A prospective, naturalistic follow-up study of treatment outcomes with clonazepam in rapid eye movement sleep behavior disorder.

BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) is characterized by prominent dream-enacting behaviors, often resulting in sleep-related injuries. OBJECTIVES: This study aimed to prospectively examine the treatment response of people with RBD treated with clonazepam, by quantitatively delineating the characteristic changes in the clinical and polysomnographic features, and to explore the factors associated with this response. METHODS: Patients diagnosed with idiopathic RBD (iRBD) were consecutively recruited and invited to complete clinical and polysomnographic (PSG) assessments and self-administered questionnaires (including the modified REM Sleep Behavior Questionnaire, RBDQ-3M) before and after the initiation of treatment with clonazepam. RESULTS: Thirty-nine iRBD patients (male: 74.4%, mean age at diagnosis: 68.3 ± 7.8 years) were recruited with a follow-up duration of 28.8 ± 13.3 months. Clonazepam was offered as the first-line treatment (starting dose: 0.43 ± 0.16 mg, range: 0.125-1.00; dose at follow-up: 0.98 ± 0.63 mg, range: 0.125-3). Treatment response, as defined by a complete elimination of sleep-related injuries and potentially injurious behaviors to self and/or to bed partner, at follow-up was reported in 66.7% of the overall study subjects. Frequency of disturbing dreams with violent and frightening content and vigorous behavioral RBD symptoms was significantly reduced, while residual nocturnal symptoms and an increase in REM-related EMG activities were observed at follow-up. Less optimal treatment outcomes were found to be associated with the presence of comorbid obstructive sleep apnea and earlier onset of RBD. CONCLUSIONS: Clonazepam differentially changes dream affect and content, as well as reduces vigorous verbal and motor behaviors. Residual RBD symptoms are common, despite treatment. Other more effective alternative or adjunctive interventions are needed for better clinical management of RBD.

Altered Sleep Stage Transitions of REM Sleep: A Novel and Stable Biomarker of Narcolepsy.

OBJECTIVES: To determine the diagnostic values, longitudinal stability, and HLA association of the sleep stage transitions in narcolepsy. METHODS: To compare the baseline differences in the sleep stage transition to REM sleep among 35 patients with type 1 narcolepsy, 39 patients with type 2 narcolepsy, 26 unaffected relatives, and 159 non-narcoleptic sleep patient controls, followed by a reassessment at a mean duration of 37.4 months. RESULTS: The highest prevalence of altered transition from stage non-N2/N3 to stage R in multiple sleep latency test (MSLT) and nocturnal polysomnography (NPSG) was found in patients with type 1 narcolepsy (92.0% and 57.1%), followed by patients with type 2 narcolepsy (69.4% and 12.8%), unaffected relatives (46.2% and 0%), and controls (39.3% and 1.3%). Individual sleep variables had varied sensitivity and specificity in diagnosing narcolepsy. By incorporating a combination of sleep variables, the decision tree analysis improved the sensitivity to 94.3% and 82.1% and enhanced specificity to 82.4% and 83% for the diagnosis of type 1 and type 2 narcolepsy, respectively. There was a significant association of DBQ1*0602 with the altered sleep stage transition (OR = 16.0, 95% CI: 1.7-149.8, p = 0.015). The persistence of the altered sleep stage transition in both MSLT and NPSG was high for both type 1 (90.5% and 64.7%) and type 2 narcolepsy (92.3% and 100%), respectively. CONCLUSION: Altered sleep stage transition is a significant and stable marker of narcolepsy, which suggests a vulnerable wake-sleep dysregulation trait in narcolepsy. Altered sleep stage transition has a significant diagnostic value in the differential diagnosis of hypersomnias, especially when combined with other diagnostic sleep variables in decision tree analysis.

Reduced striatal dopamine transmission in REM sleep behavior disorder comorbid with depression.

OBJECTIVE: To investigate dopamine transmission in patients with comorbid REM sleep behavior disorder (RBD) and major depressive disorder (MDD). METHODS: This is a case-control study including 11 medicated patients with comorbid RBD and MDD (mean age 47.5 ± 8.2), 8 medicated patients with MDD only (mean age 47.9 ± 8.4), and 10 healthy participants (mean age 46.5 ± 10.6 years). They underwent clinical assessment, video-polysomnography, olfactory tests, and neuroimaging studies ((18)F-DOPA, (11)C-raclopride, and (18)F-FDG PET neuroimaging). RESULTS: Compared with the 2 control groups, patients with comorbid RBD and MDD had significantly lower (18)F-DOPA uptake at 60 minutes in the putamen and caudate after controlling for age and sex effect (p < 0.05). There were no significant differences for the (11)C-raclopride and (18)F-FDG-PET. The (18)F-DOPA uptake in putamens had significant inverse correlation with severity of RBD symptoms (p < 0.01) and REM-related tonic muscle activity (p < 0.01). The comorbid RBD and MDD group had more impairment in olfactory function. CONCLUSION: Patients with comorbid RBD and MDD had presynaptic dopamine dysfunction and impaired olfactory function. There is a distinct possibility that the development of RBD symptoms among patients with MDD may represent an early phase of α-synucleinopathy neurodegeneration instead of a merely antidepressant-induced condition.

Acute and chronic effects of sleep duration on blood pressure.

OBJECTIVE: To evaluate the association between ambulatory blood pressure (ABP) and sleep duration as measured by 7-day sleep diary and nocturnal polysomnography in normal-weight adolescents without significant obstructive sleep apnea. METHODS: Subjects aged 10 to 17.9 years with an obstructive apnea hypopnea index <5 underwent polysomnography for 9.5 hours and 24-hour ABP monitoring commencing at noon on the same day. ABP was divided into prepolysomnography, in bed during polysomnography, and postpolysomnography periods for separate analyses. Sleep duration (SpD7) was obtained from a 7-day sleep diary, reflecting the sleep pattern in the week before admission. Total sleep time (TST) and sleep efficiency (SpE) were obtained from polysomnography. RESULTS: A total of 143 adolescents participated. SpD7 was inversely associated with systolic blood pressure (SBP) in prepolysomnography, in-bed, and postpolysomnography periods (all ß = -2 mm Hg) and with diastolic blood pressure (DBP) in prepolysomnography and in-bed periods (all ß = -1 mm Hg). TST was inversely associated with SBP in the postpolysomnography period (ß = -1.5 mm Hg). SpE was inversely associated with SBP in in-bed period (ß = -0.1 mm Hg) and with DBP in in-bed (ß = -0.1 mm Hg) and postpolysomnography (ß = -0.2 mm Hg) periods. Neither TST nor SpE was associated with SBP and DBP in prepolysomnography period. CONCLUSIONS: Short sleep duration as reflected by 7-day sleep diary was associated with higher blood pressure in normal-weight adolescents. Occasional adequate sleep may partially ameliorate the risk of high blood pressure but may not completely reverse the effect of long-term sleep insufficiency.

The effect of childhood obstructive sleep apnea on ambulatory blood pressure is modulated by the distribution of respiratory events during rapid eye movement and nonrapid eye movement sleep.

OBJECTIVE: We aimed to investigate if different childhood obstructive sleep apnea (OSA) subtypes, namely rapid eye movement (REM)-related, nonrapid eye movement (NREM)-related and stage-independent OSA would exert different effects on ambulatory blood pressure (ABP). METHODS: Data from our previous school-based cross-sectional study were reanalyzed. Subjects who had an obstructive apnea-hypopnea index (OAHI) between 1 and 10 events per hour and a total REM sleep duration of >30min were included in our analysis. REM-related and NREM-related OSA were defined as a ratio of OAHI in REM sleep (OAHIREM) to OAHI in NREM sleep (OAHINREM) of >2 and <0.5, respectively. The others were classified as stage-independent OSA. RESULTS: A total of 162 subjects were included in the analysis. In the mild OSA (OAHI, 1-5events/h) subgroup, no significant differences in any ABP parameters were found between OSA subtypes. On the other hand, in subjects with moderate OSA (OAHI, 5-10events/h), the REM-related OSA subtype had a significantly lower daytime systolic blood pressure (SBP) z score (-0.13±0.90 cf 1.15±0.67; P=.012) and nighttime SBP z score (0.29±1.06 cf 1.48±0.88, P=.039) than the stage-independent OSA subtype. Linear regression analyses revealed that OAHINREM but not OAHIREM was significantly associated with both daytime (P=.008) and nighttime SBP (P=.042) after controlling for age, gender, and body size. CONCLUSION: Children with obstructive events mainly in REM sleep may have less cardiovascular complications than those with stage-independent OSA.

Amelioration of obstructive sleep apnea in REM sleep behavior disorder: implications for the neuromuscular control of OSA.

OBJECTIVES: The relationship between REM sleep behavior disorder (RBD) and obstructive sleep apnea (OSA) remains unclear. We aimed to (1) explore the association of REM-related EMG activity (REMREEA) with OSA in RBD patients; (2) compare the severity of OSA between RBD patients with OSA (RBD-OSA) and their age-, sex-, AHI-, and BMI- matched OSA controls. DESIGN: a. Correlation study in consecutive RBD subjects and b. case-control study SETTING: Sleep laboratory PARTICIPANTS: 71 RBD patients in the correlation study and 55 subjects (28 RBD-OSA cases and 27 OSA controls) in the case-control study. INTERVENTION: N/A METHODS: Polysomnographic assessment to document the sleep architecture, sleep apnea related parameters, and REMREEA. RESULTS: (1) In the correlation study, increased REMREEA was associated with lower severity of OSA in RBD patients, including total AHI (r = -0.263), NREM AHI (r = -0.242), obstructive AHI (r = -0.265), and mean apnea duration (r = -0.353) (P < 0.05). (2) In the case-control study, RBD-OSA patients had lesser severity of sleep apnea parameters than OSA controls in terms of higher nadir SpO(2) (85.7% ± 4.9% vs 80.8% ± 5.9%, P < 0.01), shorter maximum hypopnea duration (53.8 ± 16.7 vs 69.4 ± 22.4 seconds, P < 0.05), and maximum (45.8 ± 20.5 vs 60.8 ± 19.6 sec, P < 0.01) and mean apnea duration (22.3 ± 8.1 vs 26.3 ± 5.8 sec, P < 0.05). Significant interaction effects indicated that the usual REM sleep exacerbation of sleep apneas was seen only in OSA controls but not in RBD subjects. CONCLUSIONS: This study demonstrated that excessive EMG activity in RBD might protect patients against severe OSA and suggests this may be a naturalistic model for understanding neuromuscular control of OSA.

Periodic limb movement during sleep is associated with nocturnal hypertension in children.

BACKGROUND: Increasing evidence suggests that blood pressure (BP) is significantly influenced by sleep problems in children, but the association between periodic limb movement during sleep (PLMS) and BP is still unclear. This study aims to compare ambulatory blood pressure (ABP) in children with and without PLMS. METHODS AND RESULTS: A cross-sectional study involving 314 children (mean (SD) age of 10.4 (1.7) years, boys 62.4%). Participants underwent an overnight polysomnographic study and ABP monitoring. Subjects were hypertensive if mean SBP or DBP > 95th percentile and prehypertensive if mean SBP or DBP > 90th percentile of reference. Children with PLMS (n = 17) were at significantly higher risk for nocturnal systolic (adjusted OR (95%CI) = 6.25 [1.87-20.88]) and diastolic (OR (95%CI) = 4.83 [1.66-14.07]) hypertension. However, mean nocturnal BP did not differ between children with and without PLMS. There was a trend for higher daytime BP in patients with PLMS than those children without PLMS (P = 0.084 for systolic BP z score; P = 0.051 for diastolic BP z score; P = 0.067 for systolic prehypertension). There were significant associations between log transformed PLM index and daytime systolic and mean BP z scores (P = 0.03 and 0.033 respectively) as well as that between log transformed PLM related arousal index (PLMSArI) and nocturnal diastolic and mean BP (P = 0.008 and 0.038 respectively). CONCLUSIONS: PLMS was independently associated with a wide range of BP elevations, especially nocturnal indices. Future studies should examine the underlying pathophysiologic mechanisms and effects of PLMS treatment on BP.

Diagnosis of REM sleep behavior disorder by video-polysomnographic study: is one night enough?

STUDY OBJECTIVES: Clinical features of RBD were typically episodic with limited data on the night-to-night reliability of the diagnostic video-PSGs. We aimed to assess on whether a single night study was adequate. DESIGN: Retrospective review. SETTING: Sleep laboratory. PARTICIPANTS: 55 RBD patients with at least 2 consecutive video-PSGs. INTERVENTIONS: N/A. METHODS: We analyzed 2 consecutive video-PSGs using REM-related EMG activity (REMREEA), REM sleep without atonia (RSWA), and video analysis of motor events. MEASUREMENTS AND RESULTS: A weak first night effect with increased REM sleep latency, increased stage 1 sleep, and increased arousal index were found. No differences were found in phasic and tonic EMG activity scores between night 1 and night 2. The presence of OSAS, use of CPAP, and clonazepam treatment did not affect the night-to-night variability and diagnostic accuracy. The kappas were 0.64, 0.51, and 0.31 between night 1 and night 2 for 10% REMREEA, RSWA, and video analysis respectively. Over 80% of patients could be diagnosed by various criteria in the first night, but the diagnostic ability could be enhanced to nearly 95% when combining PSG with video analysis. While both of the EMG criteria as well as the combination criteria had good reliability, video-analysis had poorer night-to-night reliability. CONCLUSIONS: A single night of video-PSG was adequate in the diagnosis of RBD in most clinical patients and the combination of PSG and video analysis could enhance the detection rate further. Our findings have important resource implications.

The prevalence of narcolepsy among Chinese in Hong Kong.

Narcolepsy is a lifelong, crippling sleep disorder. Although the discovery of the hypocretin system has been a breakthough in genetics, the epidemiological aspects of narcolepsy remain elusive. Ethnic predisposition was suggested to partially account for the 2,500-fold difference in the reported prevalence rates of narcolepsy between Japanese (0.59%) and Israeli Jews (0.00023%). We carried out a general population study, conducting a random telephone survey with a structured questionnaire, which included a validated screening instrument (a Chinese version of the Ullanlinna Narcolepsy Scale). It was followed by clinical-polysomnographic-HLA confirmation of the subjects determined to be positive for narcolepsy based on the questionnaire. Of 9,851 subjects interviewed, 28 subjects (0.28%, 58% female) were screened positive. Ninety percent had a second detailed interview, 64% had HLA typing, and over half of them had a sleep assessment. Only three subjects were found to have genuine narcolepsy. The most common nonnarcolepsy diagnoses were sleep apnea syndrome and sleep-wake schedule disorder. The prevalence rate of narcolepsy in Southern (Hong Kong) Chinese was found to be 0.034% (95% confidence interval = 0.010-0.117%). All available narcoleptic subjects were HLA DRB1-1501 positive and 50% were DQB1-0602 positive. The prevalence rate of narcolepsy among Chinese is comparable to the rates for other populations in studies with stringent epidemiological designs, suggesting that major cross-ethnic differences in the prevalence rates of narcolepsy previously reported likely resulted from methodological limitations.