Background In myotonic dystrophy type 1 (DM1), sleep disorders are common, with excessive daytime sleepiness (EDS) as a predominant feature. In myotonic dystrophy type 2 (DM2), the presence of sleep disturbances is unknown.
Objective To investigate the frequency of EDS, poor sleep quality and fatigue in DM2.
Methods 29 genetically proven DM2 patients were surveyed using the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI) and Checklist Individual Strength. The results were compared with 29 adult onset DM1 patients and 65 population controls, both matched for age and sex.
Results Only 6.9% of DM2 patients had EDS compared with 44.8% of DM1 patients and 6.2% of population controls (DM2–DM1: p=0.001; DM2–controls: p=0.51). Sleep quality was poor (PSQI >5) in both DM2 and DM1 groups, and differed significantly from population controls (DM2 6.5±3.0; DM1 6.2±3.7; controls 4.3±3.0; DM2–controls: p=0.002). Poor sleep quality was not explained by depression or other comorbidity but was mainly due to sleep disturbances as a result of nocturnal pain. Comparable with the DM1 group, DM2 patients experienced severe fatigue (DM2 38.7±13.1; DM1 42.9±8.5; controls 21.1±11.1; DM2–controls: p<0.001). Results were not confounded by abnormal thyroid function or medication use.
Conclusion These results provide new insight into the phenotype of DM2 and have consequences for clinical treatment. In addition, the absence of EDS in DM2 is a new discriminative feature with adult onset DM1.
- Myotonic dystrophy
- sleep disorders
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
The myotonic dystrophies (DM) are dominantly inherited multisystem diseases, with muscle weakness and myotonia as the main neuromuscular symptoms. Other organs are prominently involved, with frequent early onset cataracts, cardiac conduction abnormalities, gastrointestinal symptoms, endocrine changes and central nervous system symptoms.1–3 Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, with a prevalence of 5–12 per 100 000.1 4 The phenotype and genetics of myotonic dystrophy type 2 (DM2) have been described only recently, and its prevalence has not yet been established.5 6 The molecular basis of both DM1 and DM2 is a repeat instability in a non-coding part of a gene: a CTG trinucleotide repeat in the DMPK gene on chromosome 19 (DM1) and a CCTG tetranucleotide repeat in the ZNF9 gene on chromosome 3 (DM2).6 7 The resulting disruption of mRNA metabolism alters nuclear functions, including the splicing machinery. This leads to abnormal transcripts in many other genes, explaining the multisystemic nature of the diseases.7
Interestingly, repeat instability in two unrelated genes causes comparable clinical phenotypes. In fact, DM2 was not recognised as a separate disorder until 1994.5 8 However, some recent studies suggest important differences in the clinical symptomatology of DM1 and DM2. For example, the severe congenital form encountered in DM1 is absent in DM2, and there is no confirmed evidence of anticipation in DM2.
Sleep disorders are very common in DM1 and are in fact considered a core feature. Of these, excessive daytime sleepiness (EDS) is a predominant symptom.1 9–11 EDS in DM1 can be severe and has been described as resembling the sleepiness of primary hypersomnias such as narcolepsy. Besides daytime sleepiness, severe fatigue is present in up to 74% of adult onset DM1 patients.12
In contrast with DM1, virtually nothing is known about sleep and fatigue in DM2. Some authors have suggested a comparable presence of daytime sleepiness in DM213 14 but systematic studies are lacking. We therefore performed a nationwide study into EDS, sleep quality and fatigue in a cohort of DM2 patients, and compared these symptoms with both a matched group of adult onset DM1 patients and with population controls.
All known patients Dutch with DM2 (n=32) were approached to participate in the study. DM2 patients, and sex and age matched DM1 patients were retrieved from CRAMP, the Dutch neuromuscular database.15 In addition, 65 sex and age matched population controls were surveyed. All DM patients were older than 18 years of age, were ambulatory and had a genetically confirmed diagnosis. Exclusion criteria were use of central nervous system stimulant medication or assisted ventilation such as nocturnal continuous positive airway pressure. The presence of a neuromuscular disorder was the only exclusion criterion for the population controls. All subjects gave written informed consent to participate, and the study was approved by the local ethics committee.
Nocturnal sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI).16 The PSQI is a self-rated questionnaire that measures seven components of sleep over a 1 month time interval: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication and daytime dysfunction. Each component score has a range of 0–3 points. In all cases, a score of ‘0’ indicates no difficulty while a score of ‘3’ indicates severe difficulty. The sum of the seven component scores is expressed as a global score, with a range of 0–21 points. The normal threshold is 5; higher scores indicate poorer sleep quality.16
Excessive daytime sleepiness
Daytime sleepiness was measured with the Epworth Sleepiness Scale (ESS).17 The ESS measures the tendency to fall asleep during eight different situations that are commonly encountered in daily life, yielding a score range of 0–24. The upper limit of normal is 10, and ESS scores above 10 are generally taken to reflect abnormal daytime sleepiness.
The presence of fatigue was assessed using the subscale ‘fatigue severity’ of the Checklist Individual Strength (CIS).18 The CIS measures the experience of fatigue associated problems during the previous 2 weeks. The CIS fatigue severity subscale contains eight items scored on a 7 point Likert scale. Scores can range between 8 and 56; higher scores indicate higher levels of fatigue and scores of 35 or more are considered to indicate severe fatigue.18
Comorbidity and medication use
All participants completed a standardised questionnaire regarding medication use. When available, thyroid function data were retrieved from the patients' medical files. Symptoms of depression were scored using the Beck Depression Inventory for primary care (BDI-pc). This shortened version of the BDI has seven items and includes cognitive and affective symptoms.19 Somatic symptoms of depression have been removed to avoid overlap when used for patients with, for example, neuromuscular disorders. A score of 4 or more is indicative of clinical depression.
Numerical variables are shown as mean±SD (range). Categorical data are shown as a number (percentage of total). One way ANOVAs were used to compare the three study populations. Differences between DM2 and DM1 patients and between DM2 patients and population controls were then tested using t test or χ2 test. Correlations were calculated with the Pearson coefficient. A p values <0.05 was considered to be significant.
Of the 32 DM2 patients that were approached, 29 (91%) responded and completed the questionnaires at home. DM2 patients originated from 12 unrelated families. A total of 34 matched DM1 patients were selected from the CRAMP database, five of whom were excluded because of the use of modafinil (n=4) or nocturnal continuous positive airway pressure (n=1). The demographic characteristics of both patients groups and the population controls are listed in table 1.
The groups were well matched for age, sex and body mass index. Age at onset was identical for the DM groups. There were no differences between the three groups regarding use of β blockers or sleeping medication. One quarter of DM2 patients used pain medication, as did 14% of DM1 patients and 5% of population controls (DM2 vs controls, p=0.005; DM2 vs DM1, p=0.32). Thyroid function data were available for 28 DM2 patients and 14 DM1 patients; none suffered from thyroid dysfunction. Depression scores were higher in both DM groups compared with controls (BDI-pc score: DM2 2.2±2.7; DM1 2.3±3.1; controls 0.9±1.7; DM2 vs DM1 p=0.86; DM2 vs controls p=0.006).
Both DM2 and DM1 patients had significantly higher PSQI global scores than population controls, indicating a decrease in sleep quality (table 2, figure 1). Sixty-six per cent of the DM2 group showed a poor sleep quality (PSQI >5) compared with 45% in the DM1 group and 26% in controls. (DM2 vs controls p<0.001; DM2 vs DM1 p=0.11).
DM2 patients showed the worst scores on the PSQI component subjective sleep quality, which differed significantly from population controls (see table 3 for PSQI component scores). In addition, DM2 patients differed significantly from both DM1 patients and population controls regarding the PSQI component score sleep disturbances (table 3). Pain was the most commonly reported cause for sleep disturbances in the DM2 group. Sixty-nine per cent of DM2 patients reported pain as the cause of having had trouble sleeping during the past month, compared with 34% of DM1 patients and 17% of controls (DM2 vs DM1, p=0.009; DM2 vs controls, p<0.001). The PSQI component score daytime dysfunction was significantly higher in both DM2 and DM1 patients compared with population controls. The component scores on sleep duration, sleep efficiency and the use of sleeping medication did not differ significantly between the three groups (table 3).
Sleep latency in the DM2 group (28.5±26.1 min, range 2–120) was comparable with sleep latency in the DM1 group (25.1±26.4 min, range 2–120, p=0.63), and both were significantly longer than in population controls (15.2±12.6, range 3–60; p=0.001). Fifty-two per cent of DM2 patients reported falling asleep within 30 min compared with 59% in the DM1 group and 83% in the population control group. Total sleep duration was not different in the three groups.
PSQI scores were not correlated with age, age at onset or disease duration. Furthermore, there was no association between depression or fatigue scores and PSQI total score in DM2 patients (DM2: r=0.29, p=0.13; r=0.35, p=0.06, respectively). In DM1 patients and controls, small but significant associations were found between the BDI-pc and PSQI (DM1: r=0.53, p=0.003; controls: r=0.29, p=0.02).
Excessive daytime sleepiness
Patients with DM2 did not have elevated ESS scores compared with population controls, and the percentage of DM2 patients with EDS was also in the control range (table 2). One DM2 patient had an ESS score just above the cut-off (11) and another reported severe EDS, with an ESS score of 20. This latter patient also had poor nocturnal sleep quality (PSQI 11), severe fatigue (CIS fatigue 56) and symptoms of depression (BDI-pc 5). As expected, DM1 patients showed a significantly higher ESS score than population controls. Forty-five per cent of DM1 patients showed significant EDS (ESS>10) compared with 6% of population controls (table 2, figure 1). Significant associations were found between depression scores and EDS in DM2 and controls (DM2: r=0.42, p=0.03; DM1: r=0.33, p=0.08; controls: r=0.42, p=0.001). ESS scores were not correlated with age, age at onset or disease duration.
DM2 patients experienced high levels of fatigue, with 66% reporting severe fatigue (table 2, figure 1). This was also the case for DM1 patients with over 85% reporting severe fatigue (DM2 vs DM1: p=0.066). Both DM groups had significantly higher CIS fatigue scores than population controls (table 2, figure 1). As with daytime sleepiness, fatigue correlated with depression scores on the BDI-pc in DM2 and controls (DM2: r=0.47, p=0.01; DM1: r=0.21, p=0.27; controls: r=0.52, p<0.001). Other demographic variables were not associated with fatigue, except worsening of fatigue with age in DM1 (r=0.57, p=0.001).
We estimated the prevalence of poor sleep quality, daytime sleepiness and fatigue in patients with DM2, and compared these with adult onset DM1 patients and population controls. DM2 patients showed significantly worse sleep quality than population controls. High levels of fatigue were equally present in both types of DM. In striking contrast with DM1—in which EDS is a predominant feature—we found that daytime sleepiness was not part of the clinical picture of DM2.
DM2 and DM1 patients reported longer nocturnal sleep latencies than population controls. For DM1, this has been reported previously. Laberge et al found that only 47% of DM1 patients fell asleep within 30 min compared with 76% of healthy controls20 although recent polysomnographic data by this research group revealed a mean sleep latency of about 15 min in 43 DM1 patients.21 The reason for the sleep onset insomnia in DM2 is unknown, and no polysomnographic data for DM2 patients exist at the moment. It is likely that nocturnal myalgic pain is one of the influencing factors. Nocturnal sleep disturbances occurred significantly more often in DM2 than in DM1 or controls, and nocturnal pain was reported to be the most common cause. The prevalence of nocturnal awakenings because of pain was twice as high in DM2 compared with DM1. This high prevalence occurred despite the fact that almost 25% of DM2 patients received pain medication at the time of study, and 10% used hypnotics. Previous studies reported musculoskeletal pain to be a frequent symptom of DM2, and in one-third of patients pain was even the most disabling symptom.22 The major pain type associated with DM2 is exercise induced, with relief at rest. However, besides episodic pain, pain does persist for more than 6 months in many patients, indicating chronic pain.22 This is compatible with our finding of significant and sleep disturbing nocturnal pain.
The mean ESS scores in patients with DM2 were identical to the population controls and comparable with previously reported normal values.17 Furthermore, the prevalence of EDS (ESS >10) in DM2 patients was equal to that in population controls. We confirmed the high prevalence of EDS in patients with DM1.21 23 24 We excluded DM1 patients who were using psychostimulants for sleepiness, perhaps selecting patients with a relatively mild sleepiness. Therefore, the difference in the prevalence of sleepiness in DM2 and DM1 may even be underestimated in our study. The reason for this difference remains unclear. It may be an indication of relatively minor involvement of the central nervous system in DM2, as has been suggested previously.3 Further study into the differential molecular pathophysiology of both disorders may also yield new insights into the pathogenesis of hypersomnia. It is unclear why the DM1 patients with EDS were not taking psychostimulants. As there was no obvious contraindication to the use of psychostimulants in the DM1 patient group, this may have reflected differences in clinical practice by the treating physician or patient decision.
The low prevalence of EDS, despite high levels of fatigue, underscores the fact that these are clearly different symptoms.24 DM2 patients demonstrated high levels of fatigue, comparable with DM1. The proportion of DM2 patients with severe fatigue (66%) was also similar to values reported for other neuromuscular disorders, such as facioscapulohumeral dystrophy (61%) or hereditary motor and sensory neuropathy type 1 (64%).12 Fatigue was not explained by medication use such as β blockers or abnormal thyroid function.
Depression scores in both DM2 and DM1 were higher than in population controls. This has been repeatedly reported by others in DM1.23 25 26 However, most of these studies were before the advent of DNA based diagnosis and probably included a number of DM2 patients. Meola et al investigated both DM1 and DM2 patients and did not find a higher frequency of clinical depression in either.14 This difference may in part be explained by the smaller number of patients in their study and differences in study methodology (self-report versus structured interview). In the DM2 group as well as in the controls, there were correlations between depression, sleepiness and fatigue scores. This is likely to reflect the fact that small increases in the ESS may not be specific for hypersomnia. The much higher ESS scores in DM1 patients point to more severe hypersomnia related to central nervous system dysfunction, which may occur independently of depression or fatigue. Depression was associated with sleepiness and fatigue scores in the DM2 group, and should be included in the differential diagnosis when DM2 patients experience hypersomnia.
We approached all known Dutch DM2 patients from 12 families. The nationwide study combined with the high response rate of 91% makes the presence of selection bias in the DM2 group unlikely. Other strengths of this study are the DNA based diagnosis of DM2 and DM1, the use of validated questionnaires and consideration of comorbid depression and thyroid dysfunction. However, we were not informed about the range of CCTG and CTG expansion on chromosomes 3 and 21. Laberge et al found that DM1 patients with fatigue or EDS and fatigue had significantly longer CTG repeats than those with neither of these symptoms.10 In DM2 however, phenotypical influence of the size of the CCTG expansion—which is in part due to the somatic instability of the repeat—has not yet been established.27
In conclusion, the absence of EDS in DM2 is another clinical feature that differentiates DM2 from DM1, in addition to absence of a severe congenital form and genetic anticipation. We have shown a decrease in the quality of sleep in patients with DM2. This poor sleep quality was not explained by depression or other comorbidity but was mainly due to increased sleep latency and sleep disturbances. Nocturnal awakenings due to pain were the most common symptom mentioned. Fatigue is another commonly experienced symptom in DM2, and is not correlated with the use of β blockers, thyroid dysfunction or poor sleep quality.
Future studies should assess the nature of the nocturnal sleep disruption in DM2 by polysomnographic assessment—for example, to delineate the possible role of sleep related breathing disorders. Multiple sleep latency testing in DM2 patients would be less likely to demonstrate abnormalities in the absence of subjective daytime sleepiness on the ESS but may still be of value to perform as a more objective assessment. Future studies aiming to improve nocturnal sleep quality in DM2 may also assess the consequences on potential daytime sequalae such as depression, fatigue or health related quality of life.
Our findings may have important clinical consequences. In view of the negative impact of sleep disruption on the quality of life of DM2 patients, we would support a low threshold for screening for sleep disturbances—especially related to nocturnal myalgia—and for performing sleep studies. In view of the findings in the current study, pain management throughout the day and night may improve sleep and quality of life in DM2 patients.
We wish to thank the patients and controls for participating in this study and Dr G Borm for statistical assistance.
Competing interests None.
Ethics approval The study was approved by the local ethics committee.
Provenance and peer review Not commissioned; externally peer reviewed.