pii: jc- 00543-15http://dx.doi.org/10.5664/jcsm.6342
S CI E NT IF IC IN VES TIGATIONS
Obstructive Sleep-Disordered Breathing Is More Common than Central in Mild Familial Dysautonomia Max J. Hilz, MD1,2; Sebastian Moeller, MD1; Susanne Buechner, MD3; Hanna Czarkowska, MD4; Indu Ayappa, PhD5; Felicia B. Axelrod, MD6; David M. Rapoport, MD5 Department of Neurology, University of Erlangen-Nürnberg, Erlangen, Germany; 2Autonomic Unit, University Colloge of London, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; 3Department of Neurology, General Hospital of Bozen/Bolzano, Bozen/Bolzano, Italy; 4Cushing Neuroscience Institute, NS-LIJ Health System, Great Neck, NY; 5Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of Medicine, New York, NY; 6Dysautonomia Center, New York University Langone School of Medicine, New York, NY 1
Study Objectives: In familial dysautonomia (FD) patients, sleep-disordered breathing (SDB) might contribute to their high risk of sleep-related sudden death. Prevalence of central versus obstructive sleep apneas is controversial but may be therapeutically relevant. We, therefore, assessed sleep structure and SDB in FD-patients with no history of SDB. Methods: 11 mildly affected FD-patients (28 ± 11 years) without clinically overt SDB and 13 controls (28 ± 10 years) underwent polysomnographic recording during one night. We assessed sleep stages, obstructive and central apneas (≥ 90% air flow reduction) and hypopneas (> 30% decrease in airflow with ≥ 4% oxygen-desaturation), and determined obstructive (oAI) and central (cAI) apnea indices and the hypopnea index (HI) as count of respective apneas/hypopneas divided by sleep time. We obtained the apnea-hypopnea index (AHI4%) from the total of apneas and hypopneas divided by sleep time. We determined differences between FD-patients and controls using the U-test and within-group differences between oAIs, cAIs, and HIs using the Friedman test and Wilcoxon test. Results: Sleep structure was similar in FD-patients and controls. AHI4% and HI were significantly higher in patients than controls. In patients, HIs were higher than oAIs and oAIs were higher than cAIs. In controls, there was no difference between HIs, oAIs, and cAIs. Only patients had apneas and hypopneas during slow wave sleep. Conclusions: In our FD-patients, obstructive apneas were more common than central apneas. These findings may be related to FD-specific pathophysiology. The potential ramifications of SDB in FD-patients suggest the utility of polysomnography to unveil SDB and initiate treatment. Commentary: A commentary on this article appears in this issue on page 1583. Keywords: familial dysautonomia, hereditary sensory and autonomic neuropathy type III, obstructive sleep apnea, sleep-disordered breathing Citation: Hilz MJ, Moeller S, Buechner S, Czarkowska H, Ayappa I, Axelrod FB, Rapoport DM. Obstructive sleep-disordered breathing is more common than central in mild familial dysautonomia. J Clin Sleep Med 2016;12(12):1607–1614.
I N T RO D U C T I O N
BRIEF SUMMARY
Familial dysautonomia (FD), also known as Riley-Day syndrome or hereditary sensory and autonomic neuropathy type III (HSAN III), is a rare autosomal recessive disorder with extensive deficits of sensory, sympathetic, and to some extent also parasympathetic neurons.1–3 Autonomic insufficiency especially affects cardiovascular and respiratory systems4 and accounts for manifold autonomic complications including orthostatic hypotension, recumbent hypertension, dysautonomic crises with excessive hypertension, hyperhidrosis, respiratory irregularities,5 and sudden unexplained death.2 According to Axelrod et al., 32% of FD patients,1 succumb to sudden unexplained death, particularly during sleep or in early morning hours.2 FD patients are known to have respiratory and sleep disorders.1,5,6 In a large cohort of FD patients, Axelrod et al. reported a far higher risk of sudden death during sleep (68%) than during wakefulness (32%).1 Mechanisms leading to fatalities are still unknown but might be associated with sleep-related breathing abnormalities, such as “shallow” breathing or respiratory arrest.3–5 1607
Current Knowledge/Study Rationale: In patients with familial dysautonomia (FD), sleep-disordered breathing (SDB) may contribute to their increased risk of sleep-related fatalities. Particularly in FD patients without clinically overt SDB, prevalence and type of SDB are controversial, and were assessed in this study. Study Impact: In 11 mildly affected FD patients, polysomnography demonstrated higher indices of obstructive than central apneas which seems to be related to FD-specific pathophysiology. The polysomnography results enhance the understanding of SDB in FD patients and add to their improved treatment.
Previous studies in FD patients suggest that there is significant sleep-disordered breathing that has been described as primarily central.5 It has also been suggested that this may be due to their central autonomic and respiratory pathology.5–8 Yet most reports are based on only few cases8 or on methods that may underestimate the obstructive component of SDB assessed during standard polysomnography recordings.5 Guilleminault et al. reported central apneas in two FD girls.8 Similarly, Gadoth et al. recorded predominantly central sleep apneas in 13 Journal of Clinical Sleep Medicine, Vol. 12, No. 12, 2016
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FD patients but also recorded more obstructive than central sleep apneas in two of their FD patients.6 Weese-Mayer and co-workers studied breathing abnormalities in 25 FD children using a vest-like monitoring system and found central sleep apneas in 22 of the 25 children. However, the authors mentioned that their recording system could not precisely monitor obstructive apneas.5 While obstructive apneas can be treated with continuous positive airway pressure (CPAP), this treatment is less successful in central sleep apneas.9,10 In FD patients, the pathology with central and peripheral autonomic dysfunction,2,4,11–19 kyphoscoliosis,20 and craniofacial abnormalities21 may give rise to both central and obstructive sleep apneas. While patients with clinically overt respiratory problems undergo close monitoring and often receive treatment for their sleep-disordered breathing,22,23 patients with mild forms of FD and without evident respiratory problems may be at higher risk of undiagnosed sleep-disordered breathing and subsequent complications. In order to better determine the type of sleep-disordered breathing in such patients, we conducted polysomnographic recordings in eleven mildly affected FD patients without clinically manifest respiratory disturbances.
environment. Study participants rested supine ≥ 30 min after arrival in the laboratory. During this period, all monitoring devices were applied. The nocturnal polysomnography included recordings of electroencephalogram (EEG) at the standard scalp positions C3, C4, Fz, O1, O2 of the international 10-20 system, using superficial disc electrodes. Positions A1 and A2 served as reference electrodes. We also recorded the electrooculogram (EOG), electromyogram (EMG) using surface electrodes placed laterally to the chin, the body position using a multiposition mercury switch (Bio-Logic, Mundelein, IL), periodic leg movements using EMG electrodes placed over the left and right anterior tibial muscle, baseline O2 saturation by means of finger pulse oximetry (Nellcor, Pleasanton, CA), respiratory airflow using nasal cannulae connected to a commercial pressure transducer (Pro-tech PTAF2, Mukilteo, WA), supplemented by an oral thermistor, and baseline end-tidal carbon dioxide (PCO2 ) measured by infrared absorption (Colin-Pilot, Colin Medical, San Antonio, TX, USA). The output of the pressure transducer was connected to a DC amplifier with an internal 2.5 Hz low pass filter. Evaluated Sleep Parameters Polysomnography data were scored visually according to standard Rechtschaffen and Kales sleep staging criteria.28 Sleep recordings were evaluated for the following measures of sleep continuity and architecture: • Total sleep time • Sleep efficiency, defined as the total sleep time divided by the time spent in bed29 • Time awake during polysomnographic recording • Percentage of NREM sleep stages 1, 2, 3, and 4, and of REM sleep. Stages 1 and 2 were combined into non-slow wave sleep (NSWS), stages 3 and 4 were combined into slow wave sleep (SWS) in accord with current scoring rules. • Sleep onset latency, defined as the time from lights out to the first epoch of any stage other than awake • REM sleep latency, defined as the time from sleep onset to the first REM sleep episode6
METHODS
Study Participants and Methods
In 11 mildly affected FD patients (45.5% female/54.5% male; age range 15 to 50 years, mean age 28 ± 11 years) without significant and clinically overt respiratory difficulties, and in 14 age-matched control persons (50% female/50% male, age range 14 to 48 years, mean age 29 ± 10 years, p > 0.05), we assessed the body mass index (BMI = body weight / height 2) and performed polysomnographic sleep recording. The protocol was approved by the Institutional Review Board of New York University School of Medicine. Informed consent was obtained prior to the study, and the study was registered at the German Clinical Trial Register (DRKS00008852). Patient Inclusion Criteria All FD patients had the characteristic genetic haplotype, i.e., they were homozygous for the intron 20 mutation on the IKBKAP gene24 and fulfilled diagnostic criteria of FD25,26 including Ashkenazi Jewish ancestry, absence of deep tendon reflexes, overflow tears, lingual fungiform papillae, and of axon flare response following intradermal histamine injection.25,26 Pittsburgh Sleep Quality Index (PSQI) during the Month prior to Polysomnography Sleep quality during the month prior to the polysomnographic sleep recording was assessed using a validated self-administered questionnaire, the Pittsburgh Sleep Quality Index (PSQI).27 As per Buysse et al., we used a PSQI score threshold of 5 to distinguish “poor sleepers” from “good sleepers.” 27
Respiratory Events We defined respiratory events as air flow reduction of ≥ 10 s duration relative to airflow at baseline according to the American Academy of Sleep Medicine (AASM) Task Force.30 We classified respiratory events as:31 • Obstructive sleep apnea for airflow reduction of > 90% from baseline with continued or increased inspiratory effort30,32 • Central sleep apnea for airflow reduction of > 90% from baseline without respiratory effort30 • Hypopnea for any visible significant air flow reduction (> 30% decrease in airflow) associated with ≥ 4% desaturation (“preferred” AASM definition)32,33
Polysomnography Recording The polysomnographic recordings were performed in the NYU Sleep Disorders Center located in a quiet, temperature-controlled Journal of Clinical Sleep Medicine, Vol. 12, No. 12, 2016
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The apnea indices (total-AI, obstructive-oAI and central-cAI) and hypopnea index (HI) were obtained by the count of the respective apneas or hypopneas divided by total sleep or sleep stage time. Apnea-hypopnea index (AHI4%) was obtained
MJ Hilz, S Moeller, S Buechner et al. Obstructive Sleep Apneas in Familial Dysautonomia
Table 1—Patient characteristics and sleep quality parameters. Parameter Age, years BMI, kg/m2 PSQI score Global PSQI score Component scores Subjective sleep quality Sleep latency Sleep duration Habitual sleep efficiency Sleep disturbances Use of sleeping medications Daytime dysfunction Total sleep time, min Sleep efficiency, % Sleep latency, min REM sleep latency, min NSWS, % SWS, % REM, % WASO, % O2-saturation, % end-tidal PCO2, mm Hg
FD Patients (n = 11) 28 ± 11 20.1 ± 3.2
Controls (n = 13) 28 ± 10 24.9 ± 2.4
p value 0.776 < 0.001
5.1 ± 3.2
3.6 ± 1.8
0.277
0.7 ± 0.7 1.6 ± 1.5 0.6 ± 0.7 0.2 ± 0.6 0.9 ± 0.5 0.6 ± 1.2 0.6 ± 0.5 307 ± 65 76.8 ± 15.9 36.1 ± 42.9 157 ± 104 51.9 ± 15.7 20.4 ± 14.2 11.7 ± 7.0 16.1 ± 12.9 96.2 ± 3.7 44.7 ± 3.3
0.7 ± 0.5 0.9 ± 0.4 0.3 ± 0.6 0.2 ± 0.4 0.9 ± 0.4 0 0.7 ± 0.8 354 ± 83 78.2 ± 15.6 16.6 ± 11.2 140 ± 107 54.4 ± 8.9 12.5 ± 6.9 14.4 ± 6.3 18.9 ± 15.1 98.7 ± 1.2 41.2 ± 4.1
1.000 0.531 0.392 0.649 0.865 0.277 0.776 0.150 0.649 0.569 0.794 0.649 0.207 0.392 0.776 0.015 0.035
Age characteristics, the body mass index (BMI), Pittsburgh Sleep Quality Index (PSQI) score results, total sleep time (min), sleep efficiency (%), sleep latency (min), rapid eye movement (REM) sleep latency (min), non-slow wave sleep, slow wave sleep, REM sleep, wake after sleep onset (WASO), O2 -saturation, and end-tidal PCO2 at baseline in 11 FD patients and 13 controls. Statistically significant values in bold (p < 0.05).
from the total of obstructive and central apneas and all hypopneas divided by the total sleep or sleep stage time.33 We defined sleep-disordered breathing (SDB) as “mild” for AHI4% values between 5 and 15/h, as “moderate” for AHI4% values above 15/h and below 30/h, and as “severe” for AHI4% values above 30/h.33
sleep stages in FD patients and control persons, we applied Bonferroni corrections and assumed statistical significance for p values at or below 0.0025.
Statistics
PSQI scores were similar between patients and controls (5.1 ± 3.2 vs. 3.6 ± 1.8; p > 0.05). Three patients and none of the controls were on sleeping medication prior to the polysomnographic sleep recording. Five patients and 3 controls fulfilled criteria of poor sleepers with PSQI scores ≥ 5 (p > 0.05; Table 1). BMI was significantly lower in FD patients (20.1 ± 3.2) than in controls (24.9 ± 2.4, p < 0.001). At baseline (before sleep), O2 saturation was lower in the patients than the controls (96.2 ± 3.7% vs. 98.7 ± 1.2%; p = 0.015), while end-tidal PCO2 was higher in patients than controls (44.7 ± 3.3 mm Hg vs. 41.2 ± 4.1 mm Hg; p = 0.035; Table 1). In the patients, PCO2 values ranged from 38.8 mm Hg to 49.7 mm Hg. In the control persons, PCO2 values ranged from 34.2 mm Hg to 46.9 mm Hg. The total sleep time during the polysomnographic recording did not differ between patients (307 ± 65 min) and control persons (354 ± 83 min; p > 0.05). Similarly, sleep efficiency, sleep latency, and REM sleep latency did not differ significantly between patients (76.8 ± 15.9%, 36.1 ± 42.9 min, 157.1 ± 104.3 min) and controls (78.2 ± 15.6%, 16.6 ± 11.2 min, 140 ± 107 min; p > 0.05). Moreover, the percentage of
For data analysis, we used a commercially available statistical program (SPSS 20.0, SPSS Inc., Chicago, IL). We tested data for normal distribution by the Shapiro-Wilk test. PSQI scores and parameters of sleep continuity and architecture are presented as mean values ± standard deviation (SD). Parameters of sleep-disordered breathing are presented as median and lower and upper quartile values. For comparison of differences between FD patients and controls, i.e., differences in PSQI scores, parameters of sleep continuity and architecture, and differences in the respiratory event indices between groups, we used t-tests for unpaired samples in case of normal distribution, and the Mann-Whitney-U test in case of non-normal distribution of data. For non-normally distributed data, we tested withingroup differences between oAIs, cAIs, and HIs using the Friedman-test, and differences between two parameters using the Wilcoxon-test. For dichotomous parameters, such as presence or absence of sleep-disordered breathing (e.g., AHI4% > 5/h) in patients or controls, we used Fisher exact test. To account for multiple comparisons of SDB parameters during various 1609
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Table 2—AHI4% and Hypopnea/apnea indices during different sleep stages. AHI4%/h during all sleep stages persons with AHI4% > 5/h during NSWS persons with AHI4% > 5/h during SWS persons with AHI4% > 5/h during REM sleep persons with AHI4% > 5/h AI/h during all sleep stages during NSWS during SWS during REM sleep oAI/h during all sleep stages during NSWS during SWS during REM sleep cAI/h during all sleep stages during NSWS during SWS during REM sleep HI/h during all sleep stages during NSWS during SWS during REM sleep
11 FD Patients
13 Controls
p value
4.9 [3.3; 9.8] 5/11 2.9 [2.4;15.2] 4/11 1.6 [0; 2.9] 2/11 9.8 [1.2; 21.3] 7/9
0.2 [0; 0.8] 2/13 0 [0; 0.6] 2/13 0 [0; 0] 0/13 0 [0; 3.2] 2/13
0.001* 0.394 < 0.001* 0.651 0.007 0.480 0.072 0.113
1.6 [0; 3.1] 1.8 [0; 3.2] 0 [0; 0.7] 0 [0; 6.7]
0 [0; 0.2] 0 [0; 0.1] 0 [0; 0] 0 [0; 1.2]
0.055 0.041 0.277 0.569
1.4 [0; 3.1] 1.2 [0; 3.2] 0 [0; 0] 0 [0; 4.9]
0 [0; 0.1] 0 [0; 0.8] 0 [0; 0] 0 [0; 0]
0.082 0.106 0.459 0.459
0 [0; 0.2] 0 [0; 0] 0 [0; 0] 0 [0; 0]
0 [0; 0.2] 0 [0; 0] 0 [0; 0] 0 [0; 0.7]
1.000 0.691 0.733 0.691
2.9 [1.8; 5.7] 2.1 [1.1; 12.8] 1.3 [0; 2.9] 8.8 [0; 18.5]
0 [0; 0.7] 0 [0; 0.6] 0 [0; 0] 0 [0; 2.7]
0.001* 0.001* 0.022 0.035
Values are presented as median [lower; upper quartile]. Sleep disordered breathing indices are AHI4% (apneas and hypopneas with ≥ 4% oxygen desaturation per hour), apnea index (AI), obstructive (oAI), central (cAI) apnea index, and hypopnea index (HI) per hour in 11 FD patients and 13 control persons overall and during the different sleep stages. The indices were obtained by the count of the respective apneas or hypopneas divided by total sleep time or sleep stage time. We determined differences between FD patients and controls using the Mann-Whitney U-test. We compared differences in the number of patients and of controls with AHI4% > 5/h by the Fisher exact test. Statistically significant values in bold (p < 0.05). To account for multiple comparisons of SDB parameters at various sleep stages in FD patients and control persons, we applied Bonferroni corrections and assumed statistical significance only for p values ≤ 0.0025, marked by an asterisk (*).
NSWS, SWS, REM sleep, and the time awake during the polysomnographic recording were similar between patients (51.9 ± 15.7%, 20.4 ± 14.2%, 11.7 ± 7.0%, 16.1 ± 12.9%) and controls (54.4 ± 8.9%, 12.5 ± 6.9%, 14.4 ± 6.3%, 18.9 ± 15.1%; p > 0.05; Table 1). In two FD- patients (18.2%), we recorded no REM sleep.
Sleep-Disordered Breathing in FD Patients and Controls
In the 11 FD patients, AHI4% values ranged from 1.3 to 34.7/h (Table 2). One patient had severe SDB with an AHI4% value of 34.7/h. Four FD patients had mild SDB with AHI4% values between 5 and 15/h. Six patients had AHI4% values < 5/h. AHI4% values were higher in patients (median 4.9; lower quartile 3.3; upper quartile 9.8/h) than in controls (median 0.2; lower quartile 0; upper quartile 0.8/h; p = 0.001). Journal of Clinical Sleep Medicine, Vol. 12, No. 12, 2016
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One control person had severe SDB with an AHI4% value of 114.9/h. To better compare the findings of the controls to the findings of the FD patients, we excluded this outlier from the further analysis. Thus, 13 controls (53.8% female/46.2% male), were included in the analysis. Two controls had mild SDB, with AHI4% values of 12.1/h and 9.5/h. The other 11 controls had AHI4% values < 1/h (Table 2; Figure 1). AIs, oAIs, and cAIs were similar in patients and controls (Table 2). However, HIs were higher in patients (median 2.9; lower quartile 1.8; upper quartile 5.7/h) than in controls (median 0; lower quartile 0; upper quartile 0.7/h; p = 0.001; Table 2). In the patients, HIs were higher than oAIs (median 1.4; lower quartile 0; upper quartile 3.1; p = 0.026) and oAIs were higher than cAIs (median 0; lower quartile 0; upper quartile 0.2; p = 0.036), while HIs, oAIs, and cAIs did not differ in controls (Table 3).
MJ Hilz, S Moeller, S Buechner et al. Obstructive Sleep Apneas in Familial Dysautonomia
Figure 1—AHI4%/h values.
Table 3—Within-group differences between oAIs, cAIs, and HIs. Comparison of FD Patients oAI/h vs. cAI/h during all sleep stages 0.036 cAI/h vs. HI/h during all sleep stages 0.006 oAI/h vs. HI/h during all sleep stages 0.026
Controls 0.495 0.495 0.495
Values presented as p values. Within-group differences between oAIs, cAIs, and HIs during all sleep stages. We determined within-group differences between oAIs, cAIs, and HIs using the Friedman and Wilcoxon tests. Statistically significant values in bold (p < 0.05).
Obstructive Apneas Were More Common than Central Apneas in our Mildly Affected FD Patients
The apnea hypopnea index (AHI4%/h), i.e. the sum of all apneas and hypopneas with ≥ 4% oxygen desaturation divided by the total sleep time, in 11 FD patients and in 13 controls. Differences between patients and controls were assessed using the Mann-Whitney U-test.
In patients, respiratory events were most prevalent during NSWS and REM sleep and less frequent during SWS (Table 2). During SWS, controls had no respiratory events. D I SCUS S I O N In contrast to previous reports,1,5,6,8 the sleep quality—as assessed by the PSQI—and the sleep architecture—as assessed by various parameters, e.g., sleep time or efficiency—were similar in our FD patients and control persons. However, the result was not unexpected since none of our patients had a history of clinically overt sleep-disordered breathing. Yet only six of our patients had AHI4% scores below 5/h, i.e., below values required for a diagnosis of SDB, while four of our eleven FD patients met criteria of mild SDB and one patient unexpectedly even had severe SDB.33 Thus, most of our patients in fact had no clinically significant or only rather mild sleep disorders.
Central Pathology May Compromise Onset of REM Sleep in FD Patients
Two of the eleven patients (18.2%) but none of the controls did not reach REM sleep, which might be related to disturbing polysomnography conditions that interfere with sleep quality and may have prevented two patients from reaching REM sleep.34 However, absence of REM sleep may also be due to brain pathology described in FD patients.11–17 The scarce autopsies of FD patients showed spongiform degeneration of the reticular formation, particularly in the medulla, pons, and mesencephalon, but also pathology in other brain regions including the cerebellum or frontal and parietal lobes.11,12
Another discrepancy to previous sleep studies in FD patients2,5,6 is our finding of significantly higher oAIs than cAIs in the patients (with six times more obstructive than central apneas). None of the FD patients had a central apnea index above 5/h during the total sleep time; only during REM sleep, cAI was above 5/h in one patient, despite reports by previous authors of breath-holding,2,4,7 irregular breathing during sleep,8 and wakefulness.2,5 Weese-Mayer and coworkers monitored respiration in 25 FD patients during wakefulness and sleep by means of a vestlike recording system and found central apneas in 11 patients during wakefulness and in 22 patients during sleep.5 The system did not monitor airflow and defined respiratory chest and abdominal excursions with paradoxical inward movement of the chest as “potentially” obstructive apneas.5 They may thus have missed airway obstruction and found no examples meeting these criteria. If not due to the differences in recording techniques, the predominance of obstructive over central apneas in our patients as opposed to the patients studied by Weese-Mayer might be due to differences in disease severity and central pathology among both patient groups as we only included patients with mild forms of FD. Weese-Mayer noted “shallow” breathing in their FD patients,5 while Gadoth et al. concluded from their findings of sleep-related breathing irregularities that FD patients have a “decreased sensitivity of the respiratory center.”6 This central respiratory dysregulation might also have contributed to our patients’ hypopneas. Although sleep studies usually demonstrate more hypopneas than apneas,35 previous FD studies have not mentioned hypopneas as yet.5,6,8 In FD patients, anatomical anomalies and peripheral neuropathic factors could facilitate partial or complete airway closure already at a pharyngeal critical closing pressure which is higher than in healthy persons.36 Mass el al. described craniofacial anomalies in FD patients, with retrognathic position of the maxilla and particularly the mandibular, reclination of the lower incisors, and small jaws, which frequently cause difficulties in airway management during sedation or anesthesia.21 Similarly, thoracic deformities are frequent in FD patients and may compromise respiration.20 Kyphoscoliosis of FD patients, with forward inclination of the head and neck, aggravates the risk of airway collapse upon sedation or sleep.20 Bar-On et al. reported spinal deformities in 86% of their 78
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FD patients.20 Similarly, 10 of our 11 patients (90.9%) had kyphoscoliosis, and 6 patients had already undergone corrective spinal surgery. The early thoracic deformities might not only contribute to airway obstruction but might also aggravate the restrictive pulmonary dysfunction that further deteriorates with (often severe) progression of spinal deformities. Autonomic and somatic peripheral neuropathy may further increase the risk of airway constriction during sleep.37 Various reports suggest that obstructive sleep apnea patients have reduced upper airway sensation for two-point discrimination, and vibratory and thermal stimuli, and suggest that neuropathy with reduced upper airway sensitivity and altered central processing of afferent stimuli compromise the stabilizing function of pharyngeal muscles and local reflex mechanisms that assure airway patency during inspiration.37,38 FD patients typically have a prominent and progressive neuropathy with significant reduction primarily of small diameter A delta- and C-fiber count and function26 but also of Pacinian corpuscles and afferent A betafibers.39 In 28 FD patients, Gutierrez et al. recently reported prolonged latencies and reduced amplitudes for the blink and jaw jerk reflexes and the masseter silent periods but normal motor responses with facial nerve stimulation.16 The authors concluded that there is dysfunction of afferent and central reflex pathways and that development of afferent neurons—including those of brainstem reflexes—is impaired in FD.16 Dysfunction of afferent pharyngeal wall receptors and neurons may contribute to pharyngeal collapse,40 as these receptors normally fire upon negative intrapharyngeal pressure—generated by inspiration—and activate hypoglossal motoneurons.40 Although we did not measure the critical closing pressure, lung volumes, and other parameters of pulmonary function tests at the time of the sleep recordings, we assume that the increased prevalence of obstructive apneas in the FD patients may also result from reduced lung volumes which contribute to increased upper airway collapsibility.41 In FD patients, a reduction in lung volume is common2 and may be due to kyphoscoliosis or restrictive lung disease.7 Giarraffa et al. showed reduced forced vital capacity but also reduced forced expiratory volume in FD patients.42 We cannot rule out that efferent nerve fiber dysfunction might contribute to SDB in our FD patients. However, nerve biopsies and autopsies suggest that thickly myelinated fibers are largely preserved in FD patients.43–45 Moreover, biopsies showed no evidence of muscle denervation43 or motor endplate pathology.13,14 Usually, nerve conduction velocities of FD patients are normal or only slightly below normal in isolated but not all peripheral nerves.46 Recently, Macefield and coworkers reported slight though significant slowing of peroneal and ulnar motor nerve conduction velocities.47 Still, we cannot rule out that efferent motor dysfunction might to some extent contribute to an increase in the upper airway critical closing pressure and thus to SDB. However, evaluation of upper airway motor innervation would require pharyngeal electromyography to assess e.g., pharyngeal dilator muscle activity,48–50 which was not performed in our FD patients. Among other factors facilitating airway obstruction in FD patients during sleep might be altered responses to vagal feedback from pulmonary stretch receptors. Normally, the afferent Journal of Clinical Sleep Medicine, Vol. 12, No. 12, 2016
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vagal impulses of the Hering-Breuer reflex also modulate upper airway motoneuron activity and thereby influence upper airway patency.37 Even though the parasympathetic nervous system is less severely compromised in FD than is the sympathetic system,13 central processing of impulses from pulmonary and lower airway vagal afferents reaching the nucleus of the solitary tract51 might be altered in FD patients due to their inherent brainstem pathology.11–13,16 Thus, many different pathomechanisms may contribute to obstructive events in FD patients. Our findings of more frequent obstructive than central apneas might be specific for our 11 FD patients who had no clinically overt respiratory difficulties and had already reached adolescence or adulthood. Results might be different in FD patients who do not reach adolescence or adulthood but die at younger age. Previous sleep studies support this assumption.5,6,8 In FD patients who were younger than our patients, Guilleminault et al.,8 Weese-Mayer et al.,5 and Gadoth et al.6 found a higher prevalence of central than obstructive sleep apneas. Thus, central apneas might contribute to early fatalities in FD patients. Yet sudden unexpected death is a major cause of fatalities also in FD patients who reach adulthood and do not show significant and clinically overt respiratory difficulties.1 In our study, we only included older and mildly affected FD patients without overt sleep-disordered breathing, to better unravel the pathophysiology of sudden death in adolescent or adult FD patients without major respiratory difficulties. In these selected patients, obstructive apneas were significantly more common than central apneas. Yet results may be different in younger FD patients or patients with a history of respiratory irregularities.5,6,8 Although we did not measure PCO2 levels during sleep, baseline end-tidal PCO2 levels were significantly higher in our patients than in the controls. Higher PCO2 levels may reflect changes in respiratory drive.52 Yet, we saw no consistent correlation between baseline PCO2 levels and the prevalence of central apneas. The patient with the highest baseline PCO2 values, a 50-year-old woman with a resting PCO2 of 49.7 mm Hg, had neither central nor obstructive apneas during sleep. The three FD patients with central apneas had PCO2 values at 48.8 mmHg, 47.0 mm Hg, and 46.8 mm Hg. However, only one of the three patients presented with central apneas only, while the two other patients had significantly more obstructive than central apneas. One 34-year-old female patient had a resting PCO2 value of 45.6 mm Hg but developed no apneas during sleep. In the remaining 7 patients who had obstructive apneas only, PCO2 values ranged from 38.8 mm Hg to 45.6 mm Hg. Therefore, we assume that elevated PCO2 levels might also reflect a decrease in the controller gain of the respiratory feedback loop.52–54 Among the parameters possibly changing the sensitivity of central chemoreflex receptor neurons are alterations in the descending cortical input, pulmonary vagal feedback, and feedback from arterial baroreceptors or peripheral chemoreceptors.53 In FD patients, cerebral pathology11–13,17 may compromise central chemoreceptor neuron function, while impaired afferent impulses from pulmonary receptors,11–13,16,37 peripheral chemoreceptors,4 and baroreceptors19 may further contribute to deficient central respiratory control and decreased
MJ Hilz, S Moeller, S Buechner et al. Obstructive Sleep Apneas in Familial Dysautonomia
controller gain, i.e., decreased chemoresponsiveness with reduced ventilatory responses to hypoxia or hypercapnia.52 Finally, Maayan et al. reported that the loop gain, i.e., the measure of the stability or instability of the ventilator control system54 may change in FD patients during sleep and may thus critically destabilize respiration.55 In summary, hypopneas and obstructive apneas were more frequent in our FD patients than in the controls. Both predominated in the patients while central apneas were unexpectedly rare, probably due to their mild disease manifestation with no history of sleep-disordered breathing. Since even mild sleepdisordered breathing may expose FD patients to an increased cardiovascular risk,1,2,4,22,23 polysomnographic recordings may enhance treatment options for FD patients, particularly as obstructive apneas may be amenable to efficient, non-invasive CPAP therapy.22,23 R E FE R E N CES 1. Axelrod FB, Goldberg JD, Ye XY, Maayan C. Survival in familial dysautonomia: impact of early intervention. J Pediatr 2002;141:518–23. 2. Axelrod FB. A world without pain or tears. Clin Auton Res 2006;16:90–7. 3. Axelrod FB, Abularrage JJ. Familial dysautonomia: a prospective study of survival. J Pediatr 1982;101:234–6. 4. Bernardi L, Hilz M, Stemper B, Passino C, Welsch G, Axelrod FB. Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia. Am J Respir Crit Care Med 2003;167:141–9. 5. Weese-Mayer DE, Kenny AS, Bennett HL, Ramirez JM, Leurgans SE. Familial dysautonomia: frequent, prolonged and severe hypoxemia during wakefulness and sleep. Pediatr Pulmonol 2008;43:251–60. 6. Gadoth N, Sokol J, Lavie P. Sleep structure and nocturnal disordered breathing in familial dysautonomia. J Neurol Sci 1983;60:117–25. 7. Maayan HC. Respiratory aspects of Riley-Day Syndrome: familial dysautonomia. Paediatr Respir Rev 2006;7 Suppl 1:S258–9. 8. Guilleminault C, Briskin JG, Greenfield MS, Silvestri R. The impact of autonomic nervous system dysfunction on breathing during sleep. Sleep 1981;4:263–78. 9. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353:2025–33. 10. Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep 2012;35:17–40. 11. Cohen P, Solomon NH. Familial dysautonomia; case report with autopsy. J Pediatr 1955;46:663–70. 12. Brown WJ, Beauchemin JA, Linde LM. A neuropathological study of familial dysautonomia (Riley-Day Syndrome) in siblings. J Neurol Neurosurg Psychiatry 1964;27:131–9. 13. Pearson J, Axelrod F, Dancis J. Trophic functions of the neuron. V. Familial dysautonomis. Current concepts of dysautonomia: neuropathological defects. Ann N Y Acad Sci 1974;228:288–300. 14. Pearson J, Budzilovich G, Finegold MJ. Sensory, motor, and autonomic dysfunction: the nervous system in familial dysautonomia. Neurology 1971;21:486–93. 15. Pearson J, Pytel BA, Grover-Johnson N, Axelrod F, Dancis J. Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia. J Neurol Sci 1978;35:77–92. 16. Gutierrez JV, Norcliffe-Kaufmann L, Kaufmann H. Brainstem reflexes in patients with familial dysautonomia. Clin Neurophysiol 2015;126:626–33. 17. Lahat E, Aladjem M, Mor A, Azizi E, Arlazarof A. Brainstem auditory evoked potentials in familial dysautonomia. Dev Med Child Neurol 1992;34:690–3. 18. Axelrod FB, Hilz MJ, Berlin D, et al. Neuroimaging supports central pathology in familial dysautonomia. J Neurol 2010;257:198–206.
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19. Norcliffe-Kaufmann L, Axelrod F, Kaufmann H. Afferent baroreflex failure in familial dysautonomia. Neurology 2010;75:1904–11. 20. Bar-On E, Floman Y, Sagiv S, Katz K, Pollak RD, Maayan C. Orthopaedic manifestations of familial dysautonomia. A review of one hundred and thirtysix patients. J Bone Joint Surg Am 2000;82-A:1563–70. 21. Mass E, Brin I, Belostoky L, Maayan C, Gadoth N. A cephalometric evaluation of craniofacial morphology in familial dysautonomia. Cleft Palate Craniofac J 1998;35:120–6. 22. Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet 2014;383:736–47. 23. Lopez-Jimenez F, Sert Kuniyoshi FH, Gami A, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. Chest 2008;133:793–804. 24. Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 2001;68:598–605. 25. Axelrod FB, Hilz MJ. Familial dysautonomia. In: Appenzeller O, ed. Familial dysautonomia. Amsterdam: Elsevier, 2000:143–60. 26. Hilz MJ, Axelrod FB, Bickel A, et al. Assessing function and pathology in familial dysautonomia: assessment of temperature perception, sweating and cutaneous innervation. Brain 2004;127:2090–8. 27. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213. 28. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques, and scoring system for sleep states of human subjects. NIH Publication, 1968. 29. EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep 1992;15:173–84. 30. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The report of an American Academy of Sleep Medicine Task Force. Sleep 1999;22:667–89. 31. Ayappa I, Rapoport BS, Norman RG, Rapoport DM. Immediate consequences of respiratory events in sleep disordered breathing. Sleep Med 2005;6:123–30. 32. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597–619. 33. Young LR, Taxin ZH, Norman RG, Walsleben JA, Rapoport DM, Ayappa I Response to CPAP withdrawal in patients with mild versus severe obstructive sleep apnea/hypopnea syndrome. Sleep 2013;36:405–12. 34. Moser D, Kloesch G, Fischmeister FP, Bauer H, Zeitlhofer J. Cyclic alternating pattern and sleep quality in healthy subjects--is there a first-night effect on different approaches of sleep quality? Biol Psychol 2010;83:20–6. 35. Punjabi NM, Newman AB, Young TB, Resnick HE, Sanders MH. Sleepdisordered breathing and cardiovascular disease: an outcome-based definition of hypopneas. Am J Respir Crit Care Med 2008;177:1150–5. 36. Eckert DJ, Malhotra A, Jordan AS. Mechanisms of apnea. Prog Cardiovasc Dis 2009;51:313–23. 37. Krimsky WR, Leiter JC. Physiology of breathing and respiratory control during sleep. Semin Respir Crit Care Med 2005;26:5–12. 38. Kimoff RJ, Sforza E, Champagne V, Ofiara L, Gendron D. Upper airway sensation in snoring and obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:250–5. 39. Hilz MJ, Axelrod FB. Quantitative sensory testing of thermal and vibratory perception in familial dysautonomia. Clin Auton Res 2000;10:177–83. 40. Ramirez JM, Garcia AJ, 3rd, Anderson TM, et al. Central and peripheral factors contributing to obstructive sleep apneas. Respir Physiol Neurobiol 2013;189:344–53. 41. Hillman DR, Walsh JH, Maddison KJ, Platt PR, Schwartz AR, Eastwood PR. The effect of diaphragm contraction on upper airway collapsibility. J Appl Physiol 2013;115:337–45. 42. Giarraffa P, Berger KI, Chaikin AA, Axelrod FB, Davey C, Becker B. Assessing efficacy of high-frequency chest wall oscillation in patients with familial dysautonomia. Chest 2005;128:3377–81.
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MJ Hilz, S Moeller, S Buechner et al. Obstructive Sleep Apneas in Familial Dysautonomia 43. Aguayo AJ, Nair CP, Bray GM. Peripheral nerve abnormalities in the Riley-Day syndrome. Findings in a sural nerve biopsy. Arch Neurol 1971;24:106–16. 44. Dyck PJ. Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Podoslus JF, eds. Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. Philadelphia, PA: W.B. Saunders, 1993:1065–93. 45. Axelrod FB, Hilz MJ. Familial Dysautonomia. In: Vinken PJ, Bruyn GW, Appenzeller O, eds. Familial Dysautonomia. Amsterdam: Elsevier, 2000:143–60. 46. Axelrod FB, Iyer K, Fish I, Pearson J, Sein ME, Spielholz N. Progressive sensory loss in familial dysautonomia. Pediatrics 1981;67:517–22. 47. Macefield VG, Norcliffe-Kaufmann L, Gutierrez J, Axelrod FB, Kaufmann H. Can loss of muscle spindle afferents explain the ataxic gait in Riley-Day syndrome? Brain 2011;134:3198–208. 48. Carberry JC, Jordan AS, White DP, Wellman A, Eckert DJ. Upper airway collapsibility (Pcrit) and pharyngeal dilator muscle activity are sleep stage dependent. Sleep 2016;39:511–21. 49. Huang J, Pinto SJ, Yuan H, et al. Upper airway collapsibility and genioglossus activity in adolescents during sleep. Sleep 2012;35:1345–52. 50. Ehsan Z, Mahmoud M, Shott SR, Amin RS, Ishman SL. The effects of anesthesia and opioids on the upper airway: a systematic review. Laryngoscope 2016;126:270–84. 51. Kubin L, Alheid GF, Zuperku EJ, McCrimmon DR. Central pathways of pulmonary and lower airway vagal afferents. J Appl Physiol 2006;101:618–27. 52. White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 2005;172:1363–70. 53. Skow RJ, Tymko MM, MacKay CM, Steinback CD, Day TA. The effects of head-up and head-down tilt on central respiratory chemoreflex loop gain tested by hyperoxic rebreathing. Prog Brain Res 2014;212:149–72.
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54. Malhotra A, Owens RL. What is central sleep apnea? Respir Care 2010;55:1168–78. 55. Maayan C, Carley DW, Axelrod FB, Grimes J, Shannon DC. Respiratory system stability and abnormal carbon dioxide homeostasis. J Appl Physiol 1992;72:1186–93.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication December, 2015 Submitted in final revised form June, 2016 Accepted for publication July, 2016 Address correspondence to: Prof. Dr.med. habil. Max J. Hilz, Autonomic Unit, University College London, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Tel: +44 (0) 755 7289 561; Fax: +44 (0) 20 3448 3878; Email: [email protected]
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. The study was partially funded by the Dysautonomia Foundation, New York, NY. Dr. Hilz has received speaker honoraria and research support from Genzyme, a Sanofi company, Novartis Pharma GmbH, and Bayer HealthCare pharmaceuticals. Dr. Ayappa has received funding for travel, speaking, editorial activities, or royalty payments from Fisher & Paykel Healthcare. Dr. Rapoport has consulted for Cortex Pharmaceuticals, BioMarin/ Genzyme, and Luna (Morphy) Mattress. He has received funding for travel, speaking, editorial activities, or royalty payments from Sefam Medical and Fisher & Paykel Healthcare. The other authors have indicated no financial conflicts of interest. The polysomnographic recordings were performed in the New York University Sleep Disorders Center.
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S CI E NT IF IC IN VES TIGATIONS
Obstructive Sleep-Disordered Breathing Is More Common than Central in Mild Familial Dysautonomia Max J. Hilz, MD1,2; Sebastian Moeller, MD1; Susanne Buechner, MD3; Hanna Czarkowska, MD4; Indu Ayappa, PhD5; Felicia B. Axelrod, MD6; David M. Rapoport, MD5 Department of Neurology, University of Erlangen-Nürnberg, Erlangen, Germany; 2Autonomic Unit, University Colloge of London, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; 3Department of Neurology, General Hospital of Bozen/Bolzano, Bozen/Bolzano, Italy; 4Cushing Neuroscience Institute, NS-LIJ Health System, Great Neck, NY; 5Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of Medicine, New York, NY; 6Dysautonomia Center, New York University Langone School of Medicine, New York, NY 1
Study Objectives: In familial dysautonomia (FD) patients, sleep-disordered breathing (SDB) might contribute to their high risk of sleep-related sudden death. Prevalence of central versus obstructive sleep apneas is controversial but may be therapeutically relevant. We, therefore, assessed sleep structure and SDB in FD-patients with no history of SDB. Methods: 11 mildly affected FD-patients (28 ± 11 years) without clinically overt SDB and 13 controls (28 ± 10 years) underwent polysomnographic recording during one night. We assessed sleep stages, obstructive and central apneas (≥ 90% air flow reduction) and hypopneas (> 30% decrease in airflow with ≥ 4% oxygen-desaturation), and determined obstructive (oAI) and central (cAI) apnea indices and the hypopnea index (HI) as count of respective apneas/hypopneas divided by sleep time. We obtained the apnea-hypopnea index (AHI4%) from the total of apneas and hypopneas divided by sleep time. We determined differences between FD-patients and controls using the U-test and within-group differences between oAIs, cAIs, and HIs using the Friedman test and Wilcoxon test. Results: Sleep structure was similar in FD-patients and controls. AHI4% and HI were significantly higher in patients than controls. In patients, HIs were higher than oAIs and oAIs were higher than cAIs. In controls, there was no difference between HIs, oAIs, and cAIs. Only patients had apneas and hypopneas during slow wave sleep. Conclusions: In our FD-patients, obstructive apneas were more common than central apneas. These findings may be related to FD-specific pathophysiology. The potential ramifications of SDB in FD-patients suggest the utility of polysomnography to unveil SDB and initiate treatment. Commentary: A commentary on this article appears in this issue on page 1583. Keywords: familial dysautonomia, hereditary sensory and autonomic neuropathy type III, obstructive sleep apnea, sleep-disordered breathing Citation: Hilz MJ, Moeller S, Buechner S, Czarkowska H, Ayappa I, Axelrod FB, Rapoport DM. Obstructive sleep-disordered breathing is more common than central in mild familial dysautonomia. J Clin Sleep Med 2016;12(12):1607–1614.
I N T RO D U C T I O N
BRIEF SUMMARY
Familial dysautonomia (FD), also known as Riley-Day syndrome or hereditary sensory and autonomic neuropathy type III (HSAN III), is a rare autosomal recessive disorder with extensive deficits of sensory, sympathetic, and to some extent also parasympathetic neurons.1–3 Autonomic insufficiency especially affects cardiovascular and respiratory systems4 and accounts for manifold autonomic complications including orthostatic hypotension, recumbent hypertension, dysautonomic crises with excessive hypertension, hyperhidrosis, respiratory irregularities,5 and sudden unexplained death.2 According to Axelrod et al., 32% of FD patients,1 succumb to sudden unexplained death, particularly during sleep or in early morning hours.2 FD patients are known to have respiratory and sleep disorders.1,5,6 In a large cohort of FD patients, Axelrod et al. reported a far higher risk of sudden death during sleep (68%) than during wakefulness (32%).1 Mechanisms leading to fatalities are still unknown but might be associated with sleep-related breathing abnormalities, such as “shallow” breathing or respiratory arrest.3–5 1607
Current Knowledge/Study Rationale: In patients with familial dysautonomia (FD), sleep-disordered breathing (SDB) may contribute to their increased risk of sleep-related fatalities. Particularly in FD patients without clinically overt SDB, prevalence and type of SDB are controversial, and were assessed in this study. Study Impact: In 11 mildly affected FD patients, polysomnography demonstrated higher indices of obstructive than central apneas which seems to be related to FD-specific pathophysiology. The polysomnography results enhance the understanding of SDB in FD patients and add to their improved treatment.
Previous studies in FD patients suggest that there is significant sleep-disordered breathing that has been described as primarily central.5 It has also been suggested that this may be due to their central autonomic and respiratory pathology.5–8 Yet most reports are based on only few cases8 or on methods that may underestimate the obstructive component of SDB assessed during standard polysomnography recordings.5 Guilleminault et al. reported central apneas in two FD girls.8 Similarly, Gadoth et al. recorded predominantly central sleep apneas in 13 Journal of Clinical Sleep Medicine, Vol. 12, No. 12, 2016
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FD patients but also recorded more obstructive than central sleep apneas in two of their FD patients.6 Weese-Mayer and co-workers studied breathing abnormalities in 25 FD children using a vest-like monitoring system and found central sleep apneas in 22 of the 25 children. However, the authors mentioned that their recording system could not precisely monitor obstructive apneas.5 While obstructive apneas can be treated with continuous positive airway pressure (CPAP), this treatment is less successful in central sleep apneas.9,10 In FD patients, the pathology with central and peripheral autonomic dysfunction,2,4,11–19 kyphoscoliosis,20 and craniofacial abnormalities21 may give rise to both central and obstructive sleep apneas. While patients with clinically overt respiratory problems undergo close monitoring and often receive treatment for their sleep-disordered breathing,22,23 patients with mild forms of FD and without evident respiratory problems may be at higher risk of undiagnosed sleep-disordered breathing and subsequent complications. In order to better determine the type of sleep-disordered breathing in such patients, we conducted polysomnographic recordings in eleven mildly affected FD patients without clinically manifest respiratory disturbances.
environment. Study participants rested supine ≥ 30 min after arrival in the laboratory. During this period, all monitoring devices were applied. The nocturnal polysomnography included recordings of electroencephalogram (EEG) at the standard scalp positions C3, C4, Fz, O1, O2 of the international 10-20 system, using superficial disc electrodes. Positions A1 and A2 served as reference electrodes. We also recorded the electrooculogram (EOG), electromyogram (EMG) using surface electrodes placed laterally to the chin, the body position using a multiposition mercury switch (Bio-Logic, Mundelein, IL), periodic leg movements using EMG electrodes placed over the left and right anterior tibial muscle, baseline O2 saturation by means of finger pulse oximetry (Nellcor, Pleasanton, CA), respiratory airflow using nasal cannulae connected to a commercial pressure transducer (Pro-tech PTAF2, Mukilteo, WA), supplemented by an oral thermistor, and baseline end-tidal carbon dioxide (PCO2 ) measured by infrared absorption (Colin-Pilot, Colin Medical, San Antonio, TX, USA). The output of the pressure transducer was connected to a DC amplifier with an internal 2.5 Hz low pass filter. Evaluated Sleep Parameters Polysomnography data were scored visually according to standard Rechtschaffen and Kales sleep staging criteria.28 Sleep recordings were evaluated for the following measures of sleep continuity and architecture: • Total sleep time • Sleep efficiency, defined as the total sleep time divided by the time spent in bed29 • Time awake during polysomnographic recording • Percentage of NREM sleep stages 1, 2, 3, and 4, and of REM sleep. Stages 1 and 2 were combined into non-slow wave sleep (NSWS), stages 3 and 4 were combined into slow wave sleep (SWS) in accord with current scoring rules. • Sleep onset latency, defined as the time from lights out to the first epoch of any stage other than awake • REM sleep latency, defined as the time from sleep onset to the first REM sleep episode6
METHODS
Study Participants and Methods
In 11 mildly affected FD patients (45.5% female/54.5% male; age range 15 to 50 years, mean age 28 ± 11 years) without significant and clinically overt respiratory difficulties, and in 14 age-matched control persons (50% female/50% male, age range 14 to 48 years, mean age 29 ± 10 years, p > 0.05), we assessed the body mass index (BMI = body weight / height 2) and performed polysomnographic sleep recording. The protocol was approved by the Institutional Review Board of New York University School of Medicine. Informed consent was obtained prior to the study, and the study was registered at the German Clinical Trial Register (DRKS00008852). Patient Inclusion Criteria All FD patients had the characteristic genetic haplotype, i.e., they were homozygous for the intron 20 mutation on the IKBKAP gene24 and fulfilled diagnostic criteria of FD25,26 including Ashkenazi Jewish ancestry, absence of deep tendon reflexes, overflow tears, lingual fungiform papillae, and of axon flare response following intradermal histamine injection.25,26 Pittsburgh Sleep Quality Index (PSQI) during the Month prior to Polysomnography Sleep quality during the month prior to the polysomnographic sleep recording was assessed using a validated self-administered questionnaire, the Pittsburgh Sleep Quality Index (PSQI).27 As per Buysse et al., we used a PSQI score threshold of 5 to distinguish “poor sleepers” from “good sleepers.” 27
Respiratory Events We defined respiratory events as air flow reduction of ≥ 10 s duration relative to airflow at baseline according to the American Academy of Sleep Medicine (AASM) Task Force.30 We classified respiratory events as:31 • Obstructive sleep apnea for airflow reduction of > 90% from baseline with continued or increased inspiratory effort30,32 • Central sleep apnea for airflow reduction of > 90% from baseline without respiratory effort30 • Hypopnea for any visible significant air flow reduction (> 30% decrease in airflow) associated with ≥ 4% desaturation (“preferred” AASM definition)32,33
Polysomnography Recording The polysomnographic recordings were performed in the NYU Sleep Disorders Center located in a quiet, temperature-controlled Journal of Clinical Sleep Medicine, Vol. 12, No. 12, 2016
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The apnea indices (total-AI, obstructive-oAI and central-cAI) and hypopnea index (HI) were obtained by the count of the respective apneas or hypopneas divided by total sleep or sleep stage time. Apnea-hypopnea index (AHI4%) was obtained
MJ Hilz, S Moeller, S Buechner et al. Obstructive Sleep Apneas in Familial Dysautonomia
Table 1—Patient characteristics and sleep quality parameters. Parameter Age, years BMI, kg/m2 PSQI score Global PSQI score Component scores Subjective sleep quality Sleep latency Sleep duration Habitual sleep efficiency Sleep disturbances Use of sleeping medications Daytime dysfunction Total sleep time, min Sleep efficiency, % Sleep latency, min REM sleep latency, min NSWS, % SWS, % REM, % WASO, % O2-saturation, % end-tidal PCO2, mm Hg
FD Patients (n = 11) 28 ± 11 20.1 ± 3.2
Controls (n = 13) 28 ± 10 24.9 ± 2.4
p value 0.776 < 0.001
5.1 ± 3.2
3.6 ± 1.8
0.277
0.7 ± 0.7 1.6 ± 1.5 0.6 ± 0.7 0.2 ± 0.6 0.9 ± 0.5 0.6 ± 1.2 0.6 ± 0.5 307 ± 65 76.8 ± 15.9 36.1 ± 42.9 157 ± 104 51.9 ± 15.7 20.4 ± 14.2 11.7 ± 7.0 16.1 ± 12.9 96.2 ± 3.7 44.7 ± 3.3
0.7 ± 0.5 0.9 ± 0.4 0.3 ± 0.6 0.2 ± 0.4 0.9 ± 0.4 0 0.7 ± 0.8 354 ± 83 78.2 ± 15.6 16.6 ± 11.2 140 ± 107 54.4 ± 8.9 12.5 ± 6.9 14.4 ± 6.3 18.9 ± 15.1 98.7 ± 1.2 41.2 ± 4.1
1.000 0.531 0.392 0.649 0.865 0.277 0.776 0.150 0.649 0.569 0.794 0.649 0.207 0.392 0.776 0.015 0.035
Age characteristics, the body mass index (BMI), Pittsburgh Sleep Quality Index (PSQI) score results, total sleep time (min), sleep efficiency (%), sleep latency (min), rapid eye movement (REM) sleep latency (min), non-slow wave sleep, slow wave sleep, REM sleep, wake after sleep onset (WASO), O2 -saturation, and end-tidal PCO2 at baseline in 11 FD patients and 13 controls. Statistically significant values in bold (p < 0.05).
from the total of obstructive and central apneas and all hypopneas divided by the total sleep or sleep stage time.33 We defined sleep-disordered breathing (SDB) as “mild” for AHI4% values between 5 and 15/h, as “moderate” for AHI4% values above 15/h and below 30/h, and as “severe” for AHI4% values above 30/h.33
sleep stages in FD patients and control persons, we applied Bonferroni corrections and assumed statistical significance for p values at or below 0.0025.
Statistics
PSQI scores were similar between patients and controls (5.1 ± 3.2 vs. 3.6 ± 1.8; p > 0.05). Three patients and none of the controls were on sleeping medication prior to the polysomnographic sleep recording. Five patients and 3 controls fulfilled criteria of poor sleepers with PSQI scores ≥ 5 (p > 0.05; Table 1). BMI was significantly lower in FD patients (20.1 ± 3.2) than in controls (24.9 ± 2.4, p < 0.001). At baseline (before sleep), O2 saturation was lower in the patients than the controls (96.2 ± 3.7% vs. 98.7 ± 1.2%; p = 0.015), while end-tidal PCO2 was higher in patients than controls (44.7 ± 3.3 mm Hg vs. 41.2 ± 4.1 mm Hg; p = 0.035; Table 1). In the patients, PCO2 values ranged from 38.8 mm Hg to 49.7 mm Hg. In the control persons, PCO2 values ranged from 34.2 mm Hg to 46.9 mm Hg. The total sleep time during the polysomnographic recording did not differ between patients (307 ± 65 min) and control persons (354 ± 83 min; p > 0.05). Similarly, sleep efficiency, sleep latency, and REM sleep latency did not differ significantly between patients (76.8 ± 15.9%, 36.1 ± 42.9 min, 157.1 ± 104.3 min) and controls (78.2 ± 15.6%, 16.6 ± 11.2 min, 140 ± 107 min; p > 0.05). Moreover, the percentage of
For data analysis, we used a commercially available statistical program (SPSS 20.0, SPSS Inc., Chicago, IL). We tested data for normal distribution by the Shapiro-Wilk test. PSQI scores and parameters of sleep continuity and architecture are presented as mean values ± standard deviation (SD). Parameters of sleep-disordered breathing are presented as median and lower and upper quartile values. For comparison of differences between FD patients and controls, i.e., differences in PSQI scores, parameters of sleep continuity and architecture, and differences in the respiratory event indices between groups, we used t-tests for unpaired samples in case of normal distribution, and the Mann-Whitney-U test in case of non-normal distribution of data. For non-normally distributed data, we tested withingroup differences between oAIs, cAIs, and HIs using the Friedman-test, and differences between two parameters using the Wilcoxon-test. For dichotomous parameters, such as presence or absence of sleep-disordered breathing (e.g., AHI4% > 5/h) in patients or controls, we used Fisher exact test. To account for multiple comparisons of SDB parameters during various 1609
R ES U LT S
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Table 2—AHI4% and Hypopnea/apnea indices during different sleep stages. AHI4%/h during all sleep stages persons with AHI4% > 5/h during NSWS persons with AHI4% > 5/h during SWS persons with AHI4% > 5/h during REM sleep persons with AHI4% > 5/h AI/h during all sleep stages during NSWS during SWS during REM sleep oAI/h during all sleep stages during NSWS during SWS during REM sleep cAI/h during all sleep stages during NSWS during SWS during REM sleep HI/h during all sleep stages during NSWS during SWS during REM sleep
11 FD Patients
13 Controls
p value
4.9 [3.3; 9.8] 5/11 2.9 [2.4;15.2] 4/11 1.6 [0; 2.9] 2/11 9.8 [1.2; 21.3] 7/9
0.2 [0; 0.8] 2/13 0 [0; 0.6] 2/13 0 [0; 0] 0/13 0 [0; 3.2] 2/13
0.001* 0.394 < 0.001* 0.651 0.007 0.480 0.072 0.113
1.6 [0; 3.1] 1.8 [0; 3.2] 0 [0; 0.7] 0 [0; 6.7]
0 [0; 0.2] 0 [0; 0.1] 0 [0; 0] 0 [0; 1.2]
0.055 0.041 0.277 0.569
1.4 [0; 3.1] 1.2 [0; 3.2] 0 [0; 0] 0 [0; 4.9]
0 [0; 0.1] 0 [0; 0.8] 0 [0; 0] 0 [0; 0]
0.082 0.106 0.459 0.459
0 [0; 0.2] 0 [0; 0] 0 [0; 0] 0 [0; 0]
0 [0; 0.2] 0 [0; 0] 0 [0; 0] 0 [0; 0.7]
1.000 0.691 0.733 0.691
2.9 [1.8; 5.7] 2.1 [1.1; 12.8] 1.3 [0; 2.9] 8.8 [0; 18.5]
0 [0; 0.7] 0 [0; 0.6] 0 [0; 0] 0 [0; 2.7]
0.001* 0.001* 0.022 0.035
Values are presented as median [lower; upper quartile]. Sleep disordered breathing indices are AHI4% (apneas and hypopneas with ≥ 4% oxygen desaturation per hour), apnea index (AI), obstructive (oAI), central (cAI) apnea index, and hypopnea index (HI) per hour in 11 FD patients and 13 control persons overall and during the different sleep stages. The indices were obtained by the count of the respective apneas or hypopneas divided by total sleep time or sleep stage time. We determined differences between FD patients and controls using the Mann-Whitney U-test. We compared differences in the number of patients and of controls with AHI4% > 5/h by the Fisher exact test. Statistically significant values in bold (p < 0.05). To account for multiple comparisons of SDB parameters at various sleep stages in FD patients and control persons, we applied Bonferroni corrections and assumed statistical significance only for p values ≤ 0.0025, marked by an asterisk (*).
NSWS, SWS, REM sleep, and the time awake during the polysomnographic recording were similar between patients (51.9 ± 15.7%, 20.4 ± 14.2%, 11.7 ± 7.0%, 16.1 ± 12.9%) and controls (54.4 ± 8.9%, 12.5 ± 6.9%, 14.4 ± 6.3%, 18.9 ± 15.1%; p > 0.05; Table 1). In two FD- patients (18.2%), we recorded no REM sleep.
Sleep-Disordered Breathing in FD Patients and Controls
In the 11 FD patients, AHI4% values ranged from 1.3 to 34.7/h (Table 2). One patient had severe SDB with an AHI4% value of 34.7/h. Four FD patients had mild SDB with AHI4% values between 5 and 15/h. Six patients had AHI4% values < 5/h. AHI4% values were higher in patients (median 4.9; lower quartile 3.3; upper quartile 9.8/h) than in controls (median 0.2; lower quartile 0; upper quartile 0.8/h; p = 0.001). Journal of Clinical Sleep Medicine, Vol. 12, No. 12, 2016
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One control person had severe SDB with an AHI4% value of 114.9/h. To better compare the findings of the controls to the findings of the FD patients, we excluded this outlier from the further analysis. Thus, 13 controls (53.8% female/46.2% male), were included in the analysis. Two controls had mild SDB, with AHI4% values of 12.1/h and 9.5/h. The other 11 controls had AHI4% values < 1/h (Table 2; Figure 1). AIs, oAIs, and cAIs were similar in patients and controls (Table 2). However, HIs were higher in patients (median 2.9; lower quartile 1.8; upper quartile 5.7/h) than in controls (median 0; lower quartile 0; upper quartile 0.7/h; p = 0.001; Table 2). In the patients, HIs were higher than oAIs (median 1.4; lower quartile 0; upper quartile 3.1; p = 0.026) and oAIs were higher than cAIs (median 0; lower quartile 0; upper quartile 0.2; p = 0.036), while HIs, oAIs, and cAIs did not differ in controls (Table 3).
MJ Hilz, S Moeller, S Buechner et al. Obstructive Sleep Apneas in Familial Dysautonomia
Figure 1—AHI4%/h values.
Table 3—Within-group differences between oAIs, cAIs, and HIs. Comparison of FD Patients oAI/h vs. cAI/h during all sleep stages 0.036 cAI/h vs. HI/h during all sleep stages 0.006 oAI/h vs. HI/h during all sleep stages 0.026
Controls 0.495 0.495 0.495
Values presented as p values. Within-group differences between oAIs, cAIs, and HIs during all sleep stages. We determined within-group differences between oAIs, cAIs, and HIs using the Friedman and Wilcoxon tests. Statistically significant values in bold (p < 0.05).
Obstructive Apneas Were More Common than Central Apneas in our Mildly Affected FD Patients
The apnea hypopnea index (AHI4%/h), i.e. the sum of all apneas and hypopneas with ≥ 4% oxygen desaturation divided by the total sleep time, in 11 FD patients and in 13 controls. Differences between patients and controls were assessed using the Mann-Whitney U-test.
In patients, respiratory events were most prevalent during NSWS and REM sleep and less frequent during SWS (Table 2). During SWS, controls had no respiratory events. D I SCUS S I O N In contrast to previous reports,1,5,6,8 the sleep quality—as assessed by the PSQI—and the sleep architecture—as assessed by various parameters, e.g., sleep time or efficiency—were similar in our FD patients and control persons. However, the result was not unexpected since none of our patients had a history of clinically overt sleep-disordered breathing. Yet only six of our patients had AHI4% scores below 5/h, i.e., below values required for a diagnosis of SDB, while four of our eleven FD patients met criteria of mild SDB and one patient unexpectedly even had severe SDB.33 Thus, most of our patients in fact had no clinically significant or only rather mild sleep disorders.
Central Pathology May Compromise Onset of REM Sleep in FD Patients
Two of the eleven patients (18.2%) but none of the controls did not reach REM sleep, which might be related to disturbing polysomnography conditions that interfere with sleep quality and may have prevented two patients from reaching REM sleep.34 However, absence of REM sleep may also be due to brain pathology described in FD patients.11–17 The scarce autopsies of FD patients showed spongiform degeneration of the reticular formation, particularly in the medulla, pons, and mesencephalon, but also pathology in other brain regions including the cerebellum or frontal and parietal lobes.11,12
Another discrepancy to previous sleep studies in FD patients2,5,6 is our finding of significantly higher oAIs than cAIs in the patients (with six times more obstructive than central apneas). None of the FD patients had a central apnea index above 5/h during the total sleep time; only during REM sleep, cAI was above 5/h in one patient, despite reports by previous authors of breath-holding,2,4,7 irregular breathing during sleep,8 and wakefulness.2,5 Weese-Mayer and coworkers monitored respiration in 25 FD patients during wakefulness and sleep by means of a vestlike recording system and found central apneas in 11 patients during wakefulness and in 22 patients during sleep.5 The system did not monitor airflow and defined respiratory chest and abdominal excursions with paradoxical inward movement of the chest as “potentially” obstructive apneas.5 They may thus have missed airway obstruction and found no examples meeting these criteria. If not due to the differences in recording techniques, the predominance of obstructive over central apneas in our patients as opposed to the patients studied by Weese-Mayer might be due to differences in disease severity and central pathology among both patient groups as we only included patients with mild forms of FD. Weese-Mayer noted “shallow” breathing in their FD patients,5 while Gadoth et al. concluded from their findings of sleep-related breathing irregularities that FD patients have a “decreased sensitivity of the respiratory center.”6 This central respiratory dysregulation might also have contributed to our patients’ hypopneas. Although sleep studies usually demonstrate more hypopneas than apneas,35 previous FD studies have not mentioned hypopneas as yet.5,6,8 In FD patients, anatomical anomalies and peripheral neuropathic factors could facilitate partial or complete airway closure already at a pharyngeal critical closing pressure which is higher than in healthy persons.36 Mass el al. described craniofacial anomalies in FD patients, with retrognathic position of the maxilla and particularly the mandibular, reclination of the lower incisors, and small jaws, which frequently cause difficulties in airway management during sedation or anesthesia.21 Similarly, thoracic deformities are frequent in FD patients and may compromise respiration.20 Kyphoscoliosis of FD patients, with forward inclination of the head and neck, aggravates the risk of airway collapse upon sedation or sleep.20 Bar-On et al. reported spinal deformities in 86% of their 78
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FD patients.20 Similarly, 10 of our 11 patients (90.9%) had kyphoscoliosis, and 6 patients had already undergone corrective spinal surgery. The early thoracic deformities might not only contribute to airway obstruction but might also aggravate the restrictive pulmonary dysfunction that further deteriorates with (often severe) progression of spinal deformities. Autonomic and somatic peripheral neuropathy may further increase the risk of airway constriction during sleep.37 Various reports suggest that obstructive sleep apnea patients have reduced upper airway sensation for two-point discrimination, and vibratory and thermal stimuli, and suggest that neuropathy with reduced upper airway sensitivity and altered central processing of afferent stimuli compromise the stabilizing function of pharyngeal muscles and local reflex mechanisms that assure airway patency during inspiration.37,38 FD patients typically have a prominent and progressive neuropathy with significant reduction primarily of small diameter A delta- and C-fiber count and function26 but also of Pacinian corpuscles and afferent A betafibers.39 In 28 FD patients, Gutierrez et al. recently reported prolonged latencies and reduced amplitudes for the blink and jaw jerk reflexes and the masseter silent periods but normal motor responses with facial nerve stimulation.16 The authors concluded that there is dysfunction of afferent and central reflex pathways and that development of afferent neurons—including those of brainstem reflexes—is impaired in FD.16 Dysfunction of afferent pharyngeal wall receptors and neurons may contribute to pharyngeal collapse,40 as these receptors normally fire upon negative intrapharyngeal pressure—generated by inspiration—and activate hypoglossal motoneurons.40 Although we did not measure the critical closing pressure, lung volumes, and other parameters of pulmonary function tests at the time of the sleep recordings, we assume that the increased prevalence of obstructive apneas in the FD patients may also result from reduced lung volumes which contribute to increased upper airway collapsibility.41 In FD patients, a reduction in lung volume is common2 and may be due to kyphoscoliosis or restrictive lung disease.7 Giarraffa et al. showed reduced forced vital capacity but also reduced forced expiratory volume in FD patients.42 We cannot rule out that efferent nerve fiber dysfunction might contribute to SDB in our FD patients. However, nerve biopsies and autopsies suggest that thickly myelinated fibers are largely preserved in FD patients.43–45 Moreover, biopsies showed no evidence of muscle denervation43 or motor endplate pathology.13,14 Usually, nerve conduction velocities of FD patients are normal or only slightly below normal in isolated but not all peripheral nerves.46 Recently, Macefield and coworkers reported slight though significant slowing of peroneal and ulnar motor nerve conduction velocities.47 Still, we cannot rule out that efferent motor dysfunction might to some extent contribute to an increase in the upper airway critical closing pressure and thus to SDB. However, evaluation of upper airway motor innervation would require pharyngeal electromyography to assess e.g., pharyngeal dilator muscle activity,48–50 which was not performed in our FD patients. Among other factors facilitating airway obstruction in FD patients during sleep might be altered responses to vagal feedback from pulmonary stretch receptors. Normally, the afferent Journal of Clinical Sleep Medicine, Vol. 12, No. 12, 2016
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vagal impulses of the Hering-Breuer reflex also modulate upper airway motoneuron activity and thereby influence upper airway patency.37 Even though the parasympathetic nervous system is less severely compromised in FD than is the sympathetic system,13 central processing of impulses from pulmonary and lower airway vagal afferents reaching the nucleus of the solitary tract51 might be altered in FD patients due to their inherent brainstem pathology.11–13,16 Thus, many different pathomechanisms may contribute to obstructive events in FD patients. Our findings of more frequent obstructive than central apneas might be specific for our 11 FD patients who had no clinically overt respiratory difficulties and had already reached adolescence or adulthood. Results might be different in FD patients who do not reach adolescence or adulthood but die at younger age. Previous sleep studies support this assumption.5,6,8 In FD patients who were younger than our patients, Guilleminault et al.,8 Weese-Mayer et al.,5 and Gadoth et al.6 found a higher prevalence of central than obstructive sleep apneas. Thus, central apneas might contribute to early fatalities in FD patients. Yet sudden unexpected death is a major cause of fatalities also in FD patients who reach adulthood and do not show significant and clinically overt respiratory difficulties.1 In our study, we only included older and mildly affected FD patients without overt sleep-disordered breathing, to better unravel the pathophysiology of sudden death in adolescent or adult FD patients without major respiratory difficulties. In these selected patients, obstructive apneas were significantly more common than central apneas. Yet results may be different in younger FD patients or patients with a history of respiratory irregularities.5,6,8 Although we did not measure PCO2 levels during sleep, baseline end-tidal PCO2 levels were significantly higher in our patients than in the controls. Higher PCO2 levels may reflect changes in respiratory drive.52 Yet, we saw no consistent correlation between baseline PCO2 levels and the prevalence of central apneas. The patient with the highest baseline PCO2 values, a 50-year-old woman with a resting PCO2 of 49.7 mm Hg, had neither central nor obstructive apneas during sleep. The three FD patients with central apneas had PCO2 values at 48.8 mmHg, 47.0 mm Hg, and 46.8 mm Hg. However, only one of the three patients presented with central apneas only, while the two other patients had significantly more obstructive than central apneas. One 34-year-old female patient had a resting PCO2 value of 45.6 mm Hg but developed no apneas during sleep. In the remaining 7 patients who had obstructive apneas only, PCO2 values ranged from 38.8 mm Hg to 45.6 mm Hg. Therefore, we assume that elevated PCO2 levels might also reflect a decrease in the controller gain of the respiratory feedback loop.52–54 Among the parameters possibly changing the sensitivity of central chemoreflex receptor neurons are alterations in the descending cortical input, pulmonary vagal feedback, and feedback from arterial baroreceptors or peripheral chemoreceptors.53 In FD patients, cerebral pathology11–13,17 may compromise central chemoreceptor neuron function, while impaired afferent impulses from pulmonary receptors,11–13,16,37 peripheral chemoreceptors,4 and baroreceptors19 may further contribute to deficient central respiratory control and decreased
MJ Hilz, S Moeller, S Buechner et al. Obstructive Sleep Apneas in Familial Dysautonomia
controller gain, i.e., decreased chemoresponsiveness with reduced ventilatory responses to hypoxia or hypercapnia.52 Finally, Maayan et al. reported that the loop gain, i.e., the measure of the stability or instability of the ventilator control system54 may change in FD patients during sleep and may thus critically destabilize respiration.55 In summary, hypopneas and obstructive apneas were more frequent in our FD patients than in the controls. Both predominated in the patients while central apneas were unexpectedly rare, probably due to their mild disease manifestation with no history of sleep-disordered breathing. Since even mild sleepdisordered breathing may expose FD patients to an increased cardiovascular risk,1,2,4,22,23 polysomnographic recordings may enhance treatment options for FD patients, particularly as obstructive apneas may be amenable to efficient, non-invasive CPAP therapy.22,23 R E FE R E N CES 1. Axelrod FB, Goldberg JD, Ye XY, Maayan C. Survival in familial dysautonomia: impact of early intervention. J Pediatr 2002;141:518–23. 2. Axelrod FB. A world without pain or tears. Clin Auton Res 2006;16:90–7. 3. Axelrod FB, Abularrage JJ. Familial dysautonomia: a prospective study of survival. J Pediatr 1982;101:234–6. 4. Bernardi L, Hilz M, Stemper B, Passino C, Welsch G, Axelrod FB. Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia. Am J Respir Crit Care Med 2003;167:141–9. 5. Weese-Mayer DE, Kenny AS, Bennett HL, Ramirez JM, Leurgans SE. Familial dysautonomia: frequent, prolonged and severe hypoxemia during wakefulness and sleep. Pediatr Pulmonol 2008;43:251–60. 6. Gadoth N, Sokol J, Lavie P. Sleep structure and nocturnal disordered breathing in familial dysautonomia. J Neurol Sci 1983;60:117–25. 7. Maayan HC. Respiratory aspects of Riley-Day Syndrome: familial dysautonomia. Paediatr Respir Rev 2006;7 Suppl 1:S258–9. 8. Guilleminault C, Briskin JG, Greenfield MS, Silvestri R. The impact of autonomic nervous system dysfunction on breathing during sleep. Sleep 1981;4:263–78. 9. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353:2025–33. 10. Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep 2012;35:17–40. 11. Cohen P, Solomon NH. Familial dysautonomia; case report with autopsy. J Pediatr 1955;46:663–70. 12. Brown WJ, Beauchemin JA, Linde LM. A neuropathological study of familial dysautonomia (Riley-Day Syndrome) in siblings. J Neurol Neurosurg Psychiatry 1964;27:131–9. 13. Pearson J, Axelrod F, Dancis J. Trophic functions of the neuron. V. Familial dysautonomis. Current concepts of dysautonomia: neuropathological defects. Ann N Y Acad Sci 1974;228:288–300. 14. Pearson J, Budzilovich G, Finegold MJ. Sensory, motor, and autonomic dysfunction: the nervous system in familial dysautonomia. Neurology 1971;21:486–93. 15. Pearson J, Pytel BA, Grover-Johnson N, Axelrod F, Dancis J. Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia. J Neurol Sci 1978;35:77–92. 16. Gutierrez JV, Norcliffe-Kaufmann L, Kaufmann H. Brainstem reflexes in patients with familial dysautonomia. Clin Neurophysiol 2015;126:626–33. 17. Lahat E, Aladjem M, Mor A, Azizi E, Arlazarof A. Brainstem auditory evoked potentials in familial dysautonomia. Dev Med Child Neurol 1992;34:690–3. 18. Axelrod FB, Hilz MJ, Berlin D, et al. Neuroimaging supports central pathology in familial dysautonomia. J Neurol 2010;257:198–206.
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SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication December, 2015 Submitted in final revised form June, 2016 Accepted for publication July, 2016 Address correspondence to: Prof. Dr.med. habil. Max J. Hilz, Autonomic Unit, University College London, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; Tel: +44 (0) 755 7289 561; Fax: +44 (0) 20 3448 3878; Email: [email protected]
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. The study was partially funded by the Dysautonomia Foundation, New York, NY. Dr. Hilz has received speaker honoraria and research support from Genzyme, a Sanofi company, Novartis Pharma GmbH, and Bayer HealthCare pharmaceuticals. Dr. Ayappa has received funding for travel, speaking, editorial activities, or royalty payments from Fisher & Paykel Healthcare. Dr. Rapoport has consulted for Cortex Pharmaceuticals, BioMarin/ Genzyme, and Luna (Morphy) Mattress. He has received funding for travel, speaking, editorial activities, or royalty payments from Sefam Medical and Fisher & Paykel Healthcare. The other authors have indicated no financial conflicts of interest. The polysomnographic recordings were performed in the New York University Sleep Disorders Center.
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