported scale with 21 items, each rated from 0 to 3, obtaining a total score ranging from 0 to 63 (higher total scores indicate more severe depressive symptoms). A score of >14 indicates depression.
All patients underwent nocturnal pulse oximetry (NPO). Nocturnal respiratory events were defined as desaturation events greater than 4% of the mean average oxygen saturation (SaO2).11 The mean SaO2 overnight was also measured. NPO was considered altered when there were more than 15 nocturnal respiratory events/hour,11 or a mean nocturnal SaO2 of ≤93% was detected.12
Twelve patients with ALS were admitted to the sleep laboratory for overnight polysomnography. The sleep stages, arousals, periodic limb movements in sleep (PLMS), and respiratory events were scored by visual inspection according to standard criteria.13
This study was approved by the institutional review board. Written informed consent was obtained from all participants.
Statistical analyses were carried out using SPSS software (Version 10.0). Continuous variables were compared with the Mann–Whitney U test, and categorical variables were analysed using the χ2 test. Binary correlation was evaluated with Spearman's correlation (ρ). To investigate the risk factors for impaired sleep quality in the ALS population, we divided the patients with ALS into two groups—good sleepers (total PSQI score ≤5) and poor sleepers (total PSQI score >5)—and we compared the two groups for clinical and demographic characteristics, and for sleep-related complaints using a univariate statistical analysis. We controlled our results using a multiple logistic regression model. ORs and 95% CIs were calculated. Since nocturnal ventilation artificially supports breathing, maintains oxygen saturation and could improve quality of sleep, we also excluded the population of ALS patients receiving nocturnal ventilation, and we repeated the analysis on the population not receiving ventilatory support. A p value of<0.05 (two-tailed) was considered significant. Bonferroni correction was used.
A total of 100 patients with ALS (40 women, 60 men; mean age: 59.9±12 years) and 100 control subjects (47 women, 53 men; mean age: 57.9±12.8 years) were included in the study. The site of ALS onset was bulbar in 27 patients. Patients had a mean duration of ALS symptoms of 25±15.4 months, a mean ALSFRS-R score of 33.2±8.8 and a mean FVC of 73.9%±25.3. Thirty-eight patients had an altered NPO, and 21 patients used non-invasive ventilation. Seven patients were on enteral nutrition. All patients were taking riluzole. The mean BDI score was 10.1±6.4. Twenty-three (23%) patients were depressed, and 11 patients were taking antidepressants. No patients had overt dementia.
The mean global PSQI score of patients with ALS was significantly higher than control subjects (6.82±4.0 vs 4.86±3.2; p<0.001). Fifty-nine patients with ALS (59%) were classified as poor sleepers (global PSQI score >5), and 28 patients had a global PSQI score of ≥10, indicating moderate to severe dysfunction. Of the control group, 36 subjects were considered poor sleepers (36%), and the remaining 64 subjects were good sleepers; 10 subjects (10%) had a global PSQI of ≥10. The difference in prevalence of poor sleepers between patients with ALS and control subjects was statistically significant (p=0.001). A multivariate analysis adjusting for age and sex confirmed this association and quantified the risk to present poor sleep of 2.5 times greater for patients with ALS than for control subjects (95% CI 1.39 to 4.43; p=0.002). Of the seven components of PSQI in patients with ALS, three were significantly different from control subjects: ‘sleep latency,’ ‘habitual sleep efficiency’ and ‘sleep disturbances’ (table 1). There was also a trend towards lower scores in ‘subjective sleep quality’ and ‘sleep duration’ that did not reach statistical significance. The mean value of all components was >1 in patients with ALS except for ‘use of sleeping medication’ (table 1). Similar results were also obtained when we excluded the population of patients with ALS receiving nocturnal ventilation (data not shown).
Twenty-five patients reported that sleep quality was not modified by disease onset, whereas in 42%, sleep complaints appeared after disease onset. In the remaining patients, sleep quality worsened after disease onset.
Global PSQI score correlated with ALSFRS-R score (ρ=−0.47, p<0.001), ESS score (ρ=0.38, p<0.001) and BDI score (ρ=0.36, p<0.001). Also, ‘subjective sleep quality’ was related to ALSFRS-R score (ρ=−0.46, p<0.001), ESS score (ρ=0.30, p=0.003) and depression (ρ=0.35, p<0.001). ‘Sleep latency’ correlated with ALSFRS-R score (ρ=−0.39, p<0.001), FVC (ρ=−0.37, p<0.001), BDI score (ρ=0.29, p=0.004) and use of nocturnal ventilation (ρ=0.28, p=0.005). ‘Sleep duration’ was related to ALSFRS-R score (ρ=−0.30, p=0.002) and age (ρ=0.29, p=0.004). ‘Habitual sleep efficiency’ decreased with the worsening of patients' disability (ρ=−0.41, p<0.001), daytime somnolence (ρ=0.30, p=0.003), depression (ρ=0.32, p=0.001) and increasing age (ρ=0.31, p=0.002). ‘Sleep disturbances’ correlated with ALSFRS-R score (ρ=−0.30, p=0.003), ESS score (ρ=0.31, p=0.002) and use of nocturnal ventilation (ρ=0.36, p<0.001). ‘Daytime dysfunction’ was related to ESS score (ρ=0.51, p<0.001). No significant correlations were found between ‘use of sleeping medication’ and any of the clinical or demographic variables investigated.
The most common sleep problems reported by patients with ALS were: nocturia (54%), difficulties staying asleep (48%), nocturnal cramps (45%), snoring (33%) and difficulties falling asleep (32%) (table 2). A diagnosis of RLS was made in 22 patients (22%). Twenty-three patients (23%) reported EDS, and 52 (52%) patients complained of difficulties turning in bed.
Table 3 shows the clinical and demographic characteristics of patients with ALS with and without sleep complaints (global PSQI score >5). Poor sleepers were significantly more disabled than good sleepers (p<0.001), reported more depressive symptoms (p=0.003) and showed an increased ESS score (p=0.002). In the multivariate analysis—including age, sex, duration of ALS symptoms, bulbar involvement, severity of depressive symptoms, ESS score, FVC, use of nocturnal ventilation and altered NPO as confounding factors—patients' disability (OR 0.91, 95% CI 0.86 to 0.96, p=0.001) and daytime somnolence (OR 1.31, 95% CI 1.08 to 1.58, p=0.005) were the only variables significantly associated with poor sleep quality.
Among the reported night-time disturbances, patients with poor sleep suffered more frequently from difficulties falling (p<0.001) and staying asleep (p<0.001), and difficulties turning in bed (p=0.003) compared with good sleepers. There was also a tendency for increased frequency of RLS, nocturia, unrefreshing sleep and use of sleeping medications.
Overnight polysomnography was performed in 12 patients with ALS. Clinical and demographic data, and results of sleep recordings of these patients are provided in table 4. Polysomnograms revealed increased sleep latency, reduced slow-wave sleep, as well as reduced and fractured REM stages, frequent PLMS and arousal reactions, and reduced sleep efficiency. The obstructive apnoea/hypopnoea index (AHI) was slightly increased.
In this observational study, we specifically investigated the night-time problems in a large unselected ALS population. Overall, patients with ALS reported significantly more sleep disturbances than control subjects, particularly nocturia and muscle cramps, increased sleep latency and reduced sleep efficiency. Moreover, poor sleepers were significantly more disabled and reported a higher depression and increased sleepiness than good sleepers. Finally, polysomnographic studies in a subset of 12 patients showed decreased sleep efficiency and fragmented sleep architecture, increased PLMS index and AHI.
Sleep disturbances in patients with ALS, although underdiagnosed and undertreated, can result from several factors such as physiological trauma of receiving the diagnosis, reduced mobility with difficulties in turning and changing position, muscle cramps and pain, and myoclonic activity.3 Moreover, patients with ALS can present sleep disturbances secondary to sleep-disordered breathing (which are prevalent during REM sleep) because of bulbar, diaphragmatic and intercostal muscle weakness.2
In this study, almost two-thirds of patients with ALS (59%) reported sleep complaints, and one-third of patients rated their overall night-time problem as moderate or severe. All three types of insomnia symptoms resulted associated with ALS: sleep initiation, sleep maintenance (sleep fragmentation and early morning awakenings) and unrefreshing sleep. Sleep-maintenance insomnia appears to be the major problem of sleep disturbances in ALS, being reported by nearly half of the patients. Moreover, sleep-onset insomnia (difficulty falling asleep) and unrefreshing sleep were reported by one-third of the patients.
The causes of insomnia in patients with ALS are surely multifactorial, and a combination of predisposing, precipitating and perpetuating factors could play a role.14 The degenerative process itself, depression and ageing process are certainly leading causes. However, considering the results of our study, there are also many conditions that could contribute to the induction and maintenance of insomnia symptoms. Indeed, nocturia and difficulties turning in bed can cause early morning awakening, disturb sleep and increase sleep fragmentation. Muscle cramps and RLS symptoms may cause difficulty in initiating and maintaining sleep, and sleep-related breathing disturbances can fragment sleep architecture and cause daytime somnolence. The overall implication is that sleep in patients with ALS can be disrupted by a vast range of nocturnal disabilities.
Interestingly, although there was a moderate correlation with difficulties in sleep initiation and with disturbed sleep, FVC, nocturnal ventilation and altered NPO were not associated with poor sleep quality, thus confirming our previous impression that sleep complaints in patients with ALS do not depend solely on respiratory dysfunction.4 However, our findings could also be partially explained by the relatively low percentage of patients with significant respiratory impairment and by the prevailing effect of physical dysfunction and daytime sleepiness over the other variables examined. Moreover, in a proportion of patients, assisted respiration could have reversed the deleterious consequences of sleep-disordered breathing on sleep architecture, thus alleviating sleep-related complaints.15 16 Finally, it has been shown that FVC could be an insensitive index of sleep problems.17
Longitudinal studies assessing the effects of evolving disease progression and comparative studies between patients with and without respiratory involvement could be of help in clarifying this aspect.
Another finding of the present study is that physical impairment, as assessed by the ALSFRS-R, was independently associated with poor sleep quality. This result is not surprising and similar findings have already been reported in other neurodegenerative diseases, such as Parkinson's disease, in which a direct relationship between severity of disease and quality of sleep has been shown.18 19 Furthermore, increasing disability leads to respiratory impairment, depression, reduced mobility and difficulties in turning in bed that in turn can cause disturbed sleep.
Similarly to previous studies,20–22 our polysomnographic findings in a subset of 12 patients confirmed the presence of reduced sleep efficiency, fragmented sleep architecture, frequent PLMS and arousals, and increased obstructive AHI, underlying the importance of sleep assessments in selected cases. Nocturnal sleep studies should then be considered not only to discover sleep-disordered breathing, but also to unveil potential therapeutic information and strategies that, if unrecognised, would lead to continuing morbidity.
Finally, despite the high frequency of sleep complaints in our ALS population, the use of sleeping medications was low and comparable with that of control participants. This could be explained by the low rate of patients spontaneously reporting night-time problems, but might also reflect a cautious approach from physicians, concerned about possible negative effects of hypnotics on respiratory function. In our opinion, as in the general population, insomnia and sleep complaints in patients with ALS should be treated in a multifaceted approach. The clinician, then, should target any comorbid cause of sleep disruption while working on lifestyle changes, such as proper sleep hygiene, and pharmacological intervention should be introduced if needed. In this regard, benzodiazepines with a medium duration of action, or the newer hypnotics, such as zolpidem or zopiclone, could be used,3 although additional caution should be used in patients with substantial respiratory muscle weakness not receiving ventilatory support.
In conclusion, this observational study showed significant poor quality of sleep in patients with ALS, and this correlated with the severity of disease and daytime somnolence. Increased awareness of sleep–wake problems in patients with ALS is important, as effective intervention could lead to a better management of these patients.
Competing interests None.
Ethics approval Ethics approval was provided by the institutional review board of the University of Palermo.
Provenance and peer review Not commissioned; externally peer reviewed.
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