Pediatric Pulmonology 51:300–307 (2016)
Congenital Central Hypoventilation Syndrome (CCHS): Circadian Temperature Variation Rehan Saiyed, BS,1 Casey M. Rand, BS,1 Michael S. Carroll, PhD,1,2 Cynthia M. Koliboski, RT,1 Tracey M. Stewart, RT,1 Cindy D. Brogadir, RT,1 Anna S. Kenny, RT,1 Emily K.E. Petersen, RN,3 David W. Carley, PhD,4 and Debra E. Weese-Mayer, MD1,2* Summary. Background: Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, which includes a control of breathing deficit and features of autonomic nervous system (ANS) dysregulation. In recognition of the fundamental role of the ANS in temperature regulation and rhythm and the lack of any prior characterization of circadian temperature rhythms in CCHS, we sought to explore peripheral and core temperatures and circadian patterning. We hypothesized that CCHS patients would exhibit lower peripheral skin temperatures (PST), variability, and circadian rhythmicity (vs. controls), as well as a disrupted relationship between core body temperature (CBT) and PST. Methods: PST was sampled every 3 min over four 24-hr periods in CCHS cases and similarly aged controls. CBT was sampled in a subset of these recordings. Results: PST was recorded from 25 CCHS cases (110,664 measures/230 days) and 39 controls (78,772 measures/164 days). Simultaneous CBT measurements were made from 23 CCHS patients. In CCHS, mean PST was lower overall (P ¼ 0.03) and at night (P ¼ 0.02), and PST variability (interquartile range) was higher at night (P ¼ 0.05) (vs. controls). PST circadian rhythm remained intact but the phase relationship of PST to CBTrhythm was extremely variable in CCHS. Conclusions: PST alterations in CCHS likely reflect altered autonomic control of peripheral vascular tone. These alterations represent a previously unreported manifestation of CCHS and may provide an opportunity for therapeutic intervention. The relationship between temperature dysregulation and CCHS may also offer insight into basic mechanisms underlying thermoregulation. Pediatr Pulmonol. 2016;51:300–307. ß 2015 Wiley Periodicals, Inc. Key words: peripheral skin temperature; circadian rhythm; iButton; PHOX2B gene. Funding source: Shaw Foundation Grant.
INTRODUCTION
Congenital central hypoventilation syndrome (CCHS) is a neurocristopathy caused by mutations in the paired-like homeobox gene 2B (PHOX2B),1 with approximately 1,200 cases identified since initial description in 1970 by Mellins et al.2 The resulting CCHS phenotype includes a control of breathing deficit and features of physiologic and anatomic autonomic nervous system dysregulation (ANSD).1,3–5 Symptoms of CCHS-related physiologic ANSD often include decreased sympathetic and parasympathetic tone, with alterations in sweating patterns, vasomotor tone, postural blood pressure responses, heart rate variability, esophageal motility, and pupillary light response, among others.1 Anatomic ANSD features include aganglionosis of the distal hindgut (Hirschsprung disease) and tumors of neural crest origin (neuroblastoma, ganglioneuroma, and ganglioneuroblastoma), occurring in a subset of cases of CCHS. These CCHS-related observations follow intuitively considering the role of PHOX2B in determining neurodevelopmental cell fate in the sympathetic, parasympathetic, and enteric pathways.6–9 ß 2015 Wiley Periodicals, Inc.
1 Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children’s Hospital of Chicago, Stanley Manne Children’s Research Institute, Chicago, Illinois. 2
Northwestern University Feinberg School of Medicine, Chicago, Illinois.
3 Cardiovascular Thoracic Surgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois. 4 Center for Narcolepsy, Sleep and Health Research (CNSHR), University of Illinois at Chicago, Chicago, Illinois.
Mr. Saiyed and Mr. Rand are equal first authors for this manuscript.
Correspondence to: Debra E. Weese-Mayer, MD, Beatrice Cummings Mayer Professor of Pediatric Autonomic Medicine, Northwestern University Feinberg School of Medicine, Chief, Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 East Chicago Ave., Box 165, Chicago, IL 60611 E-mail: [email protected] Received 10 December 2014; Accepted 1 April 2015. DOI 10.1002/ppul.23236 Published online 18 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
Circadian Thermoregulation in CCHS
Circadian rhythms are widespread physiologic and behavioral patterns that operate on a periodicity of approximately 24 hr and are essential to health. The suprachiasmatic nucleus directs synchronization of these rhythms throughout the periphery of the body10 with growing evidence implicating thermoregulation as one of the drivers for such synchronization.11–14 The ANS plays a major role in thermoregulation through control of peripheral vasomotor tone. Core body temperature (CBT) follows a diurnal rhythm and is a commonly measured marker for analyzing circadian system timing. CBT regulation involves homeostatic responses to endogenous and exogenous cues, as well as intrinsic circadian regulation. The homeostatic component preserves an optimal core temperature (typically between 36–38 8C in humans),15,16 whereas heat production and loss also oscillate with a circadian rhythmicity.17,18 Consequently, these rhythms cause CBT to oscillate regularly through a range of approximately 1 8C in humans, reaching its peak in the late afternoon/early evening and its nadir in the early morning hours.17 CBT impacts numerous physiologic processes,19 and alterations in CBT and its rhythmicity are often early indicators of physiologic compromise. Peripheral skin temperature (PST) demonstrates a rhythm that is inverted and slightly advanced in phase relative to CBT rhythm20,21 and has been shown to be a reliable marker to assess circadian physiology.21–23 Although measures of CBT and PST each may have intrinsic value, measurement of CBT is usually invasive and noncontinuous (oral, tympanic, axillary, or rectal),15 whereas PST measurement is characterized by limited invasiveness, ease of use, low cost, and potential for continuous assessment in both the hospital and home settings. Thus, measurement of PST can be utilized as a noninvasive and inexpensive gauge of both body temperature and circadian rhythm. Indeed, several recent studies have supported using measures of PST to assess circadian rhythmicity.21–23 Additionally, measurement of PST may allow insight into the function of the ANS, and has previously offered insight into autonomic peripheral nerve dysfunction.24 Recognizing the importance of body temperature on physiologic responsiveness to hypercarbia,25 the intrinsic attenuation of the cardiorespiratory response to hypercarbia/hypoxemia in CCHS4, and related features of autonomic dysfunction with intrinsic involvement in thermoregulatory pathways, we sought to describe PST and circadian profiles in CCHS and comparably aged healthy controls. Given the objective alterations in sympathetic and parasympathetic control (and likely in vasomotor tone) in CCHS and anecdotal reports of cool extremities and low core body temperature, we hypothesized that CCHS patients would exhibit lower mean PST measures (vs. controls). Grounded in a past study
301
illustrating lower heart rate variability in CCHS than in controls,26 we hypothesized similarly lower variability of PST in these cases compared to controls. Further, in acknowledgement of the well-defined ANS and presumptive vasomotor irregularities in CCHS, coupled with recent evidence supporting hypothalamic injury in areas integral to autonomic and thermoregulatory control,27,28 we hypothesized attenuated circadian rhythmicity (vs. controls) as well as a disrupted relationship between CBT and PST. MATERIALS AND METHODS Study Subjects
All study procedures and materials were approved by the Institutional Review Board at the Ann & Robert H. Lurie Children’s Hospital of Chicago and the Stanley Manne Children’s Research Institute. Informed consent was obtained for all study participants. Recordings were completed with CCHS patients and controls from across the United States and in all calendar months. CCHS
Twenty-five PHOX2B mutation-confirmed CCHS subjects were recruited from patients referred to the Center for Autonomic Medicine in Pediatrics (CAMP) at Lurie Children’s Hospital. The heterozygous PHOX2B mutations include 22 cases with polyalanine repeat expansion mutations [PARM; 20/25 (n ¼ 6), 20/26 (n ¼ 6), 20/27 (n ¼ 8), 20/33 (n ¼ 2); normal genotype 20/20 reflecting the number of alanines on each allele] and three with nonPARM (NPARM) frameshift mutations. Controls
Thirty-nine healthy subjects with negative family history for CCHS or autonomic disorders, and who were not taking medications that could potentially impact temperature, were recruited as controls. Measurement of Peripheral Skin Temperature
PST was measured using the Thermochron iButton (DS1921H; Maxim, Dallas, TX), a wireless device with a range of 15–468 C, mean accuracy of 0.098 C, and a precision of 0.058 C as compared to a calibrated thermometer.29 During production, all iButton devices were subjected to a calibration process with three unique reference temperatures. The iButton was affixed to a cotton sports wristband22 and worn continuously on the non-dominant wrist, with participants instructed to remove it only for bathing. The iButton was programmed to record PST every 180 sec with a full recording consisting of 96 continuous hours (1,920 total data points). Participating CCHS patients completing 4-day in-hospital clinical evaluations simultaneously completed iButton recordings, and subsequently completed in-home Pediatric Pulmonology
302
Saiyed et al.
recordings, typically 1.5 weeks after in-hospital evaluation discharge. Non-inpatient CCHS cases and controls were offered in-home iButton recording participation only. For both groups, iButtons were worn starting at 8:00 a.m. on a Monday and removed after 96 hr (8:00 a.m. on Friday morning). All included data were from healthy CCHS patients and controls. Measurement of Core Body Temperature
CBT measurements were taken regularly for any patients completing the in-hospital study. Methods of core body temperature assessment included axillary, tympanic, and oral measurements as part of normal clinical care. Statistical Analysis
Prior to analysis, artifacts (such as those produced when the iButton device was detached for bathing) were removed. An automatic rejection procedure was applied in which a 28C change within one sample interval (3 min) was used to identify the start time of potential artifacts. Temperature data were voided during the interval between these time points and the time when the measurement returned to the previous level. This algorithm was effective at identifying transient artifacts corresponding to removal of the iButton for bathing, etc., but also tended to catch epochs that seemed, on visual inspection, to contain physiologically plausible values (given continuity with surrounding measurements). For this reason, this automatic procedure was followed by manual review of the waveform data to correct errors in the automatic routine. Overall, manual review restored
Congenital Central Hypoventilation Syndrome (CCHS): Circadian Temperature Variation Rehan Saiyed, BS,1 Casey M. Rand, BS,1 Michael S. Carroll, PhD,1,2 Cynthia M. Koliboski, RT,1 Tracey M. Stewart, RT,1 Cindy D. Brogadir, RT,1 Anna S. Kenny, RT,1 Emily K.E. Petersen, RN,3 David W. Carley, PhD,4 and Debra E. Weese-Mayer, MD1,2* Summary. Background: Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, which includes a control of breathing deficit and features of autonomic nervous system (ANS) dysregulation. In recognition of the fundamental role of the ANS in temperature regulation and rhythm and the lack of any prior characterization of circadian temperature rhythms in CCHS, we sought to explore peripheral and core temperatures and circadian patterning. We hypothesized that CCHS patients would exhibit lower peripheral skin temperatures (PST), variability, and circadian rhythmicity (vs. controls), as well as a disrupted relationship between core body temperature (CBT) and PST. Methods: PST was sampled every 3 min over four 24-hr periods in CCHS cases and similarly aged controls. CBT was sampled in a subset of these recordings. Results: PST was recorded from 25 CCHS cases (110,664 measures/230 days) and 39 controls (78,772 measures/164 days). Simultaneous CBT measurements were made from 23 CCHS patients. In CCHS, mean PST was lower overall (P ¼ 0.03) and at night (P ¼ 0.02), and PST variability (interquartile range) was higher at night (P ¼ 0.05) (vs. controls). PST circadian rhythm remained intact but the phase relationship of PST to CBTrhythm was extremely variable in CCHS. Conclusions: PST alterations in CCHS likely reflect altered autonomic control of peripheral vascular tone. These alterations represent a previously unreported manifestation of CCHS and may provide an opportunity for therapeutic intervention. The relationship between temperature dysregulation and CCHS may also offer insight into basic mechanisms underlying thermoregulation. Pediatr Pulmonol. 2016;51:300–307. ß 2015 Wiley Periodicals, Inc. Key words: peripheral skin temperature; circadian rhythm; iButton; PHOX2B gene. Funding source: Shaw Foundation Grant.
INTRODUCTION
Congenital central hypoventilation syndrome (CCHS) is a neurocristopathy caused by mutations in the paired-like homeobox gene 2B (PHOX2B),1 with approximately 1,200 cases identified since initial description in 1970 by Mellins et al.2 The resulting CCHS phenotype includes a control of breathing deficit and features of physiologic and anatomic autonomic nervous system dysregulation (ANSD).1,3–5 Symptoms of CCHS-related physiologic ANSD often include decreased sympathetic and parasympathetic tone, with alterations in sweating patterns, vasomotor tone, postural blood pressure responses, heart rate variability, esophageal motility, and pupillary light response, among others.1 Anatomic ANSD features include aganglionosis of the distal hindgut (Hirschsprung disease) and tumors of neural crest origin (neuroblastoma, ganglioneuroma, and ganglioneuroblastoma), occurring in a subset of cases of CCHS. These CCHS-related observations follow intuitively considering the role of PHOX2B in determining neurodevelopmental cell fate in the sympathetic, parasympathetic, and enteric pathways.6–9 ß 2015 Wiley Periodicals, Inc.
1 Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children’s Hospital of Chicago, Stanley Manne Children’s Research Institute, Chicago, Illinois. 2
Northwestern University Feinberg School of Medicine, Chicago, Illinois.
3 Cardiovascular Thoracic Surgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois. 4 Center for Narcolepsy, Sleep and Health Research (CNSHR), University of Illinois at Chicago, Chicago, Illinois.
Mr. Saiyed and Mr. Rand are equal first authors for this manuscript.
Correspondence to: Debra E. Weese-Mayer, MD, Beatrice Cummings Mayer Professor of Pediatric Autonomic Medicine, Northwestern University Feinberg School of Medicine, Chief, Center for Autonomic Medicine in Pediatrics (CAMP), Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 East Chicago Ave., Box 165, Chicago, IL 60611 E-mail: [email protected] Received 10 December 2014; Accepted 1 April 2015. DOI 10.1002/ppul.23236 Published online 18 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
Circadian Thermoregulation in CCHS
Circadian rhythms are widespread physiologic and behavioral patterns that operate on a periodicity of approximately 24 hr and are essential to health. The suprachiasmatic nucleus directs synchronization of these rhythms throughout the periphery of the body10 with growing evidence implicating thermoregulation as one of the drivers for such synchronization.11–14 The ANS plays a major role in thermoregulation through control of peripheral vasomotor tone. Core body temperature (CBT) follows a diurnal rhythm and is a commonly measured marker for analyzing circadian system timing. CBT regulation involves homeostatic responses to endogenous and exogenous cues, as well as intrinsic circadian regulation. The homeostatic component preserves an optimal core temperature (typically between 36–38 8C in humans),15,16 whereas heat production and loss also oscillate with a circadian rhythmicity.17,18 Consequently, these rhythms cause CBT to oscillate regularly through a range of approximately 1 8C in humans, reaching its peak in the late afternoon/early evening and its nadir in the early morning hours.17 CBT impacts numerous physiologic processes,19 and alterations in CBT and its rhythmicity are often early indicators of physiologic compromise. Peripheral skin temperature (PST) demonstrates a rhythm that is inverted and slightly advanced in phase relative to CBT rhythm20,21 and has been shown to be a reliable marker to assess circadian physiology.21–23 Although measures of CBT and PST each may have intrinsic value, measurement of CBT is usually invasive and noncontinuous (oral, tympanic, axillary, or rectal),15 whereas PST measurement is characterized by limited invasiveness, ease of use, low cost, and potential for continuous assessment in both the hospital and home settings. Thus, measurement of PST can be utilized as a noninvasive and inexpensive gauge of both body temperature and circadian rhythm. Indeed, several recent studies have supported using measures of PST to assess circadian rhythmicity.21–23 Additionally, measurement of PST may allow insight into the function of the ANS, and has previously offered insight into autonomic peripheral nerve dysfunction.24 Recognizing the importance of body temperature on physiologic responsiveness to hypercarbia,25 the intrinsic attenuation of the cardiorespiratory response to hypercarbia/hypoxemia in CCHS4, and related features of autonomic dysfunction with intrinsic involvement in thermoregulatory pathways, we sought to describe PST and circadian profiles in CCHS and comparably aged healthy controls. Given the objective alterations in sympathetic and parasympathetic control (and likely in vasomotor tone) in CCHS and anecdotal reports of cool extremities and low core body temperature, we hypothesized that CCHS patients would exhibit lower mean PST measures (vs. controls). Grounded in a past study
301
illustrating lower heart rate variability in CCHS than in controls,26 we hypothesized similarly lower variability of PST in these cases compared to controls. Further, in acknowledgement of the well-defined ANS and presumptive vasomotor irregularities in CCHS, coupled with recent evidence supporting hypothalamic injury in areas integral to autonomic and thermoregulatory control,27,28 we hypothesized attenuated circadian rhythmicity (vs. controls) as well as a disrupted relationship between CBT and PST. MATERIALS AND METHODS Study Subjects
All study procedures and materials were approved by the Institutional Review Board at the Ann & Robert H. Lurie Children’s Hospital of Chicago and the Stanley Manne Children’s Research Institute. Informed consent was obtained for all study participants. Recordings were completed with CCHS patients and controls from across the United States and in all calendar months. CCHS
Twenty-five PHOX2B mutation-confirmed CCHS subjects were recruited from patients referred to the Center for Autonomic Medicine in Pediatrics (CAMP) at Lurie Children’s Hospital. The heterozygous PHOX2B mutations include 22 cases with polyalanine repeat expansion mutations [PARM; 20/25 (n ¼ 6), 20/26 (n ¼ 6), 20/27 (n ¼ 8), 20/33 (n ¼ 2); normal genotype 20/20 reflecting the number of alanines on each allele] and three with nonPARM (NPARM) frameshift mutations. Controls
Thirty-nine healthy subjects with negative family history for CCHS or autonomic disorders, and who were not taking medications that could potentially impact temperature, were recruited as controls. Measurement of Peripheral Skin Temperature
PST was measured using the Thermochron iButton (DS1921H; Maxim, Dallas, TX), a wireless device with a range of 15–468 C, mean accuracy of 0.098 C, and a precision of 0.058 C as compared to a calibrated thermometer.29 During production, all iButton devices were subjected to a calibration process with three unique reference temperatures. The iButton was affixed to a cotton sports wristband22 and worn continuously on the non-dominant wrist, with participants instructed to remove it only for bathing. The iButton was programmed to record PST every 180 sec with a full recording consisting of 96 continuous hours (1,920 total data points). Participating CCHS patients completing 4-day in-hospital clinical evaluations simultaneously completed iButton recordings, and subsequently completed in-home Pediatric Pulmonology
302
Saiyed et al.
recordings, typically 1.5 weeks after in-hospital evaluation discharge. Non-inpatient CCHS cases and controls were offered in-home iButton recording participation only. For both groups, iButtons were worn starting at 8:00 a.m. on a Monday and removed after 96 hr (8:00 a.m. on Friday morning). All included data were from healthy CCHS patients and controls. Measurement of Core Body Temperature
CBT measurements were taken regularly for any patients completing the in-hospital study. Methods of core body temperature assessment included axillary, tympanic, and oral measurements as part of normal clinical care. Statistical Analysis
Prior to analysis, artifacts (such as those produced when the iButton device was detached for bathing) were removed. An automatic rejection procedure was applied in which a 28C change within one sample interval (3 min) was used to identify the start time of potential artifacts. Temperature data were voided during the interval between these time points and the time when the measurement returned to the previous level. This algorithm was effective at identifying transient artifacts corresponding to removal of the iButton for bathing, etc., but also tended to catch epochs that seemed, on visual inspection, to contain physiologically plausible values (given continuity with surrounding measurements). For this reason, this automatic procedure was followed by manual review of the waveform data to correct errors in the automatic routine. Overall, manual review restored
