Sleep pattern changes in older adults include the advance of sleep timing to earlier hours and a higher number of awakenings.Reference Li, Vitiello and Gooneratne1 Also, such age-related changes are also positively associated with sleep complaints.Reference Duffy, Scheuermaier and Loughlin2 In myotonic dystrophy type 1 (DM1), a pleiotropic autosomal dominant disorder caused by the expansion of a CTG repeat in the DMPK gene, discrepancies in the quality of nocturnal sleep have been documented, with self-reports of either sleep disruption or deep, restorative sleep.Reference Laberge, Dauvilliers, Thorpy and Billiard3 A previous study has revealed that DM1 patients are more likely than control subjects to report difficulty falling asleep, nonrestorative sleep, and sleep inertia upon morning awakenings.Reference Laberge, Bégin, Montplaisir and Mathieu4 DM1 patients were also described as long, quiet sleepers.Reference van der Meché, Bogaard, van der Sluys, Schimsheimer, Ververs and Busch5
Since reduced sleep quality or quantity can exact a heavy toll on social participation and quality of life, and poor sleep results in increased risk of significant morbidity and mortality, it is relevant to characterize the progression of sleep complaints in this slowly progressive neuromuscular disease. The objective of the present study was to characterize the evolution of sleep complaints in a large sample of patients affected by DM1.
A longitudinal design was used to collect data in 200 DM1 patients at Time 1 (T1) [79 males; mean age (SD) = 43.6 years (10.3)] and, 9 years later, in 115 of these patients at Time 2 (T2) [43 males; mean age (SD) = 52.3 years (10.3)]. Patients aged 18 years and older with either the classic or mild phenotype were recruited through the Saguenay Neuromuscular Clinic registry (Québec, Canada). The mean (SD) CTG repeat number was 809.2 (529.4). More details on the study protocol can be found elsewhere.Reference Laberge, Gallais, Auclair, Dauvilliers, Mathieu and Gagnon6 The IRB of the Chicoutimi hospital approved the study protocol and written informed consent was obtained from all participants.
A modified version of the Sleep Questionnaire and Assessment of Wakefulness (SQAW) was used.Reference Laberge, Bégin, Montplaisir and Mathieu4,Reference Miles and Guilleminault7 Patients had to indicate whether each question “always,” “often,” “sometimes,” or “never” applied. All answers were dichotomized by the pairing of choices “never/sometimes” (scored 0) and “often/always” (scored 1). Patients were also asked two open-ended questions pertaining to their habitual sleep/wake schedule (What time do you usually go to bed? What time do you usually get up?). McNemar tests and repeated measures t-tests were used to determine if there are differences between T1 and T2. Cohen’s h was used to calculate effect sizes for proportions. Analyses were carried out using SPSS for Windows (version 25.0).
Table 1 shows that the proportion of DM1 patients who reported getting one or more daytime naps (22.1 vs. 34.5, p < 0.05), waking up too early in the morning and not being able to go back to sleep (11.4 vs 21.1, p < 0.05), using caffeine or stimulants to remain alert (7.0 vs. 19.3, p < 0.01), choking or stopping breathing while sleeping (10.7 vs 23.2, p < 0.01), and getting up at night to urinate (42.5 vs 54.9, p < 0.05) increased between T1 and T2. Conversely, the proportion of DM1 patients reporting having a very restorative sleep decreased at T2 vs T1 (60.5 vs 48.2, p < 0.05). Cohen’s h revealed medium to large differences between these latter T1 and T2 proportions (0.63 < h < 0.73).
Table 1: Proportion of myotonic dystrophy (DM1) patients with sleep complaints at Time 1 (T1) and Time 2 (T2)
A bold p-value indicates a statistically significant difference at an alpha level below 0.05.
Moreover, the proportion of DM1 patients reporting symptoms of narcolepsy and restless legs syndrome did not vary over the 9 years. More particularly, cataplexy (6.1 vs 6.1, n.s.), hypnagogic hallucinations (2.6 vs 2.6, n.s), sleep paralysis (0.9 vs. 0.9, n.s.), feelings of weariness or pain in the legs upon morning awakenings (14.9 vs 16.7, n.s.), and legs restlessness at bedtime (11.4 vs 11.4, n.s.) did not vary between T1 and T2 (data not shown).
Lastly, DM1 patients reported a mean earlier bedtime at T2 than at T1 (23:53 vs 23:19, p < 0.001) as well as a mean earlier wake time (9:06 vs 8:36, p < 0.01) at T2 than at T1 (data not shown).
Evidence suggest an age-related weakening of the homeostatic and circadian sleep mechanisms, affecting nighttime sleep consolidation and daytime sleep propensity.Reference Salo, Vahtera and Ferrie8 In this respect, several of the well-acknowledged age-related modifications in sleep could be observed in DM1 patients during the 9-year follow-up period, including advanced sleep timing, higher occurrence of early morning awakenings, less restful sleep, and increased frequency of daytime naps.Reference Li, Vitiello and Gooneratne1,Reference Vitiello9 As older adults commonly experience an advance of sleep schedule to earlier hours, likely due to an age-related phase advance in their circadian rhythm,Reference Li, Vitiello and Gooneratne1 DM1 patients went to bed and woke up approximately 30 minutes earlier at T2 than at T1. As a corollary, their total time in bed does not differ between these two points of time (9.2 vs. 9.3 hours, n.s.).Reference Laberge, Gallais, Auclair, Dauvilliers, Mathieu and Gagnon6 Advancing into the fifth decade of older age is habitually characterized by a shorter sleep duration, but that may not apply to this patient population in whom a strong tendency to oversleep was early noted.Reference Phemister and Small10 Indeed, a longer than habitual nocturnal sleep duration was reported in DM1 patients as compared to controls.Reference Laberge, Dauvilliers, Thorpy and Billiard3 Also, older adults may be more prone than young adults to wake up close to their core body temperature nadir, which may result in earlier awakenings.Reference Li, Vitiello and Gooneratne1 Even though DM1 patients report rather long sleep durations, their inability to fall back asleep after waking up too early could impinge upon their capacity to get needed sleep with age. In view of the above-mentioned age-related increase in daytime sleep propensity, it is unsurprising that a growing proportion of DM1 patients use caffeine/stimulants to stay alert. It should also be borne in mind that daytime sleepiness levels were found to augment between T1 and T2 in this patient sample.Reference Laberge, Gallais, Auclair, Dauvilliers, Mathieu and Gagnon6 While most authors are of the opinion that DM1-related excessive daytime sleepiness (EDS) can largely be ascribed to a primary central sleep regulation dysfunction, this does not dispel the notion that aging itself is associated with an increase in daytime sleep propensity in this patient population.
The prevalence of other common sleep issues found in older adults, such as nighttime urination and pauses in breathing during sleep, also increased significantly over 9 years in DM1 patients. Regardless of the cause, nighttime urination, or nocturia, can reduce sleep duration and consolidation, leading to impaired alertness during the day.Reference Duffy, Scheuermaier and Loughlin2 In the same vein, it has been observed in adults with DM1 that respiratory muscle weakness may cause obstructive sleep apnea, central sleep apnea, as well as nocturnal hypoventilation, which may ultimately increase daytime sleepiness levels. It is noteworthy, however, that the development of sleep-disordered breathing (SDB) abnormalities in DM1 is not solely caused by muscle weakness; there are also changes in the central nervous system control of respiration that contribute to abnormal breathing in patients with DM1.Reference Serisier, Mastaglia and Gibson11
In addition, a parallel can be drawn between the greater proclivity of DM1 patients for daily napping 9 years after the baseline and the age-related decline in daily and social activities also documented in this patient sample.Reference Raymond, Levasseur, Mathieu and Gagnon12 Older adults may have more opportunities to nap than younger adults owing to both biological changes and lifestyle changes that accompany aging, namely less time spent on work and social activities.Reference Li, Vitiello and Gooneratne1 Furthermore, other significant life changes, such as loss of independence and social isolation, can namely increase stress and anxiety, which can also contribute to sleep issues. Conversely, it should be noted that sleep loss may act as a cause of social isolation.
Considering that aging is associated with less robust circadian rhythms,Reference Li, Vitiello and Gooneratne1 it could also be relevant to quantify daily rhythmic behavior with instruments such as the social rhythm metric (SRM) and use actigraphy to characterize circadian sleep-wake cycles so to clarify the relationship between social participation and sleep-wake rhythm disturbances in DM1 patients. Besides, age-related changes in neuroendocrine functions contribute to alterations of sleep quality in normal aging.Reference Li, Vitiello and Gooneratne1 It is well acknowledged that endocrine dysfunction increases over time in DM1 patients. More particularly, previous results in this patient cohort showed that patients with a history of hypothyroidism exhibit at T2 a daytime sleepiness score 26% higher than that of patients without this health condition at T1.Reference Laberge, Gallais, Auclair, Dauvilliers, Mathieu and Gagnon6 However, no study has yet investigated the relationship between sleep disturbances and hormone levels in DM1.
A polysomnographic (PSG) study has shown that patients with DM1 have more sleep apneas, abnormalities in rapid-eye movement (REM) sleep regulation, and periodic leg movements during sleep (PLMS) than sex- and age-matched normal controls.Reference Yu, Laberge and Jaussent13 Even though there are inevitably differences among studies in terms of study design, age ranges, and ascertainment methods, comparison of the present results with that of other prospective, longitudinal cohort studies investigating sleep complaints in large cohorts of adultsReference Santos-Silva, Bittencourt and Pires14–Reference Titova, Lindberg, Elmståhl, Lind and Benedict15 suggests that difficulties initiating or maintaining sleep, early morning awakening, non refreshing sleep, and disturbed sleep are more frequent in DM1 patients. Besides, our cross-sectional study using the SQAW in healthy control subjects and DM1 patients lends credence to this opinion.Reference Laberge, Bégin, Montplaisir and Mathieu4
One important drawback of this study is the absence of a control group. Future studies must confirm that the effect of ageing and time is comparable in healthy controls and DM1 patients using the same measurement instruments. Other study limitations include the risk of recall bias associated with any self-reported data and the fact that sleep was not assessed by objective means (i.e., actigraphy, polysomnography or vigilance test).
The present results indicate that sleep-related complaints augmented substantially over 9 years in a relatively young cohort of DM1 patients (the mean age increasing from about 43 to 52 years during the follow-up period). One may reasonably assume that these sleep disturbances (and their augmentation) are greater than what would have been observed in a control group of the same age. Also, one must note that DM1 has been described as a progeroid disease in virtue of its many signs of accelerated aging.Reference Meinke, Hintze, Limmer and Schoser16 In this regard, there is a distinct possibility that the age-related sleep changes reported herein may reflect an accelerated aging process. It is still important, however, to point out that this progressive neuromuscular condition remains largely unknown by practicians, and even more so its prominent sleep-wake disorders. Physicians need to better identify and treat sleep problems in DM1, including using psychostimulants, validated daytime sleepiness rating scales, PSG, nocturnal oximetry, and early detection of respiratory failure, to help alleviate the burden they impose on patients and their caregivers. Future studies must investigate why sleep problems worsen over time in this patient population.
Acknowledgments
We would like to thank all participants. The study was funded by the Canadian Institutes of Health Research (CIHR; Grant nos. MOP-49556 and JNM-108412) and Muscular Dystrophy Canada.
Statement of Authorship
J.M. and C.G. have initiated and supervised the longitudinal study; L.L., A.M., and C.G. have written the paper; L.L. and C.G. have participated in the data collection; A.M. and J.A. have performed the statistical analysis. All authors approved the manuscript.
Disclosures
LL has acted as consultant for Harmony Biosciences and CG has acted as consultant for Biogen and Ionis. All other authors declare no conflicts of interest.
