J Neurol (2014) 261:889–893 DOI 10.1007/s00415-014-7293-z

ORIGINAL COMMUNICATION

Sleep disorders in spinal and bulbar muscular atrophy (Kennedy’s disease): a controlled polysomnographic and self-reported questionnaires study Andrea Romigi • Claudio Liguori • Fabio Placidi • Maria Albanese • Francesca Izzi • Elisabetta Uasone • Chiara Terracciano • Maria Grazia Marciani Nicola Biagio Mercuri • Raffaella Ludovisi • Roberto Massa



Received: 10 December 2013 / Revised: 7 February 2014 / Accepted: 19 February 2014 / Published online: 4 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract No data are available regarding the occurrence of sleep disorders in spinal and bulbar muscular atrophy (SBMA). We investigated the sleep-wake cycle in SBMA patients compared with healthy subjects. Nine SBMA outpatients and nine age-matched and sex-matched healthy controls were evaluated. Subjective quality of sleep was assessed by means of the Pittsburgh Sleep Quality Index (PSQI). The Epworth Sleepiness Scale was used in order to evaluate excessive daytime sleepiness. All participants underwent a 48-h polysomnography followed by the multiple sleep latency test. Time in bed, total sleep time and sleep efficiency were significantly lower in SBMA than controls. Furthermore, the apnea–hypopnea index (AHI) was significantly higher in SBMA than controls. Obstructive sleep apnea (OSA: AHI [5/h) was evident in 6/9 patients (66.6 %). REM sleep without atonia was evident in three patients also affected by OSA and higher AHI in REM; 2/9 (22.2 %) SBMA patients showed periodic limb movements in sleep. The global PSQI score was higher in SBMA versus controls. Sleep quality in SBMA is poorer than in controls. OSA is the most common sleep disorder in SBMA. The sleep impairment could be induced both by OSA or/and the A. Romigi (&)  C. Liguori  F. Placidi  M. Albanese  F. Izzi  E. Uasone  N. B. Mercuri  R. Ludovisi Neurophysiopathology Unit, Department of Systems Medicine, Sleep Medicine Centre, Tor Vergata University and Hospital, Rome, Italy e-mail: [email protected] C. Terracciano  M. G. Marciani  R. Massa Neurology Unit, Department of Systems Medicine, Neuromuscular Centre, Tor Vergata University and Hospital, Rome, Italy N. B. Mercuri  R. Massa IRCCS Santa Lucia Foundation, Rome, Italy

neurodegenerative processes involving crucial areas regulating the sleep-wake cycle. Keywords Sleep disordered breathing  Spinal and bulbar muscular atrophy  Polysomnography  MSLT  Daytime sleepiness  REM sleep without atonia

Introduction Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is a rare X-linked recessive neurodegenerative disorder, caused by the expansion of a CAG repeat, encoding a polyglutamine tract, within the first exon of the androgen receptor (AR) gene on chromosome Xq11-12 [1]. The phenotype is characterized by weakness, atrophy and fasciculations of bulbar, facial and limb muscles, due to the degeneration of lower motor neurons in the spinal cord and brainstem [2]. Nuclear accumulations of mutant polyglutamine-expanded AR are present in motoneurons, as well as in hypothalamus, locus coeruleus, reticular formation of pons and nucleus raphe pontis, considered as key areas for the circadian regulation of the sleep-wake cycle [3, 4]. Considering these findings, we investigated sleep disorders in SBMA patients by means of objective and subjective instruments, in order to assess the relationship between sleep and SBMA in a controlled design.

Subjects and methods Nine consecutive patients with a molecular diagnosis of SBMA (all males, aged 33–76) and nine healthy male controls (aged 37–78) participated in the study. The two groups did not significantly differ (p [ 0.05) with respect

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to age (51.22 ± 16.18 vs 48.56 ± 13.12) and body mass index (24.23 ± 4.13 vs 23.05 ± 1.95). Subjects did not take medications interfering with CNS or known to influence sleep at the time of the sleep laboratory investigation. All subjects provided their informed consent prior to enrolment into the study, which had been approved by the Institution’s Ethical Committee. Polysomnographic and sleep quality evaluation All participants underwent a 48-h dynamic ambulatory polysomnogram (A-PSG) in order to evaluate diurnal and nocturnal sleep (Somnoscreen, SOMNOmedics GmbHRandersacker, Germany) as described elsewhere [5]. Since the first night was considered as an adaptation night, only the results from the second one were used for analysis. No patients showed and reported diurnal naps during the first 24-h session potentially interfering with sleep architecture of the second night. Sleep analysis, apnea/hypopnea events and leg movements were scored according to standard criteria [5–8]. Apnea-Hypopnea Index (AHI) [5 and Periodic Limb Movements Index (PLMI) [15 were considered pathological [5]. REM sleep without atonia (RSWA) is empirically defined as excessive amounts of sustained or intermittent elevation of submental electromyogram (EMG) tone or excessive phasic submental EMG twitching with the other features of REM sleep that are desynchronized EEG and rapid eye movements. RSWA was scored as recently validated [9]. A-PSG was followed by the multiple sleep latency test (MSLT) to objectively evaluate daytime somnolence [5]. Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were performed as described elsewhere [5].

J Neurol (2014) 261:889–893

bed (TIB, p = 0.004), total sleep time (TST, p = 0.0005) and sleep efficiency (SE, p = 0.006). On the other hand, patients presented an increased value of the wake after sleep onset (WASO, p = 0.008) and in the number of awakenings for each hour of sleep (AWK/h, p = 0.008). AHI was significantly higher in SBMA patients than controls (p = 0.001). In particular, we documented obstructive sleep apnea (OSA) episodes, whereas no central apneas were detected. In addition we found significantly higher AHI both in REM (p = 0.006) and in NREM (p = 0.001) and ODI (p = 0.023) in SBMA vs control, whereas mean SaO2 was similar in both groups. No significant differences were observed in other polysomnographic variables. Data are summarized in Table 1. Sleep disorders: polysomnographic data SE was \90 % in 8/9 SBMA patients (88.8 %) vs 2/9 control subjects (22.2 %). Six of the nine SBMA patients (66.6 %) vs no controls were affected by OSA, 3/6 showed mild OSA (AHI \15/h), two moderate OSA syndrome (OSAS) (AHI \30/h) and one severe OSAS (AHI [30/h). Three SBMA patients (33 %) lacking a history of dream enactment behavior showed RSWA and OSA (AHI, respectively, 16.6/h, 16.5/h and 6.1/h) with higher AHI in REM sleep (AHI in REM vs NREM, respectively, 51.6/h vs 7.6/h; 37.4/h vs 12.8/h; 13.3/h vs 4.6/h). We found RSWA in REM epochs lacking respiratory events, in addition we did not consider REM epochs with respiratory arousals to evaluate muscle tone in order to exclude that the increased muscle tone have not been the consequence of REM related respiratory events. None of the healthy subjects showed RSWA. Finally, two SBMA patients (22 %) presented a pathological PLMI (140.5/h and 23/h, respectively) whereas one control subject showed a PLMI of 17.6/h (11.1 %).

Statistical analysis

Diurnal sleepiness: objective evaluation

Statistical analysis was performed by means of the nonparametric Mann–Whitney U test (Statistica 10.0 program Statsoft Inc, USA), reporting mean values and standard deviations (p value \0.05 was considered significant). We compared subjective and objective data of SBMA vs healthy subjects. Due to the small size of our sample and to the narrow range (40–47) of CAG expansion size detected, we did not attempt to correlate CAG repeat length and sleep parameters.

No significant differences in the mean sleep latency (MSL) during the MSLT were observed between patients and controls. Three of the nine patients (33.3 %) presented a MSL \8 min. The first one (MSL 7.75 min) had also a moderate OSAS (AHI 16.6/h), the second one (MSL 7.25 min) was affected by mild OSA (AHI 9.2/h) and severe periodic limb movements (PLMS) (PLMI 140.5/h), the third one (MSL 5.5 min) was not affected by OSA and/ or PLMS. We did not detect SOREMPs in both SBMA and controls. Data are summarized in Table 1.

Results Nocturnal sleep: polysomnographic data

Nocturnal sleep and diurnal sleepiness: subjective evaluation

Compared with controls, the analysis of macrostructural data showed in SBMA patients a significant reduction in time in

Seven of the nine patients (77.8 %) reported sleep complaints as measured by means of the PSQI. The PSQI global score

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Table 1 Nocturnal and diurnal objective sleep variables SBMA (n = 9) (mean ± SD)

Controls (n = 9) (mean ± SD)

p value

Nocturnal sleep TIB time in bed (min)

422.11 ± 63.90

484.44 ± 43.27

0.004*

TST total sleep time (min)

307.59 ± 53.19

437.78 ± 36.12

0.0005* 0.008*

WASO (min)

105.97 ± 61.85

35.89 ± 26.45

Sleep efficiency (%)

75.17 ± 13.11

90.7 ± 4.52

0.006*

Sleep onset (min)

8.54 ± 7.49

10.78 ± 11.45

NS

REM sleep N1 (%)

124.61 ± 97.31 10.47 ± 6.75

115 ± 48.78 5.98 ± 4.53

NS NS

N2 (%)

49.58 ± 9.28

52.8 ± 6.22

NS

N3 (%)

23.26 ± 6.96

27.97 ± 21.18

NS

REM (%)

16.67 ± 8.07

20.11 ± 6.22

NS

No. awakenings/h

7.50 ± 5.71

2.46 ± 1.70

0.008*

PLMS

19.27 ± 46.04

2.10 ± 5.82

NS

AHI

10.36 ± 9.76

0.84 ± 1.26

0.001*

AHI in REM sleep

14.4 ± 18.13

1.3 ± 0.6

0.006*

AHI in nonREM sleep

8.41 ± 9.46

0.9 ± 1.6

0.001*

Oxygen desaturation index (ODI)

7.7 ± 9.57

0.87 ± 1.36

0.023*

Oxygen saturation (mean)

93.2 ± 1.92

94.5 ± 1.66

NS

Daytime somnolence (MSLT) Average sleep latency

11.76 ± 4.60

15.52 ± 3.37

NS

SOREMPs

0 (0)

0 (0)



Sleep stages are calculated as percentage to total sleep time (TST) = total minutes of stages non-REM 1 (N1), 2 (N2), 3 (N3), REM; time in bed: time from light ‘‘off’’ to light ‘‘on’’; WASO wake after sleep onset in minutes; REM latency in minutes from sleep onset to initial epoch of REM sleep; sleep latency first two episodes of stage 1 or the first epoch of any other sleep stage; SaO2 is oxygen saturation expressed as mean percentage. Statistical analysis was performed by means of the Mann–Whitney Test SBMA spinal and bulbar muscular atrophy, MSLT multiple sleep latency test, PLMS periodic limb movements during sleep, AHI apnea–hypopnea index, SOREMPs sleep-onset REM periods * p level of \0.05 was considered significant

was significantly increased in comparison with controls (SBMA 9.44 ± 4.19 vs controls 2.89 ± 1.05 p = 0.0009). In addition, four of the seven components of the PSQI were significantly altered compared with controls: (1) sleep quality (SBMA 1.55 ± 0.53 vs controls 0.67 ± 0.5 p = 0.01); (2) sleep duration (SBMA 1.11 ± 0.6 vs controls 0.33 ± 0.5 p = 0.02); (3) habitual sleep efficiency (SBMA 1.22 ± 1.2 vs controls 0 ± 0 p = 0.01); (4) sleep disturbances (SBMA 2 ± 0.7 vs controls 1 ± 0, p = 0.005). We detected a significant statistical difference in the ESS score between SBMA and controls (SBMA 8.44 ± 5.17 vs controls 2.55 ± 1.13, p = 0.002). Two of the nine patients showed an ESS [10 (one affected by moderate OSAS, AHI = 16.5/h).

Discussion To our knowledge this is the first polysomnographic study regarding the sleep-wake cycle and daytime somnolence in

SBMA. In a small cohort of unselected patients, we report a higher frequency of complaints of OSA, RSWA and impairment of nocturnal sleep quality, compared to sexmatched and age-matched healthy controls. Indeed, we found a severe nocturnal sleep disruption in SBMA vs controls, as documented by the poorer sleep quality (lower TST, SE and TIB) related to the increased sleep fragmentation (higher WASO, AWK/h and AHI). Nevertheless, we did not detect daytime sleepiness in SBMA patients. The most common sleep disturbance observed in SBMA was OSA, present in two-thirds of the patients with different severity. On the other hand, we did not detect central sleep apneas in SBMA. Therefore, OSA may represent the primary cause of sleep impairment in our sample. Sleep disorders and particularly sleep-disordered breathing are common in patients with neuromuscular diseases, contributing to sleep disruption [10, 11]. Pharyngeal and respiratory muscle weakness and hypotonia predispose to airway collapse and obstructive sleep

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respiratory events especially during REM sleep. Although the effect of sleep breathing disorders may represent the primary cause of poor sleep quality in SBMA, the observed degeneration of brain structures controlling the sleep-wake cycle could play an important role in impairing the sleep pattern. In addition, we found RSWA in one-third of SBMA patients also affected by OSA and lacking a history of nocturnal dream enactment behaviors. These patients showed higher AHI in REM sleep (more than threefolds), albeit apneic events were not confined in REM sleep. RSWA could be related to the pathophysiology of SBMA involving the brainstem and diencephalon, particularly in the pedunculopontine and laterodorsal tegmental nuclei representing critical modulators of REM sleep [12]. However, RSWA and RBD has been described as a hypothetical compensatory and protective mechanism against OSA [13]. We hypothesize that SBMA may predispose to RSWA for its intrinsic neurodegenerative mechanisms, and that OSA may represent a compensatory trigger that may unmask a RSWA propensity as recently observed in myotonic dystrophy type 2 [14]. On the other hand, Huang et al. [13] reported that patients with RBD and OSA not affected by neuromuscular diseases, presented shorter duration of apneas and hypopneas during REM than NREM sleep. Excessive EMG activity associated with RBD probably exerted a protective mechanism from long apneas resulting in shorter respiratory events, less REM sleep-related exacerbation, and probably a lower frequency of apneas and hypopneas. In our SBMA sample, RSWA was found in three patients with higher REM sleep related AHI. Notwithstanding that this finding may be apparently in contrast with the results from Huang [13], we should consider that patients with neuromuscular diseases may experience OSA that is worse in REM sleep [11]. In addition, SDB in the early stages of neuromuscular disorders may occur predominantly in REM sleep because of greater muscle atonia and decreased chemoreceptor responsiveness, but with progression of the disease it may appear in non-REM sleep and wakefulness [11]. Therefore, RSWA may represent an attempt to protect from sleep apnea SBMA patients showing REM-related worsening or significant REM-predominant OSA as found in our sample. Interestingly, subjective sleep quality was also impaired in SBMA. PSQI showed disturbed sleep in 77.8 % of SBMA patients, with the main complaints of sleep quality, sleep duration, habitual sleep efficiency and sleep disturbances. Therefore, we found a good agreement between objective and subjective measure of TST, SE and sleep fragmentation parameters (WASO, AWK/ h). Then, PSQI may represent an easy instrument to precociously evaluate and detect sleep disturbance in SBMA patients.

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Regarding daytime somnolence, the pathological sleepiness detected by MSLT in one-third of patients probably failed statistical significance due to the small sample. Furthermore, subjective evaluation of diurnal sleepiness showed a significant higher score of ESS without reaching pathological levels in SBMA patients, confirming the poor reliability of this scale with MSLT in OSA and neuromuscular disorders [5, 14, 15]. In summary, OSA seems to be a common symptom in SBMA, but daytime somnolence may be unrecognized because of overlapping with fatigue and tiredness. Ambulatory sleep studies represent easy and inexpensive means of identifying OSA in patients with SBMA and, given the high frequency of sleep-disordered breathing in our sample, should be performed to early diagnose sleep apnea. Further prospective studies involving larger samples should clarify the real magnitude of sleep disordered breathing and the role of CNS degenerative mechanisms on sleep-wake modulation in SBMA. Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.

References 1. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79 2. Katsuno M, Banno H, Suzuki K et al (2010) Clinical features and molecular mechanisms of spinal and bulbar muscular atrophy (SBMA). Adv Exp Med Biol 685:64–74 3. Adachi H, Katsuno M, Minamiyama M et al (2005) Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 128:659–670 4. Hobson JA, Pace-Schott EF (2002) The cognitive neuroscience of sleep: neuronal systems, consciousness and learning. Nat Rev Neurosci 3:679–693 5. Romigi A, Izzi F, Pisani V et al (2011) Sleep disorders in adultonset myotonic dystrophy type 1: a controlled polysomnographic study. Eur J Neurol 18:1139–1145 6. The Report of an American Academy of Sleep Medicine Task Force (1999) Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 22:667–689 7. ASDA (1993) The atlas task force. Recording and scoring leg movements. Sleep 16:748–759 8. American Academy of Sleep Medicine (2005) ICSD-2-international classification of sleep disorders, 2nd ed.: diagnostic and coding manual. American Academy of Sleep Medicine, Westchester 9. Consens FB, Chervin RD, Koeppe RA et al (2005) Validation of a polysomnographic score for REM sleep behavior disorder. Sleep 28:993–997 10. Romigi A, Albanese M, Liguori C et al (2013) Sleep-wake cycle and daytime sleepiness in the myotonic dystrophies. J Neurodegener Dis 2013:13, Article ID 692026. doi:10.1155/2013/692026 11. Bhat S, Gupta D, Chokroverty S (2012) Sleep disorders in neuromuscular diseases. Neurol Clin 30:1359–1387

J Neurol (2014) 261:889–893 12. Rye DB (1997) Contributions of the pedunculopontine region to normal and altered REM sleep. Sleep 20:757–788 13. Huang J, Zhang J, Lam SP et al (2011) Amelioration of obstructive sleep apnoea in REM sleep behaviour disorder: implications for the neuromuscular control of OSA. Sleep 34:909–915 14. Romigi A, Albanese M, Placidi F et al (2013) Sleep disorders in myotonic dystrophy type 2: a controlled polysomnographic study

893 and self-reported questionnaires. Eur J Neurol. doi:10.1111/ene. 12226 15. Chervin RD, Aldrich MS (1999) The Epworth Sleepiness Scale may not reflect objective measures of sleepiness or sleep apnea. Neurology 52:125–131

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Sleep disorders in spinal and bulbar muscular atrophy (Kennedy's disease): a controlled polysomnographic and self-reported questionnaires study.

No data are available regarding the occurrence of sleep disorders in spinal and bulbar muscular atrophy (SBMA). We investigated the sleep-wake cycle i...
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