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Poor Sleep Quality in Patients With Amyotrophic Lateral Sclerosis at the Time of Diagnosis

Diaz-Abad, Montserrat, MD*; Buczyner, Jennifer R., MD; Venza, Brigit R., MD, MS; Scharf, Steven M., MD, PhD*; Kwan, Justin Y., MD§; Lubinski, Brooke, BS; Russell, James W., MD, MS║,**

Journal of Clinical Neuromuscular Disease: December 2018 - Volume 20 - Issue 2 - p 60–68
doi: 10.1097/CND.0000000000000234
Original Article
Open
SDC

Objectives: Patients with amyotrophic lateral sclerosis (ALS) have poor sleep quality, but little is known about which factors affect sleep at time of diagnosis.

Methods: Patients with newly diagnosed ALS were administered the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Beck Depression Inventory–Revised, and ALS Functional Rating Scale and were compared with controls.

Results: Forty-three patients, age 63.8 ± 11.5 years, ALS Functional Rating Scale 30.7 ± 5.0. Poor sleep quality was frequent: 27 (63%) patients had PSQI >5 compared with 16 (37%) controls (P = 0.031); with higher PSQI (7.1 ± 4.1 vs. 4.7 ± 2.8, P = 0.003). PSQI correlated with Beck Depression Inventory–Revised (r = 0.344, P = 0.024) and inability to turn in bed (r = −0.335, P = 0.033).

Conclusions: Patients with newly diagnosed ALS have poor sleep quality, which is associated with depression and difficulty turning in bed. Longitudinal studies to examine the evolution of sleep quality and the effectiveness of individualized interventions are needed in patients with ALS.

*Department of Medicine, University of Maryland, Baltimore, MD;

Comprehensive Neurology of the Palm Beaches, Palm Beach Gardens, FL;

Department of Neurology, Kaiser Permanente, Capitol Hill Medical Center, Washington, DC;

§Department of Neurology, Temple University School of Medicine, Philadelphia, PA;

University of Maryland School of Medicine, Baltimore, MD; and

Departments of Neurology and

**Anatomy and Neurobiology, VA Maryland Health Care Center, University of Maryland, Baltimore, MD.

Reprints: Montserrat Diaz-Abad, MD, Division of Pulmonary and Critical Care Medicine, Sleep Disorders Center, University of Maryland School of Medicine, 100 North Greene St, Room 214, Baltimore, MD 21201 (e-mail: mdiaz@som.umaryland.edu).

Supported in part by Department of Veterans Affairs (Biomedical and Laboratory Research Service and Rehabilitation Research and Development, 101RX001030), Baltimore Geriatric Research, Education, and Clinical Center (GRECC), NIH NIDDK 1R01DK107007-01A1.

The authors report no conflicts of interest.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease frequently leading to paralysis and death generally within 2–5 years of onset. There are no long-term effective therapies for patients with ALS, and the prognosis is poor. Thus, the main focus of ALS management is symptomatic treatment and palliative care.1

Sleep disturbances in patients with ALS have been attributed to a wide variety of factors including nocturnal hypoventilation, obstructive sleep apnea, restless legs syndrome, discomfort from reduced mobility and difficulty positioning in bed; pain, cramps, and depressed mood.2–4 Patients have also been noted to have excessive daytime sleepiness and poor sleep quality with reported improvement after the use of noninvasive ventilation (NIV)5,6 and stimulants such as modafinil.7

Recently, studies have focused on sleep disorders as manifestations of ALS. Although nocturnal hypoventilation and obstructive sleep apnea are particularly common in this population,8 high prevalence of poor sleep quality6,9 and other sleep disorders such as restless leg syndrome10 and periodic limb movements in sleep11 have also been reported. These studies, however, have evaluated patients at various stages of disease, sometimes including patients with advanced ALS who required NIV or enteral nutrition.6,9,11

Because ALS can start in any region of the cranial spinal axis and gradually progresses causing weakness in different muscle groups, symptoms may vary over time. It is unclear whether patients with ALS have a high frequency of poor sleep quality during the earliest phase of the disease, which is often the time of disease diagnosis. The aim of this study was to determine whether poor sleep quality was present in patients with newly diagnosed ALS and whether risk factors associated with poor sleep quality were present. We hypothesized that significant sleep disturbances would be present in patients with ALS at the time of disease diagnosis.

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MATERIALS AND METHODS

The study was performed at the University of Maryland ALS Clinic, a specialized multidisciplinary clinic in the University of Maryland Medical System. The study was approved by the institutional review board, and written informed consent was obtained from all eligible participants.

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Patient Selection

To recruit patients with newly diagnosed ALS, patients were included in the study if they were newly diagnosed with definite or probable ALS according to revised El Escorial criteria12 by a neuromuscular disease specialist. Patients were enrolled at the time of their first visit to the ALS clinic. Patients who transferred care from other centers were excluded. A sex- and age-matched (by decade) control group consisted of individuals with a normal neurological evaluation.

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Procedure

Patients with ALS completed questionnaires during their initial clinic visit (within a 30-minute period) and underwent a full medical evaluation by a neuromuscular disease specialist and a pulmonary/sleep specialist. Data collected included demographics, duration of symptoms before diagnosis, and site of disease onset. Spirometry and respiratory muscle pressure measurements were performed during the visit according to standard techniques.13,14 Forced vital capacity (FVC) and maximal inspiratory pressures (MIPs—measured at residual volume) were reported as percent predicted of normal.15,16 Control subjects completed a demographic questionnaire as well as the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS).

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Questionnaires

  1. PSQI (patients with ALS and controls): This was used to assess global sleep quality during the previous month. The questionnaire consists of 7 components: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, and daytime dysfunction. The frequency of symptoms per week is scored from 0 to 3. The global PSQI score ranges from 0 to 21, and a higher score indicates worse sleep quality. A global PSQI score of >5 indicates poor sleep quality.17
  2. ESS (patients with ALS and controls): This was used to evaluate daytime sleepiness. The ESS is a trait scale and measures the likelihood of falling asleep in 8 different situations of daily life. Each answer is scored on a scale of 0–3. The total ESS score ranges from 0 to 24, and a higher score indicates increasing sleepiness. A score of >9 indicates excessive daytime sleepiness.18
  3. The ALS Functional Rating Scale (ALSFRS) (patients with ALS): This is a disease-specific scale used to assess functional status and disease severity. It assesses the patient's level of functional impairment in performing 1 of 10 common tasks: (1) speech, (2) salivation, (3) swallowing, (4) handwriting, (5) cutting food and handling utensils (with or without gastrostomy), (6) dressing and hygiene, (7) turning in bed and adjusting bed clothes, (8) walking, (9) climbing stairs, and (10) breathing. Each answer is scored on a scale of 0–4, and the total score ranges from 0 to 40. A higher value indicates a higher functional status. Bulbar impairment is quantified using the first 3 questions of the scale.19
  4. Beck Depression Inventory–Revised (BDI II) (patients with ALS): This scale assesses the severity of symptoms of depression, if present. The BDI-II contains 21 questions each scored on a scale of 0–3, and the total score ranges from 0 to 63. Higher total scores indicate more severe symptoms of depression. The severity cutoffs are: 0–13, minimal symptoms; 14–19, mild symptoms; 20–28, moderate symptoms; and 29–63, severe symptoms of depression.20
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Data Analysis

Data were collated and expressed as mean ± SD, n (%) or as median (25%–75% interquartile range) as indicated. Normality was tested using the Kolmogorov–Smirnov test. The Student t test for unpaired variates was used to compare 2 mean values in normally distributed data. The Mann–Whitney rank sum test was used to compare 2 groups of non-normally distributed data. Associations were assessed using linear regression for normally distributed data and Spearman correlation coefficients for categorical data or non-normally distributed data. Differences in frequencies were tested using the Fisher exact test. The null hypothesis was rejected at P < 0.05. Statistical analysis was conducted using SigmaPlot 11.0 (Systat Software Inc, San Jose, CA).

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RESULTS

Patient Characteristics

Forty-three patients with ALS (63.8 ± 11.5 years) and 43 controls (61.3 ± 8.7 years) participated in this study. Symptom duration before diagnosis was 14.9 ± 7.1 months, and 15 patients with ALS (35%) had symptom onset in the bulbar region. Table 1 shows demographics and baseline data. The mean ALSFRS score was 30.7 ± 5.0, FVC was 70 ± 24 percent predicted, and MIP was 39 ± 16 percent predicted. None of the patients were using NIV or had a gastrostomy tube to assist nutrition.

TABLE 1

TABLE 1

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Sleep Quality

Twenty-seven (63%) patients with ALS had a PSQI >5 indicating poor sleep quality compared with 16 (37%) controls having a PSQI >5 (P = 0.031). The mean global PSQI score in patients with ALS was 7.1 ± 4.1, and was significantly higher than the control group PSQI score of 4.7 ± 2.8 (P = 0.003).

Table 2 lists specific symptoms from answers on the PSQI. Among patients with ALS, the median self-reported sleep time was 7 hours, and the median latency to sleep was 15 minutes, with only 6 (14%) patients taking >30 minutes to fall asleep. Sleep maintenance disturbance was frequent, and the most common items that disrupted sleep (defined as present at least 3 times per week) were as follows: (1) bathroom use, (2) waking up in the middle of the night or early morning, and (3) pain. Regarding daytime symptoms, 11 (26%) patients reported difficulty in maintaining their enthusiasm at least 3 times per week. Compared with controls, patients with ALS reported more frequent awakening in the middle of the night or early morning, problems maintaining enthusiasm during the daytime and awakening later in the morning. Patients with ALS also reported impaired habitual sleep efficiency and more daytime dysfunction compared with controls (Table 3).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

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Factors Associated With Poor Sleep Quality

Sleep quality was not associated with age, sex, duration of ALS symptoms, type of ALS at disease onset, daytime sleepiness (ESS), body mass index, ALSFRS, ALSFRS bulbar subscore, FVC, or MIP. There was no difference in PSQI based on the ALSFRS at different severity cutoffs. Sleep quality was correlated with symptoms of depression. There was a positive correlation between the PSQI and BDI II scores, r = 0.344 (P = 0.024) (Fig. 1). The mean BDI II score was 11.3 ± 6.7, with 10 (23%) patients having mild symptoms and 5 (12%) patients having moderate symptoms of depression. The mean BDI II score was 13.7 ± 6.5 in poor sleepers versus 7.8 ± 5.3 in good sleepers (P = 0.004). Although sleep quality was not associated with functional status as assessed by the ALSFRS score, the patient's ability to turn in bed and adjust bed clothes was associated with poor sleep quality, r = −0.335 (P = 0.033). Ten (23%) patients were unable to or experienced great difficulty performing this task. These patients had a mean PSQI of 9.7 ± 4.9 compared with patients who performed the task normally or slowly and clumsily but without help (score 3–4) who had a mean PSQI score 6.6 ± 3.5 (P = 0.035).

FIGURE 1

FIGURE 1

Patients tended to under-recognize their poor sleep quality. Despite the high global PSQI scores, when asked to rate their sleep quality overall, 37 (86%) patients reported their overall sleep quality as very good or fairly good.

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Excessive Daytime Sleepiness

Despite a high prevalence of poor sleep quality, few patients noted excessive daytime sleepiness on the ESS. Six (14%) patients and 2 (5%) controls had ESS >9 (P = 0.265). Mean ESS in the patients with ALS was 6.6 ± 3.0, which was higher compared with a mean ESS of 5.0 ± 3.1 in controls (P = 0.020). Daytime sleepiness was not associated with sleep quality but was associated with respiratory muscle weakness, with a negative correlation between the ESS and the FVC, r = −0.371 (P = 0.016), and between the ESS and the MIP, r = −0.341 (P = 0.031) (Fig. 2). Among patients with FVC <70% predicted, the mean ESS was 7.7 ± 2.9, which was higher compared to patients with FVC ≥70% predicted, 5.4 ± 2.7 (P = 0.012).

FIGURE 2

FIGURE 2

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DISCUSSION

In our study, we demonstrated poorer sleep quality in patients with ALS at the time of diagnosis compared with controls. In patients with ALS, poor sleep quality was associated with symptoms of depression and limited mobility in bed. Although few patients reported excessive daytime sleepiness, this was associated with respiratory muscle weakness.

Several studies have showed that poor sleep quality is frequent in patients with ALS. In a group of 20 patients with ALS starting NIV, average PSQI was 8, similar to our study.6 Lo Coco et al performed a detailed sleep evaluation in 100 patients with ALS and reported a mean PSQI score of 6.8 ± 4.0, with 59% of patients classified as poor sleepers,9 and poor sleep quality was associated with ALSFRS-R, ESS, and BDI scores. In contrast to our study, these investigators examined patients who had longer disease duration and greater impaired motor function, including patients using NIV and enteral nutrition. The similar poor sleep quality results in both studies and the shorter ALS disease duration (14.9 ± 7.1 months) in our study suggest that self-reported poor sleep quality may be an early symptom in patients with ALS.

Mild to moderate depressive symptoms were reported by one-third of our patients and was the major factor associated with poor sleep quality. Kurt et al21 describe a wide range of reported prevalence of depression in patients with ALS, and a rate of 9–11% with the use of structured interviews. Sleep disturbances such as insomnia or hypersomnia are well-known symptoms of depression, and patients with depression have poorer sleep quality than controls.17 Conversely, increased sleep disturbance such as insomnia or hypersomnia may precede the onset of depression;22 thus, the relationship between mood and sleep is complex and often bidirectional. It is unclear whether depression is the cause of poor sleep quality in patients with ALS.

Most of our patients did not have sleep onset insomnia or abnormal sleep duration. The primary sleep disturbances were impaired sleep maintenance and postural discomfort, which have been previously noted in patients with ALS. Studies have demonstrated that patients with ALS wake multiple times a week, in the middle of the night or morning, and/or have difficulty turning in bed or adjusting bed clothes.9

Of note, daytime sleepiness was not a prominent feature of the disturbed sleep pattern in most patients. When this symptom was present, it was associated with respiratory muscle weakness and was not associated with self-reported sleep quality. In patients with chronic obstructive pulmonary disease, a high frequency of self-reported poor sleep quality was also not associated with excessive daytime sleepiness.23 Similarly, other patients with ALS have been noted to have poor sleep quality without excessive daytime sleepiness.6 Thus, excessive daytime sleepiness is not always a sensitive marker of poor sleep quality.

In the patients with ALS, there was mild to moderate respiratory muscle weakness as estimated by FVC and MIP that correlated with daytime sleepiness. Bulbar dysfunction in patients with ALS can cause upper airway narrowing or closure secondary to weakness of the abductor muscles and add an additional load to the respiratory system. This in turn could result in nocturnal hypoventilation leading to nocturnal arousals/awakenings, sleep fragmentation, and sleep maintenance insomnia. Sleep fragmentation may be responsible for excessive daytime sleepiness. Our findings are similar to those in previous studies that showed a correlation between the ESS score and respiratory muscle strength in patients with ALS.5,24

In our study, patients with ALS tended to underestimate their poor sleep quality. Most patients rated their overall sleep quality as good despite high PSQI scores consistent with poor sleep quality. The cause for this discordant finding is not well understood. One possibility is that patients might be overwhelmed by the prominent loss of motor function and physical disability and might neglect their nocturnal symptoms. Another possibility is that patients with ALS maintain quality of life even with disease progression by adapting their expectations of daily life, and this could extend to sleep time.25 Without a structured sleep assessment, the significant sleep disturbances that are present in these patients may be under recognized.

Our single-center study has several limitations. We examined patients recently diagnosed with ALS, which is not synonymous with symptom onset. Patients with ALS are evaluated in a multidisciplinary ALS clinic after varying disease duration and having disparate symptoms. The delay from the time of symptom onset until diagnosis remains unacceptably long.26 However, evaluating sleep at diagnosis is currently the best available surrogate for understanding sleep disorders early in the course of ALS. Sleep quality and excessive daytime sleepiness measures were based on data from questionnaires and were the only measures compared between patients with ALS and controls. Objective studies of sleep and nocturnal respiration such as polysomnography were not performed at the time of disease diagnosis. Because of the cross-sectional nature of the study, our findings are limited to only one time point. It is possible that sleep quality fluctuates during the course of the disease due to adaptations to motor impairment by the patients, implementation of pharmacological and nonpharmacological interventions, disease progression,27 initiation of NIV therapy,6 and variability of symptoms from month to month such as depression.28 Although we focused on patients with newly diagnosed ALS, it is not uncommon for patients to have varying disease duration and symptomology before their diagnosis.1 To account for some of this variability in our study, we examined relationship between sleep quality and symptom duration and did not find an association. There is also the possibility that some of the sleep symptoms preceded the onset and/or diagnosis of ALS and are unrelated to the disease.

Our findings lead us to believe that poor sleep quality in patients with ALS at the time of diagnosis is likely multifactorial. It is possible that those patients who have impaired respiratory function also have nocturnal hypoventilation and present with more daytime sleepiness. Other contributing factors may include nocturnal postural discomfort, limited mobility, depressive symptoms, or sometimes a combination of several factors. It is important to determine the underlying causes of poor sleep quality in patients with ALS to tailor-specific interventions to each patient.

This study emphasizes the importance of assessing sleep quality and disturbances in patients with ALS. ALS practice parameters recognize insomnia as common in ALS, but no specific recommendations are made for its treatment because of a lack of evidence. However, recently interventions such as NIV therapy have been shown to improve sleep quality6 providing one therapeutic option to improve sleep in at least some patients with ALS and an additional potential indication for the use of NIV. Because there is no effective cure for ALS, the goal is to palliate symptoms.1 Hence, attention to sleep quality should be part of this comprehensive symptom-based care.

In conclusion, patients with newly diagnosed ALS have a high frequency of self-reported poor sleep quality that was associated with symptoms of depression and difficulty turning in bed. Despite significant sleep disturbances, few patients reported excessive daytime sleepiness, which was associated with respiratory muscle weakness. Given the high prevalence of poor sleep in these patients, longitudinal studies to examine the evolution of sleep quality and the effectiveness of individualized interventions are needed in patients with ALS.

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ACKNOWLEDGMENTS

The authors thank the ALS Association and the DC/MD/VA Chapter for the continued support of the University of Maryland ALS Center of Excellence and our patients.

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Keywords:

amyotrophic lateral sclerosis; sleep quality; depression; limited mobility

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