TY - JOUR
AU - Silvani,, Alessandro
AB - Abstract Study Objectives Arterial blood pressure (ABP) decreases during sleep compared with wakefulness and this change is blunted in mouse models of and adult patients with narcolepsy type 1 (NT1). We tested whether: (1) pediatric patients with NT1 have similar cardiovascular autonomic abnormalities during nocturnal sleep; and (2) these abnormalities can be linked to hypocretin-1 cerebrospinal fluid concentration (CSF HCRT-1), sleep architecture, or muscle activity. Methods Laboratory polysomnographic studies were performed in 27 consecutive drug-naïve NT1 children or adolescents and in 19 matched controls. Nocturnal sleep architecture and submentalis (SM), tibialis anterior (TA), and hand extensor (HE) electromyographic (EMG) activity were analyzed. Cardiovascular autonomic function was assessed through the analysis of pulse transit time (PTT) and heart period (HP). Results PTT showed reduced lengthening during total sleep and REM sleep compared with nocturnal wakefulness in NT1 patients than in controls, whereas HP did not. NT1 patients had altered sleep architecture, higher SM EMG during REM sleep, and higher TA and HE EMG during N1–N3 and REM sleep when compared with controls. PTT alterations found in NT1 patients were more severe in subjects with lower CSF HRCT-1, but did not cluster or correlate with sleep architecture alterations or muscle overactivity during sleep. Conclusion Our results suggest that pediatric NT1 patients close to disease onset have impaired capability to modulate ABP as a function of nocturnal wake–sleep transitions, possibly as a direct consequence of hypocretin neuron loss. The relevance of this finding for cardiovascular risk later in life remains to be determined. narcolepsy, pediatrics, sleep, pulse transit time, heart rate, periodic limb movements during sleep, electromyography, cluster analysis Statement of Significance Arterial blood pressure (ABP) decreases during sleep and this phenomenon is blunted in mouse models of and adult patients with narcolepsy type 1 (NT1). By analyzing pulse transit time, we provide evidence that a similar dysfunction occurs in children and adolescents with NT1. This phenomenon correlates with cerebrospinal fluid hypocretin-1 concentration, but appears unrelated to sleep architecture alterations or to electromyographic overactivity during sleep. Pediatric patients with NT1 may thus be less capable than controls to modulate ABP as a function of changing nocturnal wake–sleep states. This may result from the loss of hypocretin neurons, a component of the central autonomic network, and might contribute to increase cardiovascular risk in adulthood. Introduction Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness, sleep attacks, occurrences of rapid-eye-movement (REM) sleep at sleep onset, cataplexy (i.e. sudden muscle weakness during wakefulness triggered by strong, mainly positive, emotions), and other symptoms linked to REM sleep dysfunction. NT1 is caused by the near-complete loss of the hypothalamic neurons that release the neuropeptides hypocretin 1 and 2 (also named orexin A and B), as mirrored by the evidence of cerebrospinal fluid hypocretin-1 deficiency that is now recognized as a unique biological disease marker [1]. Hypocretin neurons are more electrically active during wakefulness than during sleep [2]. In experimental models, however, hypocretin-1 remains at a relatively high concentration in the brain interstitial fluid during sleep compared with wakefulness, possibly because of slow peptide clearance [3]. A number of dysfunctions have been described during sleep in adult patients with NT1, including alterations of sleep structure [4] and signs of muscle overactivity such as periodic limb movements during sleep (PLMS) [5] and REM sleep without atonia [6]. Cardiovascular autonomic dysfunctions during sleep, such as increased values of heart rate and a blunted fall of arterial blood pressure, have been reported in mouse models of NT1 and confirmed in adult NT1 patients, who often show a nondipping pattern of arterial blood pressure [7, 8]. Most clinical studies on NT1 to date have been performed in young adult patients. However, NT1 most often arises during childhood, with age-specific features including marked hypersomnolence, rapid weight gain, precocious puberty, and a complex movement disorder during wakefulness, particularly in cases close to the disease onset [9]. Partly because of these specific features, the diagnosis of pediatric NT1 is challenging and often delayed by several years [9]. Alterations of sleep architecture [10, 11] and muscle overactivity [12, 13] during sleep have also been reported in children and adolescents with NT1. In contrast, available evidence on cardiovascular autonomic changes during sleep in pediatric patients with NT1 is limited, with only one prior recent study of heart rate variability that suggested a blunted fall of sympathetic modulation during sleep [10]. In recent years, analysis of pulse transit time (PTT), the time delay for the pressure wave to travel between two arterial sites [14], to study the control of arterial blood pressure has been facilitated by computing methods that are based on noninvasive electrocardiography and pulse oximetry recordings, with applications to pediatric sleep studies [15]. In particular, PTT lengthens if vessels become less stiff due to a decrease in arterial blood pressure [14], such as when occurring physiologically during sleep [16]. The aims of the present study were the following: (1) to test whether PTT values during nocturnal sleep show reduced lengthening, with respect to wakefulness, in pediatric patients with NT1 versus control subjects, as predicted from analyses of arterial blood pressure during sleep in mouse models of and adult patients with NT1 [7, 8]; and (2) if present, to test whether these sleep-dependent cardiovascular autonomic abnormalities can be linked to alterations in sleep architecture and/or sleep-related muscle activity. Methods Subjects Twenty-seven drug-naïve children and adolescents with NT1 and 19 controls were recruited at the Center for Narcolepsy of the Department of Biomedical and Neuromotor Sciences of the University of Bologna. The control group was composed of children and adolescents in whom a clinical suspicion of hypersomnia was not confirmed after diagnostic evaluation, and who were free of other neurological disorders. The NT1 and control groups were matched for sex and age (Table 1; overall age range 5.8–19.0 years). All NT1 patients met International Classification of Sleep Disorders criteria including: (1) unequivocal cataplexy documented during in-laboratory testing [17]; (2) persistent daytime sleepiness; (3) at least two sleep-onset REM sleep periods and mean sleep latency <8 min during a multiple sleep latency test; and (4) when available, evidence of cerebrospinal fluid hypocretin-1 deficiency (i.e. level < 110 pg/mL). The presence of human leukocyte antigen (HLA) DQB1*0602 was assessed in all patients. Subjects were classified as normal weight, overweight, or obese based on body mass index distributions as a function of age and gender as reported in the pediatric Italian population [18]. All subjects and/or their parents/tutors gave written informed consent, in agreement with the Convention of Helsinki, to the study protocol. The study was also approved by our local Ethical Committee. Table 1. Demographic characteristics of NT1 and control subjects . NT1 . Controls . P . Age (years) 12.4 ± 0.6 13.6 ± 0.7 0.215 Male/female 18/9 14/5 0.611 BMI category (normal/overweight\obese) 5/17/5 11/4/4 0.010† Cerebrospinal fluid hypocretin-1 (pg/mL) 30 ± 5 327 ± 9 <0.001* Disease duration (years) 3.3 ± 0.5 N/A . NT1 . Controls . P . Age (years) 12.4 ± 0.6 13.6 ± 0.7 0.215 Male/female 18/9 14/5 0.611 BMI category (normal/overweight\obese) 5/17/5 11/4/4 0.010† Cerebrospinal fluid hypocretin-1 (pg/mL) 30 ± 5 327 ± 9 <0.001* Disease duration (years) 3.3 ± 0.5 N/A BMI, body mass index; NT1, narcolepsy type 1; N/A, not applicable. Values are shown as mean ± SEM, with N = 26/12 and 27/19 patients/controls for hypocretin-1 levels and for the other indexes, respectively. *Significance of between-group differences (p < 0.05) assessed with t-test. †Significance of between-group differences (p < 0.05) assessed with chi-square test. Open in new tab Table 1. Demographic characteristics of NT1 and control subjects . NT1 . Controls . P . Age (years) 12.4 ± 0.6 13.6 ± 0.7 0.215 Male/female 18/9 14/5 0.611 BMI category (normal/overweight\obese) 5/17/5 11/4/4 0.010† Cerebrospinal fluid hypocretin-1 (pg/mL) 30 ± 5 327 ± 9 <0.001* Disease duration (years) 3.3 ± 0.5 N/A . NT1 . Controls . P . Age (years) 12.4 ± 0.6 13.6 ± 0.7 0.215 Male/female 18/9 14/5 0.611 BMI category (normal/overweight\obese) 5/17/5 11/4/4 0.010† Cerebrospinal fluid hypocretin-1 (pg/mL) 30 ± 5 327 ± 9 <0.001* Disease duration (years) 3.3 ± 0.5 N/A BMI, body mass index; NT1, narcolepsy type 1; N/A, not applicable. Values are shown as mean ± SEM, with N = 26/12 and 27/19 patients/controls for hypocretin-1 levels and for the other indexes, respectively. *Significance of between-group differences (p < 0.05) assessed with t-test. †Significance of between-group differences (p < 0.05) assessed with chi-square test. Open in new tab Study protocol Two consecutive 24-h video-polysomnographic recordings (the first for adaptation, the second for diagnostic purposes) were carried out in a single sleep laboratory room before the execution of a fixed five-nap Multiple Sleep Latency Test on the third day [19, 20]. During daytime, oscillometric readings of systolic and diastolic arterial blood pressure and heart rate (on average 4, range 2–6 measurements per subject) were taken at bedside during quiet wakefulness, and averaged for each subject for the purpose of analysis. Before averaging, readings of heart rate were converted to values of heart period (HP, i.e. 60,000/heart rate, in ms), which are linearly related to cardiac sympathetic and parasympathetic tone [21]. Subjects were not allowed to drink caffeinated beverages from the afternoon preceding recording and were allowed to sleep until spontaneous morning awakening. Light-out time was based on individual habitual bedtime. The following signals were recorded: electroencephalogram (including frontal, central, and occipital leads, referred to the contralateral mastoid); electrooculogram (electrodes placed 1 cm above the right outer cantus and 1 cm below the left outer cantus and referred to the left mastoid); electromyogram (EMG) of the submentalis muscle, the right and left tibialis anterior muscles, and the right and left hand extensor muscles (bipolar derivations with electrode pairs placed 3 cm apart and impedance ≤ 10 kΩ); and electrocardiogram (anode in position V4 and cathode attached to the manubrium of the sternum). The sleep respiratory pattern of each patient was monitored using oral and nasal airflow thermistors, nasal pressure probes, and thoracic and abdominal respiratory effort strain gauges. Oxygen saturation was monitored with finger pulse oxymetry. PTT was computed based on electrocardiogram and pulse oximetry data (SOMNOscreen Plus apparatus, SOMNOmedics GmbH). Sleep signals were sampled at 256 Hz (512 Hz for the electrocardiogram) and stored on hard disk in European data format for further analysis. Sleep stages were scored following standard criteria on 30-s epochs [22]. Mathematical data analysis was performed using Matlab (The Mathworks, Inc.). The analysis was restricted to time after ≥24 h from start of recordings, so as to avoid first-night effects [23]. Indexes of cardiovascular autonomic function during nocturnal sleep Cardiovascular autonomic function during sleep was assessed by analyzing PTT and HP values during sleep stages N1–N2, N3, and REM sleep (stage R sleep), either in absolute values or as percentages (%PTT, %HP) of the corresponding values during wakefulness in a lying position after lights off. This normalization was chosen because previous studies on mouse models of NT1 highlighted the blunting of sleep-related differences in arterial blood pressure from wakefulness as a key cardiovascular anomaly [7, 8]. Normalization of PTT values during sleep with respect to wakefulness has also previously been employed in children as a method to compensate for differences in individual cardiac pre-ejection period [24]. Differences between PTT and HP values during nocturnal sleep and corresponding values during daytime wakefulness were also computed and divided by PTT and HP values during daytime wakefulness to yield indexes analogous to day-night “dipping” of arterial blood pressure [25], which was found to be reduced in adult patients with NT1 [26]. Indexes of nocturnal sleep architecture Sleep structure was evaluated by computing total sleep time, sleep efficiency, sleep latency, REM sleep latency, time spent in wakefulness after sleep onset, number of transitions between wake-sleep states (considering wakefulness and sleep stages N1, N2, N3, and REM sleep as five individual states) per hour between the start and the end of nocturnal sleep (frameshift index), and percentage of total sleep time spent in sleep stages N1–N2, N3, and REM sleep. Indexes of muscle activity during nocturnal sleep The apnea–hypopnea index (AHI) was computed to estimate sleep-disordered breathing using standard pediatric criteria for all the subjects [27]. To quantify muscle activity during sleep, PLMS indexes were also computed during sleep stages N1–N3 and REM sleep according to the WASM criteria [28]. The EMG activity of submentalis muscles during sleep was quantified using the REM sleep atonia index (RAI), a validated index of the fraction of time spent in REM sleep with muscle atonia [29]. In addition, distributions of normalized EMG values (DNE) of submentalis muscles during sleep stages N1–N3 and REM sleep were computed as previously published [30]. The DNE involves rectifying and averaging every 0.5 s the EMG signal during lights off, trimming the extreme, potentially artefactual, values of rectified and averaged EMG (raEMG) distribution (top and bottom 0.5% of the distribution), and scaling the remaining distribution to its maximum and minimum using the formula: EMGNORM=(raEMG−min(raEMG))/(max(raEMG)−min(raEMG))×100 where EMGNORM indicates normalized EMG values and max and min indicate maximum and minimum values, respectively. The EMGNORM distribution obtained for lights off for each muscle and subject was split into separate DNEs corresponding to sleep stages N1–N3 and REM sleep. These DNEs were then quantified based on a fixed set of centiles (50th, 75th, 95th, 97th, and 99th centile) from median (50th centile) upwards, in line with the hypothesis that pediatric NT1 entails muscle overactivity during sleep. The same DNE analysis was also applied to quantify the distributions of tibialis anterior and hand extensor EMG activities during sleep. These distributions were computed as the average DNE of the available artifact-free EMG signals from muscles on right and left limbs. Artifacts in submentalis EMG, which did not preclude its contribution to sleep scoring but potentially affected quantitative analysis, occurred in four patients with NT1 and one control subject. The values of RAI and submentalis DNE for these subjects were thus excluded from the analysis. Artifacts in tibialis anterior EMG potentially impacting quantitative analysis occurred in one control subject on the left side, three NT1 patients on the right side, and one NT1 patient on both sides. These values were excluded from the analysis, leading to an effective loss of average tibialis anterior DNE results in one patient with NT1. Recordings of hand extensor EMG were performed in 15 patients with NT1 and 13 control subjects. Artifacts in these signals occurred on the left side in one control subject and on the right side in another, leading to no effective loss of average hand extensor DNE results. The consideration of a given EMG tracing as artefactual for the purpose of these quantitative EMG analyses was based on visual assessment of raw tracings by an experienced investigator (SV), blind to the results of the quantitative analysis. Statistical analysis The statistical analysis was performed using SPSS V.18 (SPSS, Inc.). Differences between groups, including in demographic and sleep characteristics, were analyzed with Student’s t-tests except for those concerning sex and body weight classification, which were analyzed using a chi-square test. Analyses of indexes based on PTT, HP, and DNE were performed using mixed-model ANOVAs, with Huynh–Feldt correction in case the sphericity assumption was not met. Indexes quantifying sleep architecture and EMG activity were screened to identify those that showed a statistical link to, and therefore represented potential causes of, PTT-based indexes of cardiovascular autonomic dysfunction. The screening started from indexes whose values differed significantly between pediatric patients with NT1 and controls (see Results). These variables were subjected to hierarchical cluster analyses based on squared Euclidean distances between z-scores within variables. Since the sample size with available hand extensor muscle recordings was lower than the total sample size, two cluster analyses were performed: one excluding hand extensor DNE indexes to maximize sample size, and the other including these indexes to maximize information. Both cluster analyses were performed on the whole sample under study (i.e. NT1 patients and controls), consistently with the purpose of identifying potential determinants of cardiovascular autonomic dysfunction during sleep, as opposed to discriminating between NT1 patients and controls. Pearson’s linear correlation coefficients were eventually computed between PTT-based indexes of cardiovascular autonomic dysfunction during sleep and indexes that clustered with them, thus decreasing the likelihood of statistical false-positive results. Partial correlations corrected for age were computed in case one or both indexes of a given pair showed significant correlations with age. The correlation analysis was performed on the whole sample under study as well as separately for each group. Data are shown as means ± SEM, with significance set at p < 0.05. The sample size was determined based on subject recording availability, with no statistical power analysis performed a priori. The full study sample size was N = 27/19 patients/control subjects. Due to missing data, the sample size was reduced to N = 26/19, N = 26/12, N = 23/18, and N = 15/13 patients/controls for comparisons involving tibialis anterior DNE, cerebrospinal fluid hypocretin-1 levels, RAI/submentalis DNE, and hand extensor DNE, respectively. For reference, a-posteriori sensitivity estimates indicated that the size of the full study sample afforded detection of between-group differences with a 0.86 effect size (two-tailed t-test, 80% power, significance at p < 0.05), whereas detectable effect size increased to 1.10 for the comparisons involving hand extensor DNE, which had the lowest sample size (G*Power [31] version 3.1.9.2). Results Characteristics of the study sample The demographic characteristics of the study sample are reported in Table 1. Cerebrospinal fluid hypocretin-1 levels were significantly lower (p < 0.001) in NT1 patients than in controls, as expected, and did not correlate significantly with age or disease duration in patients (p ≥ 0.073). The proportions of patients with NT1 that had normal body weight, were overweight, or were obese differed significantly from those in the control group (p = 0.006), with a greater fraction of patients being overweight compared with controls. Cardiovascular autonomic function The values of systolic and diastolic arterial blood pressure and of HP obtained with intermittent conventional brachial measurements during daytime wakefulness did not differ significantly between NT1 patients (106 ± 2, 63 ± 1 mm Hg, and 848 ± 31 ms) and control subjects (104 ± 2, 61 ± 1 mm Hg, and 849 ± 35 ms; p ≥ 0.196). In both groups, PTT and HP increased significantly from daytime wakefulness to nighttime sleep, as expected, without significant differences between groups (Figure 1A–C). However, the effect of wake–sleep states on nighttime values of PTT differed significantly between patients with NT1 and control subjects (Figure 1D), while that on the nighttime values of HP did not (Figure 1F). In particular, the values of PTT and HP during the nocturnal sleep stages increased in both subject groups with respect to the corresponding values during nocturnal wakefulness in the lying position, resulting in increases in %PTT and %HP. However, in patients with NT1, %PTT was significantly lower (i.e. nearer to unity) than in control subjects (Figure 1E), whereas this was not the case for %HP (Figure 1G). The difference in %PTT between patients with NT1 and control subjects was most robust during REM sleep (Figure 1E), and was also significant during total nighttime sleep (102.2% ± 0.4% vs. 103.9% ± 0.5% in NT1 patients vs. controls, p = 0.010). Figure 1. Open in new tabDownload slide Values of PTT and HP in pediatric patients with NT1 and control subjects. (A, B) Pulse transit time (PTT) and heart period (HP) during daytime wakefulness (W) and nighttime sleep (S) in pediatric patients with narcolepsy type 1 (NT1) and control subjects. (C) PTT and HP dip from daytime W to nighttime S. (D, E) PTT during nighttime W in a lying position, sleep stages N1–N2, N3, and R, expressed in absolute values (D) or as percentage of the values during W (%PTT, E). (F, G) Corresponding results for HP and %HP. [*]p = 0.024, main effect of subject group (ANOVA). *p = 0.010, t-test. Data are means ± SEM with N = 27/19 NT1 patients/control subjects. Figure 1. Open in new tabDownload slide Values of PTT and HP in pediatric patients with NT1 and control subjects. (A, B) Pulse transit time (PTT) and heart period (HP) during daytime wakefulness (W) and nighttime sleep (S) in pediatric patients with narcolepsy type 1 (NT1) and control subjects. (C) PTT and HP dip from daytime W to nighttime S. (D, E) PTT during nighttime W in a lying position, sleep stages N1–N2, N3, and R, expressed in absolute values (D) or as percentage of the values during W (%PTT, E). (F, G) Corresponding results for HP and %HP. [*]p = 0.024, main effect of subject group (ANOVA). *p = 0.010, t-test. Data are means ± SEM with N = 27/19 NT1 patients/control subjects. The values of %PTT during total nocturnal sleep (Figure 2A) and during REM sleep (Figure 2B) correlated positively and significantly with cerebrospinal fluid hypocretin-1 in patients. The values of %PTT during REM sleep also depended significantly (p = 0.045) on whether the patients were obese (97% ± 1%), overweight (100% ± 1%), or had normal body weight (99% ± 1%). Figure 2. Open in new tabDownload slide Indexes of cardiovascular autonomic function during nocturnal sleep and of sleep structure correlated with cerebrospinal fluid hypocretin-1 concentration in pediatric patients with NT1. (A-B) Pulse transit time during total nocturnal sleep (A) or nocturnal rapid-eye-movement (REM) sleep (B) as percentage of the values during nighttime wakefulness in a lying position (%PTT). (C) Percentage of total sleep time spent in stage N1. (D) Wakefulness after sleep onset (WASO). Hypocretin-1 levels were measured in the cerebrospinal fluid. Each circle corresponds to a patient with narcolepsy type 1 (NT1). Panels show regression lines with 95% confidence intervals and Pearson’s correlation coefficients (r) and their significance (P), with N = 26. Figure 2. Open in new tabDownload slide Indexes of cardiovascular autonomic function during nocturnal sleep and of sleep structure correlated with cerebrospinal fluid hypocretin-1 concentration in pediatric patients with NT1. (A-B) Pulse transit time during total nocturnal sleep (A) or nocturnal rapid-eye-movement (REM) sleep (B) as percentage of the values during nighttime wakefulness in a lying position (%PTT). (C) Percentage of total sleep time spent in stage N1. (D) Wakefulness after sleep onset (WASO). Hypocretin-1 levels were measured in the cerebrospinal fluid. Each circle corresponds to a patient with narcolepsy type 1 (NT1). Panels show regression lines with 95% confidence intervals and Pearson’s correlation coefficients (r) and their significance (P), with N = 26. Nocturnal sleep architecture Compared with control subjects, patients with NT1 had significantly lower values of sleep latency and REM sleep latency, spent a significantly greater percentage of total sleep time in sleep stage N1, and had significantly higher values of wakefulness after sleep onset (Table 2). The percentage of total sleep time spent in sleep stage N1 and the values of wakefulness after sleep onset correlated negatively and significantly with cerebrospinal fluid hypocretin-1 levels in patients (Figure 2C and D). Table 2. Nocturnal sleep architecture in pediatric patients with NT1 and control subjects . NT1 . Controls . P . Total sleep time (min) 477 ± 12 482 ± 14 0.785 Sleep efficiency (%) 89 ± 2 92 ± 1 0.106 Sleep latency (min) 6 ± 2 14 ± 2 0.022* REM sleep latency (min) 18 ± 9 90 ± 9 <0.001* N1% 11 ± 1 6 ± 1 0.008* N2% 38 ± 2 37 ± 3 0.635 N3% 27 ± 2 33 ± 3 0.073 R% 24 ± 1 23 ± 1 0.846 Wakefulness after sleep onset (min) 50 ± 7 26 ± 4 0.008* Frameshift index (h−1) 15 ± 1 13 ± 1 0.067 . NT1 . Controls . P . Total sleep time (min) 477 ± 12 482 ± 14 0.785 Sleep efficiency (%) 89 ± 2 92 ± 1 0.106 Sleep latency (min) 6 ± 2 14 ± 2 0.022* REM sleep latency (min) 18 ± 9 90 ± 9 <0.001* N1% 11 ± 1 6 ± 1 0.008* N2% 38 ± 2 37 ± 3 0.635 N3% 27 ± 2 33 ± 3 0.073 R% 24 ± 1 23 ± 1 0.846 Wakefulness after sleep onset (min) 50 ± 7 26 ± 4 0.008* Frameshift index (h−1) 15 ± 1 13 ± 1 0.067 Indexes of nocturnal sleep architecture in pediatric patients with narcolepsy type 1 (NT1) and control subjects. REM, rapid-eye-movement. N1%, N2%, N3%, and R%, time spent in sleep stages N1, N2, N3, and REM sleep, respectively, expressed as percentage of total sleep time. Values are shown as mean ± SEM with N = 27/19 patients/controls. *Significance of between-group differences (p < 0.05, t-test). Open in new tab Table 2. Nocturnal sleep architecture in pediatric patients with NT1 and control subjects . NT1 . Controls . P . Total sleep time (min) 477 ± 12 482 ± 14 0.785 Sleep efficiency (%) 89 ± 2 92 ± 1 0.106 Sleep latency (min) 6 ± 2 14 ± 2 0.022* REM sleep latency (min) 18 ± 9 90 ± 9 <0.001* N1% 11 ± 1 6 ± 1 0.008* N2% 38 ± 2 37 ± 3 0.635 N3% 27 ± 2 33 ± 3 0.073 R% 24 ± 1 23 ± 1 0.846 Wakefulness after sleep onset (min) 50 ± 7 26 ± 4 0.008* Frameshift index (h−1) 15 ± 1 13 ± 1 0.067 . NT1 . Controls . P . Total sleep time (min) 477 ± 12 482 ± 14 0.785 Sleep efficiency (%) 89 ± 2 92 ± 1 0.106 Sleep latency (min) 6 ± 2 14 ± 2 0.022* REM sleep latency (min) 18 ± 9 90 ± 9 <0.001* N1% 11 ± 1 6 ± 1 0.008* N2% 38 ± 2 37 ± 3 0.635 N3% 27 ± 2 33 ± 3 0.073 R% 24 ± 1 23 ± 1 0.846 Wakefulness after sleep onset (min) 50 ± 7 26 ± 4 0.008* Frameshift index (h−1) 15 ± 1 13 ± 1 0.067 Indexes of nocturnal sleep architecture in pediatric patients with narcolepsy type 1 (NT1) and control subjects. REM, rapid-eye-movement. N1%, N2%, N3%, and R%, time spent in sleep stages N1, N2, N3, and REM sleep, respectively, expressed as percentage of total sleep time. Values are shown as mean ± SEM with N = 27/19 patients/controls. *Significance of between-group differences (p < 0.05, t-test). Open in new tab Muscle activity during nocturnal sleep Compared with control subjects, patients with NT1 had significantly higher values of the PLMS indexes during sleep stages N1–N3 and REM sleep and significantly lower values of RAI, whereas the AHI did not differ significantly between groups (Table 3). None of these indexes correlated significantly with cerebrospinal fluid hypocretin-1 levels in patients (p ≥ 0.155). Table 3. Values of indexes of respiratory, submentalis, and tibialis anterior muscle control during nocturnal sleep in pediatric patients with NT1 and control subjects . NT1 . Controls . P . AHI (h−1) 0.4 ± 0.1 0.6 ± 0.2 0.284 PLMiN1–N3 (h−1) 6.4 ± 1.4 1.9 ± 0.6 0.006* PLMiR (h−1) 7.8 ± 2.2 0.4 ± 0.3 0.003* RAI 0.79 ± 0.03 0.92 ± 0.01 <0.001* . NT1 . Controls . P . AHI (h−1) 0.4 ± 0.1 0.6 ± 0.2 0.284 PLMiN1–N3 (h−1) 6.4 ± 1.4 1.9 ± 0.6 0.006* PLMiR (h−1) 7.8 ± 2.2 0.4 ± 0.3 0.003* RAI 0.79 ± 0.03 0.92 ± 0.01 <0.001* Values of indexes of apnea–hypopnea (AHI), periodic limb movements (PLMi) during nocturnal sleep stages N1–N3 and rapid-eye-movement (REM) sleep (R), and REM sleep atonia (RAI) in pediatric patients with narcolepsy type 1 (NT1) and control subjects. Values are shown as mean ± SEM, with N = 23/18 and 27/19 patients/controls for RAI and for the other indexes, respectively. *p < 0.05, t-test. Open in new tab Table 3. Values of indexes of respiratory, submentalis, and tibialis anterior muscle control during nocturnal sleep in pediatric patients with NT1 and control subjects . NT1 . Controls . P . AHI (h−1) 0.4 ± 0.1 0.6 ± 0.2 0.284 PLMiN1–N3 (h−1) 6.4 ± 1.4 1.9 ± 0.6 0.006* PLMiR (h−1) 7.8 ± 2.2 0.4 ± 0.3 0.003* RAI 0.79 ± 0.03 0.92 ± 0.01 <0.001* . NT1 . Controls . P . AHI (h−1) 0.4 ± 0.1 0.6 ± 0.2 0.284 PLMiN1–N3 (h−1) 6.4 ± 1.4 1.9 ± 0.6 0.006* PLMiR (h−1) 7.8 ± 2.2 0.4 ± 0.3 0.003* RAI 0.79 ± 0.03 0.92 ± 0.01 <0.001* Values of indexes of apnea–hypopnea (AHI), periodic limb movements (PLMi) during nocturnal sleep stages N1–N3 and rapid-eye-movement (REM) sleep (R), and REM sleep atonia (RAI) in pediatric patients with narcolepsy type 1 (NT1) and control subjects. Values are shown as mean ± SEM, with N = 23/18 and 27/19 patients/controls for RAI and for the other indexes, respectively. *p < 0.05, t-test. Open in new tab The results of the DNE analysis of the submentalis, tibialis anterior, and hand extensor EMG activity during sleep are shown in Figure 3. Submentalis DNE did not differ significantly between NT1 patients and controls during sleep stages N1–N3 (Figure 3A), whereas during REM sleep, all submentalis DNE centiles were significantly higher in NT1 patients versus controls (Figure 3D). The 97th and 99th centiles of the average tibialis anterior DNE were significantly higher in NT1 patients than in controls during sleep stages N1–N3 (Figure 3B) and REM sleep (Figure 3E). Similarly, the 95th, 97th, and 99th centiles of the average hand extensor DNE were significantly higher in NT1 patients versus controls during sleep stages N1–N3 (Figure 3C) and REM sleep (Figure 3F). None of the DNE indexes that differed significantly between NT1 patients and controls correlated significantly with cerebrospinal fluid hypocretin-1 levels in patients (p ≥ 0.383). Figure 3. Open in new tabDownload slide Distributions of normalized electromyographic activity (EMGNORM) of submentalis, tibialis anterior and hand extensor muscles during nocturnal sleep stages N1–N3 and rapid-eye-movement (REM) sleep in pediatric patients with narcolepsy type 1 (NT1) and control subjects. *p < 0.05, NT1 patients versus controls (t-test). Data are means ± SEM with N = 15–26 versus 13–19 patients/controls for different comparisons, as detailed in the Statistical Analysis section. Figure 3. Open in new tabDownload slide Distributions of normalized electromyographic activity (EMGNORM) of submentalis, tibialis anterior and hand extensor muscles during nocturnal sleep stages N1–N3 and rapid-eye-movement (REM) sleep in pediatric patients with narcolepsy type 1 (NT1) and control subjects. *p < 0.05, NT1 patients versus controls (t-test). Data are means ± SEM with N = 15–26 versus 13–19 patients/controls for different comparisons, as detailed in the Statistical Analysis section. Hierarchical clustering to screen variables linked to cardiovascular autonomic dysfunction during nocturnal sleep Figure 4 shows the results of two different runs of hierarchical clustering involving PTT-based indexes of cardiovascular autonomic function during sleep, indexes of sleep architecture, and indexes of EMG activity during sleep in the whole sample under study. The analysis performed considering all the indexes that differed significantly between patients with NT1 and control subjects (Figure 4A) revealed two main clusters. One cluster (top) included DNE- and PLMS-based indexes of EMG activity together with sleep latency, the percentage of total sleep time spent in sleep stage N1, and wakefulness after sleep onset. The second cluster (bottom) consisted of a subcluster including the %PTT indexes during total nocturnal sleep and REM sleep, which clustered with REM sleep latency and RAI, albeit with a high rescaled distance. These results were confirmed by the alternative cluster analysis performed excluding hand extensor DNE-based indexes to maximize sample size (Figure 4B). Figure 4. Open in new tabDownload slide Hierarchical clustering of indexes of altered nocturnal sleep in pediatric patients with NT1 and control subjects. Panel A and B are dendrograms showing the results of a hierarchical cluster analyses performed on subjects with no missing indexes to maximize information (A) or on all subjects to maximize sample size (B) (cf. Methods section for details). SM, TA, HE: submentalis, tibialis anterior, and hand extensor muscles, respectively. N1%, percentage of total sleep time spent in sleep stage N1. N1–N3 and R, sleep stages N1–N3 and rapid-eye-movement (REM) sleep, respectively. Numbers refer to the corresponding centiles of the distribution of normalized electromyographic activities. PLMi, indexes of periodic limb movements during sleep. Sleep and REM Lat., sleep and REM sleep latency, respectively. WASO, wakefulness after sleep onset. %PTT, values of pulse transit time during total nocturnal sleep (S) or R expressed as % of the value of PTT during nighttime wakefulness in a lying position. RAI, REM sleep atonia index. Figure 4. Open in new tabDownload slide Hierarchical clustering of indexes of altered nocturnal sleep in pediatric patients with NT1 and control subjects. Panel A and B are dendrograms showing the results of a hierarchical cluster analyses performed on subjects with no missing indexes to maximize information (A) or on all subjects to maximize sample size (B) (cf. Methods section for details). SM, TA, HE: submentalis, tibialis anterior, and hand extensor muscles, respectively. N1%, percentage of total sleep time spent in sleep stage N1. N1–N3 and R, sleep stages N1–N3 and rapid-eye-movement (REM) sleep, respectively. Numbers refer to the corresponding centiles of the distribution of normalized electromyographic activities. PLMi, indexes of periodic limb movements during sleep. Sleep and REM Lat., sleep and REM sleep latency, respectively. WASO, wakefulness after sleep onset. %PTT, values of pulse transit time during total nocturnal sleep (S) or R expressed as % of the value of PTT during nighttime wakefulness in a lying position. RAI, REM sleep atonia index. Correlation analysis to identify variables linked to cardiovascular autonomic dysfunction during sleep The analysis of linear correlations between indexes indicated that %PTT during total nocturnal sleep and %PTT during REM sleep correlated positively and significantly with each other in the whole sample and in each subject group (r ≥ 0.78, p < 0.001). In contrast, neither %PTT during total nocturnal sleep nor %PTT during REM sleep correlated significantly with REM sleep latency (p ≥ 0.099). The values of RAI correlated positively and significantly with age in the whole sample (r = 0.51, p = 0.001) and in NT1 patients (r = 0.57, p = 0.005), but not in control subjects (p = 0.230). The correlations between RAI, REM sleep latency, and the %PTT indexes, computed correcting for age as appropriate, were not statistically significant (p = 0.052 for RAI versus REM sleep latency in the whole sample, p ≥ 0.107 otherwise). Discussion Our study yielded three main findings: (1) PTT values lengthened less from nocturnal sleep to nocturnal wakefulness in pediatric patients with NT1 versus controls, suggesting blunted sleep-related changes in arterial blood pressure, and this alteration was associated with lower cerebrospinal fluid hypocretin-1 levels; (2) nocturnal EMG overactivity of pediatric patients with NT1 was generalized, involving submentalis muscles during REM sleep and upper and lower limb muscles during sleep stages N1–N3 and REM sleep, and it was not correlated with cerebrospinal fluid hypocretin-1 levels; and (3) cluster and correlation analyses showed that alterations in PTT during nocturnal sleep in pediatric patients with NT1 could not be explained by alterations in sleep structure or by EMG overactivity during sleep, suggesting that sleep-related alterations in arterial blood pressure may be a direct result of the hypocretin loss associated with NT1. PTT is rapidly gaining popularity as a cost-effective, unobtrusive method to gauge cardiovascular control during sleep, particularly in children [15]. With the simple technical approach adopted in this study, PTT is computed based on data from a finger pulse oximeter and the electrocardiogram, both of which were part of our standard polysomnography setup (SOMNOscreen Plus apparatus, SOMNOmedics GmbH). Commercial pulse oximeters may not be suitable for PTT estimation, as they heavily process the photoplethysmography waveform to reduce movement artifacts [14, 32]. With our setup, PTT includes the pre-ejection period between the electrocardiographic R wave peak and the onset of the aortic pulse wave [14]. Thus, lengthening of the PTT in a given subject, with this approach, implies that either the pre-ejection period is lengthened or the pulse wave velocity in the arterial tree is reduced. The pre-ejection period is a validated marker of sympathetic cardiac control, and becomes longer with weaker sympathetic control [33]. The pulse wave velocity depends directly on the stiffness of the arterial vessel wall, which, in turn, depends directly on arterial blood pressure [14]. Sympathetic activity to the heart and resistance vessels is a key determinant of arterial blood pressure. Thus, lengthening of the PTT during sleep compared with wakefulness (Figure 1A and D) is consistent with a decrease in sympathetic activity to the heart and/or to blood vessels during sleep. A decrease in sympathetic activity to the heart and resistance blood vessels has indeed been demonstrated during sleep in animal models [16, 34]. Along these lines, our finding that %PTT was lower in pediatric patients with NT1 than in control subjects during nocturnal sleep overall and during REM sleep in particular (Figure 1E) suggests that in these patients, nocturnal sleep and particularly REM sleep entail a blunted decrease in sympathetic activity to the heart and/or to blood vessels compared with nocturnal wakefulness in the lying position. Further mechanistic insight may be provided by the corresponding analysis of HP and %HP, which did not differ significantly between pediatric patients with NT1 and control subjects (Figure 1F and G). This is of interest because HP is linearly related to cardiac sympathetic and parasympathetic nerve activities [21]. While cardiac sympathetic and parasympathetic activity may occasionally show positive covariation, such as in the diving response [35], the physiological pattern during sleep is characterized by reciprocal changes in the two autonomic branches [34]. Moreover, a recent study on pediatric patients with NT1 during sleep did not detect changes in cardiac parasympathetic modulation [10], which correlates with cardiac parasympathetic tone [36]. Taken together, and with all the limitations associated with indirect measurements in the pediatric sample under study, the present data obtained on PTT and HP suggest that it was arterial blood pressure, and not sympathetic activity to the heart, that decreased less during total nocturnal sleep, and particularly during REM sleep, compared with nocturnal wakefulness in the lying position in pediatric patients with NT1 versus control subjects. This conclusion fits well with results on mouse models of NT1 [7, 37, 38] and adult patients with NT1 [39] (see also [8] for a recent translational review). The cardiovascular autonomic alteration we found in pediatric patients with NT1 during sleep was relatively mild. Accordingly, differences in PTT between nighttime sleep and daytime wakefulness were preserved in these patients (Figure 1C), whereas a nondipping pattern of arterial blood pressure is common in adult patients with NT1 [26, 39, 40]. Along these lines, pediatric patients with NT1 do not have a significantly increased risk of circulatory or cardiovascular diseases shortly after NT1 onset [41]. It remains to be determined whether a mild cardiovascular autonomic dysfunction arising at a critical young age, such as the one we found in pediatric NT1 patients during nocturnal sleep, may eventually increase cardiovascular risk later in life, also considering the peculiar pathophysiology and therapeutic options of adult patients with NT1. On the one hand, muscle sympathetic nerve activity during relaxed wakefulness is normal in adult patients with NT1 before nocturnal sleep [42], whereas it is significantly reduced during the day [43]. This might represent a cardiovascular protective factor for these patients. On the other hand, treatment with psychostimulants increases diastolic arterial blood pressure and heart rate in adult patients with NT1, potentially increasing their cardiovascular risk [44]. The overall balance may favor cardiovascular risk, as enhanced morbidity due to circulatory or cardiovascular diseases [45, 46] as well as increased mortality [46, 47] have been reported for adult patients with NT1. The mechanisms underlying the blunted fall in arterial blood pressure observed during sleep in pediatric patients with NT1 remain to be understood [8]. We found that values of %PTT clustered with REM sleep latency and RAI (Figure 4). This link was robust, persisting despite the change in variable sets employed for hierarchical clustering, but was not tight (see high rescaled distance between indexes in Figure 4), and was not accompanied by significant linear correlations between these variables. On the other hand, the alteration in %PTT indexes in pediatric patients with NT1 was more severe in subjects with lower cerebrospinal fluid hypocretin-1 levels (Figure 2A and B). Our data are thus consistent with the hypothesis that the changes in %PTT in pediatric patients with NT1 are a direct consequence of hypocretin deficiency, rather than an epiphenomenon secondary to EMG overactivity during sleep or to altered sleep structure. The observation of blunted sleep-related differences in arterial blood pressure both in hypocretin knock-out mice [7], which lack hypocretins but have viable hypocretin neurons [48], and in hypocretin-ataxin3 transgenic mice [7, 37, 38], which lack the whole hypocretin neurons [49], also indicates a causal role of hypocretin deficiency. Accordingly, hypocretin neurons are an important part of the central autonomic network involved in cardiovascular control [50]. Nevertheless, we cannot rule out the possibility that indexes of sleep structure or motor control during sleep not included in the present analyses, such as indexes of state dissociation [51–53], would have clustered and correlated significantly with %PTT. The finding that obese pediatric patients with NT1 had the greatest alteration in %PTT during REM sleep should also be confirmed and extended to evaluate its robustness and causal contribution. We performed the most comprehensive evaluation to date of cardiovascular autonomic dysfunction, sleep architecture alterations, and EMG overactivity during nocturnal sleep in pediatric patients with NT1. Our findings on alterations in sleep architecture (Table 2) and those on PLMS indexes and RAI (Table 3) broadly matched previous results [10, 13, 54]. We extend previous reports by finding that in pediatric patients with NT1, increases in sleep stage N1 and wakefulness after sleep onset were more severe in subjects with lower cerebrospinal fluid hypocretin-1 levels (Figure 2C and D), and that the lack of atonia during REM sleep (RAI) was more severe in younger NT1 patients. We also confirmed the validity of submentalis DNE [30], a novel translational technique of EMG analysis applicable to different muscles and species, in pediatric patients with NT1, confirming previous findings on neck muscle DNE in NT1 mouse models [30]. The DNE analysis of tibialis anterior muscles in the present study revealed higher values in the rightmost tail (97th and 99th centiles) of the EMG distributions during sleep stages N1–N3 and REM sleep in pediatric patients with NT1 versus control subjects (Figure 3B and E). By comparison, a previous study employing DNE found that the 97th and 99th centiles of the tibialis anterior EMG distributions had higher values in adult subjects with idiopathic REM sleep behavior disorder (RBD) than in control subjects [30]. This is of interest because RBD is common in pediatric patients with NT1, although with features different from those of idiopathic RBD in adults, such as calm, repetitive, and slow gesturing [13]. In addition, we obtained for the first time quantitative evidence that a pattern of muscle overactivity similar to that observed for tibialis anterior muscles also characterizes the hand extensor muscles during the sleep stages N1–N3 and REM sleep in pediatric patients with NT1 (Figure 3C and F). Periodic arm movements involving the extensor digitorum brevis muscle have been reported in adult patients with restless legs syndrome, although they were much less frequent than periodic leg movements during sleep [55]. Further studies are needed to confirm our finding on hand extensor muscle overactivity during sleep in pediatric patients with NT1, and to clarify whether and to what extent this is associated with PLMS or RBD. An important limitation of this study is that due to the rarity of NT1 and to the difficulty of obtaining full polysomnographic recordings from control children and adolescents, we analyzed all available subject recordings that satisfied inclusion criteria instead of determining the sample size a priori with a statistical power analysis. As a result, our study may have been inadequately powered. This limitation may have been particularly relevant to analyses of hand extensor EMG recordings, which were available only from a subset of subjects (cf. Statistical Analysis section for details). The sample size of the present study was nonetheless sufficient to detect significant differences in %PTT and in indexes of sleep disruption and EMG overactivity, including the overactivity of hand extensor muscles, between pediatric patients with NT1 and control subjects. Another important limitation of the present study is that it gauged autonomic cardiovascular control during sleep only indirectly, based on PTT and HP analyses. However, direct measurements of arterial blood pressure and sympathetic nerve activity during sleep would have been ethically unjustified on pediatric patients with NT1 and even more so in control children and adolescents. In conclusion, our data comprehensively evaluate autonomic and muscle tone activity during nocturnal sleep in pediatric patients with NT1. Pediatric patients with NT1 showed lower ability compared with controls to modulate arterial blood pressure as a function of wake–sleep states during the night, a finding influenced by cerebrospinal fluid hypocretin-1 levels and obesity, but not by sleep disruption or EMG overactivity. The unique signature of autonomic alteration found in children and adolescents close to NT1 disease onset mandates further experimental work on mice to understand the neuronal networks involved and to rescue the phenotype, and follow-up clinical cardiovascular studies across age on patients to prevent possible long-term negative outcomes. Funding E.M. is funded by donations from patients and by an unrestricted grant by Jazz Pharmaceutical. Acknowledgments We are indebted to all the children, adolescents, and families who participated in this study, most notably to the Italian Association of Narcolepsy (AIN Onlus) patients and the late AIN President, Mr. Icilio Ceretelli, who prematurely passed away on November 7, 2018. Without their contributions, this study would not have been possible. Conflict of interest statement. S.V., S.R., F.P., M.M., E.A., R.F., and A.S. have no financial and nonfinancial disclosures. E.M. received research support from Jazz Pharmaceuticals, Merck, Glaxo Smith Kline, and Vox Media and personal fees from Novo Nordisk and Reset Pharmaceuticals. G.P. participated in advisory board for Jazz, Bioprojet, and Idorsia. Work Performed: IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; and Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. References 1. Kornum BR , et al. Narcolepsy . Nat Rev Dis Primers. 2017 ; 3 : 16100 . 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TI - Cardiovascular autonomic dysfunction, altered sleep architecture, and muscle overactivity during nocturnal sleep in pediatric patients with narcolepsy type 1
JF - SLEEP
DO - 10.1093/sleep/zsz169
DA - 2019-12-24
UR - https://www.deepdyve.com/lp/oxford-university-press/cardiovascular-autonomic-dysfunction-altered-sleep-architecture-and-SRu9GArGSA
VL - 42
IS - 12
DP - DeepDyve
ER -