Sleep and Biological Rhythms 2008; 6: 95–101
doi:10.1111/j.1479-8425.2008.00339.x
ORIGINAL ARTICLE
Sleep disturbance in adults with Angelman syndrome Kirstie N ANDERSON,1,2 Samantha PILSWORTH,2 Sarah JAMIESON,2 Julian RAY,3 John M SHNEERSON2 and Graeme G LENNOX3 1
Department of Neurosciences, Newcastle General Hospital, Newcastle upon Tyne, 2Respiratory Support and Sleep Center, Papworth Hospital and 3Department of Neurology, Addenbrookes Hospital, Cambridge, UK
Abstract Angelman syndrome is a neurodevelopmental disorder characterized by severe learning difficulties, epilepsy, and a typical behavioral phenotype. The diagnostic criteria state that 20–80% of individuals have decreased sleep need and abnormal sleep–wake cycles. A wide variety of sleep problems have been reported, including reduced total sleep time, frequent night awakenings and nocturnal enuresis. Most previous reports have used sleep questionnaires to assess the frequency of various sleep disorders. Most patients studied have been children or adolescents and only one previous study has used complex sleep studies (polysomnography). We report three adult sisters with Angelman’s syndrome who have been assessed with sleep diaries, actigraphy and, in one case, overnight polysomnography. Despite sleep diaries showing prolonged sleep with a mean of 9 h a night with few nocturnal arousals, the actigraphy in all three patients showed increased sleep fragmentation and in one the polysomnography was strikingly abnormal, with a greatly reduced total sleep time and very frequent, predominantly obstructive sleep apneas fragmenting night sleep (desaturation index 63.3 of total sleep time). Despite over 10 h in bed, she had only 69.5 min of actual sleep. There was no evidence of a circadian rhythm disorder. This is the first report of polysomnography in an adult with Angelman syndrome and it highlights the need to look for the presence of sleep apnea in this group, which may be an under-recognized cause of nocturnal sleep disturbance. Key words: actigraphy, Angelman syndrome, polysomnography, sleep disordered breathing.
INTRODUCTION Angelman syndrome (AS) is a genetically determined neurodevelopmental disorder caused by deletion or non-functioning of the maternal allele at 15q11-q13. Genetic mechanisms include the deletion of maternal 15q11-q13 (70%), paternal uniparental disomy of chromosome 15 (2–5%), methylation imprinting mutations (2–5%), UBE3A and other presumed single gene Correspondence: Dr Kirstie N Anderson, Department of Neurosciences, Newcastle General Hospital, Westgate Rd, Newcastle upon Tyne, NE4 6BE, UK. Email:
[email protected] Accepted for publication 29 December 2007.
© 2008 The Authors Journal compilation © 2008 Japanese Society of Sleep Research
mutations (20–25%). A cytogenetic or DNA diagnosis is made in 80–85% of patients.1 Diagnostic criteria were established in 19952 and have been recently revised.3 All affected individuals have severe developmental delay with minimal speech output, gait ataxia and characteristic jerky (puppet-like) movements. There is also a typical behavioral phenotype of a happy disposition and inappropriate laughter. Seizures and an abnormal electroencephalograms (EEG) are found in 80% of cases as well as dysmorphic craniofacial features (microcephaly, deep-set eyes and midfacial hypoplasia) and obesity. Sleep problems are common in AS and are included in the diagnostic criteria. These state that ‘between 20 and 80% of children have abnormal sleep–wake cycles
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and diminished need for sleep’.3 The sleep disturbance in AS is recognized as a considerable cause of distress to carers.4 Several questionnaire studies have assessed the prevalence of sleep disorders in both children and young adults with AS,4–9 but few studies have used any other method of sleep assessment in AS. Only one group has performed complex sleep studies (polysomnography) in children and there have been no studies of either actigraphy or polysomnography in adults. The natural history of sleep disturbance in AS patients is not known. We have used sleep diaries and actigraphy in three adults with AS and overnight polysomnography in one of the patients to try and understand more about the causes of sleep disturbance in adults with AS. These results and the implications for future treatment and study of adults with AS are discussed.
METHODS Patients The three patients (SW, JW and HW) were sisters aged 28, 29 and 32, respectively, who had been diagnosed with AS in childhood on the basis of characteristic clinical features. Subsequent genetic testing had confirmed a deletion of maternal 15q11-q13. All three had the typical craniofacial abnormalities, obesity (their body mass index was 33, 35 and 34, respectively), severe learning difficulties with minimal speech output, epilepsy and jerky dyskinesia. All these patients had been investigated with normal computerized tomography brain imaging but had abnormal EEG). Standard 12 lead EEG recordings had been performed on several occasions during wakefulness in all three patients and had always shown abnormal rhythmic slow activity and spike and wave discharges that were most marked posteriorly. They were all under regular neurological review (GGL). They were initially studied because of their snoring. At the time of their sleep investigations they lived with their parents but had carers at night. SW and JW were taking anticonvulsant medication during the period of investigation but HW had very infrequent seizures and was on no medication.
Sleep investigations A detailed history was taken from the parents and carers who completed sleep diaries10 for all three patients for a 2-week period detailing wake and sleep times and daily activities. Two weeks of actigraphy recording was carried out during this time. The patients wore a wrist-
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mounted activity and light monitor (AWL model Actiwatch, Cambridge, Cambridge Neurotechnology) for 14 days. Data, analyzed using the Actiwatch analysis software (Cambridge, 2001) were then subjected to non-parametric circadian rhythm analysis. This is more suitable than cosinor or other parametric analyses for the quantitative analysis of non-sinusoidal data.11 One patient (HW) went on to have polysomnography using a standard procedure including a video recording, a sleep EEG (leads C3-A2, C4-A1), bilateral eye movements and submental electromyography (EMG). Respiratory effort was detected with chest and abdominal bands measuring inductance, airflow was detected with nasal cannulae measuring pressure, and oxygen saturation of arterial blood was also measured. Airflow limitation and changes in respiratory effort were used to detect increased upper-airway resistance. All respiratory events were scored according to standard criteria.12 Obstructive apneas were distinguished from central apneas by the presence of snoring, paradoxical chest wall and abdominal movements. Sleep stages were manually scored according to the Rechstaffen and Kales standard criteria in 30-s epochs.13 Sleep latency, sleep efficiency and the percentage of stage 1, stage 2, stage 3, stage 4 and rapid eye movement (REM) sleep to total sleep time were recorded independently. The patient was on no medication at the time of the study. The polysomnography was not carried out at the same time as the actigraphy.
RESULTS The parents reported that sleep had been fragmented in childhood in all three sisters with frequent nocturnal awakening, but that over time their sleep had improved during the night, apart from occasional nocturnal enuresis or encopresis. One patient (JW) gave occasional vocalizations at night which appeared to be during sleep but did not have any other parasomnia. They denied symptoms of excessive daytime somnolence, restless legs, sleepwalking or nocturnal choking or gasping. They noted that all three children snored loudly. They had not witnessed apneas. The sleep diaries showed a regular pattern of sleep and waking for all three patients, which was largely determined by the time that their parents put them to bed, although the parents reported that all three patients appeared to be sleepy and ready to go to bed when they did. The sleep diary and actigraphy data is summarized in Table 1 and the actograms are shown in Figure 1. For all
© 2008 The Authors Journal compilation © 2008 Japanese Society of Sleep Research
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Table 1 Actigraphy data of patients SW, JW and HW
Sleep diary mean TST (h) Actigraphy mean TST (h) Sleep efficiency (%) Sleep fragmentation index
SW
JW
HW
8.8 7 74 79
10 8.5 85 48
10 7.6 77 80.5
TST, total sleep time.
patients, the 2-week actigraph recording showed regular activity cycles with no evidence of a circadian rhythm disorder. There were frequent nocturnal arousals, not all of which were accounted for by the enuresis or encopresis documented by the carers. There was no reported daytime napping. There was a clear discrepancy between the length and efficiency of sleep assessed using the sleep diaries compared to the sleep assessments derived from the actigraphy data, with a mean length of night sleep recorded by diary as 10, 10 and 8.8 h for SW, JW and HW, respectively. The mean length of night sleep recorded by actigraphy was 7, 8.5, 7.6 h with a low sleep efficiency and high sleep fragmentation index. These data are also shown in Table 1. The polysomnography in HW was strikingly abnormal, with very frequent obstructive and occasional central sleep apneas causing marked sleep disruption. The hypnogram is shown in Figure 2. She slept very poorly with a markedly prolonged sleep latency of 339.5 min and sleep efficiency of only 11.2% of the time in bed (total sleep time 69.5 min, sleep period time 248.5 min, time in bed 622 min) and during the two short periods that she slept she did not achieve stage 4 sleep and had no REM sleep at all. During the two brief periods of sleep she snored loudly and had repeated hypopneas and apneas. These were associated with oxygen desaturation down to 75% and were mostly obstructive, with only a few being central. In total there were six central apneas, 46 obstructive apneas and 140 hypopneas. The desaturation index of time in bed was 18.5 but 58.7 of total sleep time. The apnea hypopnea index was 63 of total sleep time. There were no significant periodic limb movements (PLMI) of sleep (PLMI = 3). During the entire time in bed the video recording showed that the patient was lying still on her back. She did not get up at any stage and she looked as if she was asleep. The apneas were scored as obstructive, given the presence of snoring, chest and abdominal wall movements but during many of the apneas there was very little chest wall movement and minimal respiratory effort. She had no vocalizations or parasomnias during the night.
© 2008 The Authors Journal compilation © 2008 Japanese Society of Sleep Research
The EEG showed abnormal rhythmic, slow theta activity similar to that seen in previous 12 lead EEGs performed during wakefulness. The frequency with which this theta activity occurred did not differ between the waking EEG and the EEG in the polysomnography and there was no evidence for any seizure activity, allowing for the limited EEG channels. The rhythmic, slow theta activity did not coincide with the central apneas and occurred throughout the entire recording. The EEG recording also showed that even the brief periods of sleep were very fragmented and the central apneas could occur during both light sleep and apparent wakefulness, according to the EEG. During the periods of prolonged wakefulness early in the night with a sustained alpha rhythm on the EEG, there were no apneas. A representative section of the EEG, EMG and airflow during sleep and wakefulness is shown in Figure 3.
DISCUSSION Sleep disturbance is well recognized in AS and numerous questionnaire studies have assessed the prevalence of sleep disorders in both children and young adults.4–9 They have highlighted a decreased total sleep time, frequent night awakenings, nocturnal enuresis and encopresis in 40–90% of these patients. Some authors noted that the symptoms were most marked between the ages of two to six and that there was an improvement in some of the patients after the age of six.6,8 Others have found more persistent problems. The largest study to date studied 109 patients between the ages of 2–44 using a detailed questionnaire and found a severe sleep disorder in 40% with no associations between sleep and other variables such as epilepsy or age.4 Common problems were nocturnal enuresis (93%), frequent night waking (37%) and early morning waking (10%), although snoring was reported in 26% as well as restless sleep (25%), daytime napping (22%) and sleep apnea (4%). Another recent questionnaire studying 49 patients aged between 2 and 26 found no difference between sleep disturbance and different types of genetic abnormalities and no improvement with age. However, it highlighted a variety of sleep problems causing fragmentation of night sleep and daytime somnolence including sleep disordered breathing.14 Few studies have used any other methods beyond questionnaires to assess sleep disturbance in AS. Sleep recordings have been used to study EEG changes during sleep15,16 but only one group has carried out overnight sleep studies in AS patients. Miano and colleagues17,18 performed overnight polysomnography in children
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Figure 1 The actograms for (a) SW, (b) JW and (c) HW, respectively. All were carried out during the same 2-week period, using 1-min epochs. For each patient, data is plotted for14 consecutive days over a 48-h time base for clarity.
with AS (age range 5–14) and compared them to agematched children with other causes of epilepsy and developmental delay. The AS patients had decreased sleep efficiency and REM sleep but increased slow wave sleep. The authors noted sleep disordered breathing in 30% of AS patients with an apnea/hypopnea index of >5/h. They also found that 70% had a periodic leg movement index of >5/h. There have been no sleep studies in adults with AS using either polysomnography or actigraphy. Our patients were initially selected for the study as they all snored and the authors were interested in assessing their sleep, given the apparent lack of symptoms in adulthood compared to childhood. Our patients were all still living at home and although their parents reported they had sleep disturbances in childhood they did not feel that, as adults, sleep was problematic, apart from the need for nocturnal toileting. The total amount of sleep time reported by both parents and carers averaged over 9 h. The time that the patients went to bed depended upon the carers and parents rather than necessarily being governed by the patients’ own intrinsic sleep need and this may possibly have contributed to their sleep fragmentation. Actigraphy is a simple, cheap and non-invasive method of assessing sleep–wake cycles and circadian rhythm.19 It is often useful in patient groups where admission to hospital for in- patient polysomnography might be distressing or difficult, such as for those with
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dementia. In our patients there was no evidence of a disorder of the circadian cycle with regular sleep–wake cycles and no evidence of either a delay or an advance in the sleep phase over time. From this study it does not appear to be a circadian rhythm abnormality that is the cause of the previously reported reduction in total sleep time in these patients. Actigraphy has not previously been used to study activity patterns over time in this patient population. It was apparent from the actigraphy that their sleep was considerably more fragmented than was reported by their carers. However the actigraphy still estimated a sleep time of >6 h for all patients. In contrast, despite the reports of sound night-time sleep, the polysomnography in HW was strikingly abnormal, with a dramatically reduced total sleep time due in large part to sleep apneas which were predominantly obstructive. The patient had no deep sleep or REM sleep during the recording. However, she was lying still on her back during her entire time in bed and did not get up at any stage, which corresponded to her parent and carer descriptions of her sleeping soundly. There was no evidence for increased epileptiform activity contributing either to arousals or to the apneas, as the frequency of the predominantly posterior rhythmic slow activity characteristic of AS did not change between waking and sleep recordings. The polysomnography was performed on one night only because the extent of the patient’s learning difficulties, which meant that her parents had to be present at all times, and they were unwilling for
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Sleep disturbance in Angelmans
Figure 2 (a) Hypnogram. REM, rapid eye movement sleep; 1–4, non-REM sleep stages; MT, movement; w = wake. Extremely small amounts of light sleep are shown with no detectable REM or stage 3 and 4 sleep; (b) snoring trace; (c) A, apnea; CA, central apnea; CH, central hyponea; H, hypopnea; MH, mixed apnea; OA, obstructive apnea; OH, obstructive hyponea. There are very frequent central and obstructive apneas (d) showing a drop in oxygen desaturation that corresponds to the period of the most marked apneas.
her to have a more prolonged in-patient stay. This means we must take into account the possibility of a first night effect contributing to her increased sleep latency. Despite this, the cause of her striking sleep fragmentation during the night was related to sleep disordered breathing, which is unlikely to have been related to sleeping in a different environment. No other studies have previously correlated EEG activity and airflow data in detail. Previous polysomnography studies examining the sleep of children did not find such striking sleep apnea. This may be due to the increasing obesity seen in adult life or progressive neurodegeneration with age that might contribute to some of the central apneas. It may be that sleep disordered breathing increases within AS in adulthood due to the increasing obesity. Obesity is a characteristic part of AS and tends to increase with age.2 This would justify longitudinal studies in the future to
© 2008 The Authors Journal compilation © 2008 Japanese Society of Sleep Research
see if the cause of sleep disturbance has different etiologies in childhood compared to adulthood. Such striking sleep disordered breathing has not previously been reported. The patient was studied when she was taking no sedative medication. Based on the currently available literature, this study suggests that the nature of the sleep disturbance in AS may be different in older patients. In our patient the family did not wish to try any treatment for the sleep disturbed breathing because of the lack of symptoms and the potential difficulty of using continuous positive airways pressure or home oxygen. It is therefore not possible to know whether treatment of the sleep disordered breathing would have any impact of her daytime alertness or quality of life. The patient who was studied did not have a severe seizure disorder, but many AS patients do. Given that sleep disturbance is likely to lower the seizure threshold,20 a treatable cause for sleep disturbance deserves further study.
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(a)
(b)
Time (30 s)
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Figure 3 Detailed electroencephalograms (EEG) and airflow recordings showing (a) a representative section of 60 s of the polysomnography recording during fragmented sleep (time of night 05.56 hours). Two typical obstructive apneas are shown (OA) with EEG, electromyography (EMG), peak flow, chest and abdominal wall movements and oxygen desaturations; (b) a 30-s representative sample of EEG during a prolonged period of wakefulness earlier in the night (01.15 hours) with no evidence of sleep disordered breathing. LOC, left electroculogram electrodes; ROC, right electroculogram electrodes. 䉳
No previous studies have looked for sleep disordered breathing in adults with AS and only a few sleep studies have looked at adults with learning difficulties, with or without epilepsy.21 In this study there was no evidence for an intrinsic circadian disorder using actigraphy. The striking central and obstructive sleep apnea seen during polysomnography in our patient highlights the need for further sleep studies in adults with AS to see if this is a common cause for sleep fragmentation in this group. In those who are clearly symptomatic treatment might improve daytime alertness and possibly control seizures.
ACKNOWLEDGMENTS We would like to thank the parents of the three sisters for their help and participation as well as Martin King, Respiratory Support and Sleep Centre for technical assistance.
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