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Periodic Leg Movement, Nasal CPAP, and Expiratory Muscles
CHEST
Original Research SLEEP DISORDERS
Periodic Leg Movement, Nasal CPAP, and Expiratory Muscles Won Hee Seo, MD; and Christian Guilleminault, MD, DBiol
Background: Periodic leg movements (PLMs) may appear during nasal CPAP titration, persisting despite the elimination of hypopneas. Methods: Systematic recordings of expiratory abdominal muscles on the right and left sides with surface electromyographic (EMG) electrodes lateral to navel, and close from the lateral side of abdomen, were added during nasal CPAP titration for treatment of obstructive sleep apnea (OSA). Positive airway pressure was titrated during nocturnal polysomnography, based on analysis of the flow curve derived from the CPAP equipment and EEG analysis, including persistence of phases A2 and A3 of the cyclic alternating pattern (CAP). The requirement was to eliminate American Association of Sleep Medicine (AASM)-defined hypopnea and also flow limitation and abnormal EEG patterns. When CPAP reached valid results, it was lowered at the time of awakening by 2 or 3 cm H2O, and titration was performed again. Data collected during a 7-month period on adults with a prior diagnosis of OSA who had received treatment with nasal CPAP regardless of age and sex were rendered anonymous and were retrospectively rescored by a blinded investigator. Results: Eighty-one successively seen patients with PLMs during CPAP titration were investigated. Elimination of AASM-defined hypopnea was not sufficient to eliminate the PLMs observed during the titration; higher CPAP eliminated flow limitation and CAP phases A2 and A3 and persisting PLMs. PLMs were associated with simultaneous EMG bursts in expiratory abdominal muscles. Conclusions: The presence of PLMs during CPAP titration indicates the persistence of sleepdisordered breathing. PLMs during CPAP titration are related to the presence of abdominal expiratory muscle activity. CHEST 2012; 142(1):111–118 Abbreviations: AASM 5 American Association of Sleep Medicine; CAP 5 cyclic alternating pattern; EMG 5 electromyography; NREM 5 non-rapid eye movement; OSA 5 obstructive sleep apnea; PAP 5 positive airway pressure; PLM 5 periodic leg movement; PSG 5 polysomnography; REM 5 rapid eye movement; SDB 5 sleep-disordered breathing
limb movements (PLMs) during sleep are Periodic involuntary, repetitive, stereotypic, short-lasting, seg-
mental movements of the lower and sometimes upper extremities.1,2 Studies have indicated a wider variety of movements, including movements of the upper extremities, as part of PLMs during sleep.3 The presence of PLMs during sleep has been assessed by polysomnography (PSG) using two surface electrodes Manuscript received June 21, 2011; revision accepted December 7, 2011. Affiliations: From Stanford University Sleep Medicine Division, Stanford Outpatient Medical Center, Redwood City, CA. Funding/Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Christian Guilleminault, MD, DBiol, Stanford University Sleep Medicine Division, Stanford Outpatient Medical Center, 450 Broadway M/C 5704, Redwood City, CA 94063; e-mail: [email protected]
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over both anterior tibialis muscles, and the scoring of PLMs is based on the amplitude of anterior tibialis electromyographic (EMG) discharges.4 PLMs may be associated with evidence of EEG changes of arousal and with changes in the plethysmographic curve obtained from the finger oximeter, which indicate sympathetic stimulation.5 PLMs during sleep may be seen with different sleep disorders,6-9 including sleep-disordered breathing (SDB),10,11 and PLMs may appear during nasal CPAP titration. About 2 years ago, to improve respiratory evaluation during sleep in patients during SDB diagnostic and nasal positive airway pressure (PAP) titration, systematic © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.11-1563 CHEST / 142 / 1 / JULY 2012
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recordings of extra EMG leads monitoring intercostaldiaphragmatic and expiratory abdominal muscles (rectus and external-oblique, right and left side) were added during PSG12,13 (Fig 1). Appropriate muscle contractions during inspiration and expiration were checked previously by asking subjects to perform respiratory maneuvers while awake and supine and during monitoring with esophageal manometry (esophageal pressure).12,13 In all further recordings, biocalibrations, including respiratory movements, nasal and buccal inspiration, and active expiration, were performed before sleep onset. We performed nasal CPAP titrations based on analysis of both a flow curve derived from the PAP equipment and EEG analysis, including the persistence of phases A2 and A3 of the cyclic alternating pattern (CAP), as reported previously in the literature.14,15 We requested that during the night, at the time of returning to bed after a bathroom break or a long awakening, pressure be lowered by several centimeters of water pressure (usually between 2 and 3 cm H2O) after reaching the optimal PAP pressure and that the titration be resumed from this lowered pressure, allowing confirmation of the most appropriate pressure for patient care. Optimal titration is based on the absence of American Association of Sleep Medicine (AASM)defined hypopnea4 and also on the elimination of “flow limitation” and the disappearance of phases A2 and A3 of the CAP.14-16 Performing a retrospective analysis on successively seen patients, we studied PLMs seen during nasal CPAP, including both “treatment-emergent” PLMs and those noted at the beginning of the titration, and we also investigated when the PLMs disappeared. We concomitantly measured respiratory muscle activity with surface electrodes and investigated their relation to PLMs.
Materials and Methods Research Protocol All data collected during a 7-month period on successively seen adult patients with a prior diagnosis of obstructive sleep apnea (OSA), demonstrated by PSG, who had received treatment with nasal CPAP regardless of age and sex, were rendered anonymous. An individual not involved in the research protocol identified patients reported to have had PLMs during nasal CPAP titration, eliminating patients with a history of restless leg syndrome or other neurologic or clinical syndromes with a reported association with PLMs during sleep, and obese patients. Each individual data set was then given a random identifier number for research purposes. The anonymous recording and clinical information constituted the research material. PSG recordings were rescored by only one individual blinded to clinical or prior PSG information; the anonymous clinical information was then provided with the research identifying number, and statistical analyses were 112 Downloaded From: http://journal.publications.chestnet.org/ on 07/18/2012
performed. Research comparison and evaluation of the anonymous data were approved by the Stanford institutional review board (approval number 15494). Polysomnography The overnight in-laboratory PSG included systematic monitoring of EEG (C3/A2, C4/A1, Fpz/A1-A2, O1-O2), electrooculography (right and left electrooculogram), chin and bilateral leg EMG, ECG (modified V2 lead), respiratory efforts (chest and abdominal respiratory-inductive-plethysmography effort belts, intercostals-diaphragmatic EMGs and abdominal expiratory muscles EMGs-right and left surface electrodes placed over rectus and oblique muscles [Fig 1]), oral thermistor, oxygen saturation (finger pulse oximetry with photoplethysmography sensor, producing also a plethysmography curve), body position, and neck microphone. The airflow curve was derived using Philips Respironics nasal CPAP equipment, using an algorithm developed by the company, with a tachometer and a pressure generator that analyzed airflow and provided a respiratory curve temporally synchronized with the other monitored variables placed on the computerized sleep recording system. Mask leaks, delivered pressure, and other measurements provided by the air pressure generator (Philips Respironics equipment) were also monitored with instrumental and biologic calibrations performed before sleep onset and at the end of data collection (the continuous video monitoring conducted during titration was not provided to the scorer). The minimum recording time was 7 h. Nasal PAP Calibration During the nocturnal recording, technologists were requested to reach the appropriate nasal CPAP as early as possible during the night, increasing pressures as fast as possible while maintaining sleep. The recommendation was to increase the nasal positive pressure by at least 1 cm H2O every 20 min if possible, until the nasal pressure curve presented a physiologic round inspiratory shape, and patterns not only of hypopneas but also of flow limitation (as described in the literature) did not exist. The sleep EEG was taken into consideration for confirming appropriate pressure, by looking for EEG evidence of AASM arousal but was also based on a 60-s absence of phases A2 and A3 of CAP.4,14,15 The presence of PLMs also led to an increase in pressure. Once the optimal pressure was reached, per protocol, the pressure was lowered in association with an awakening, and recording resumed at the lower pressure (2 to 3 cm H2O lower) following the same protocol. Because the supine position is considered to be the position with the greatest risk of breathing abnormalities during sleep and because patients, when introduced to nasal CPAP, most commonly use this position, nasal CPAP titrations were performed in this position with usage of one pillow elevating the head by about 8° to 10°. Data Analyses The same investigator, who was blinded to the clinical information, rescored all PSG recordings based on the following scoring criteria: wake and sleep stages were scored according to international manuals and criteria4,17 with EEG arousal (ⵑ 3 s)17 scored independently from respiratory events. The presence of CAP with phases A2 and A3 (associating a mixture of EEG synchronization and desynchronization during the phase A) was noted during the non-rapid eye movement (NREM) sleep titration.14,15 Oxygen desaturation readings were checked to verify the absence or deletion of artifacts (indicated by a sympatheticrelated peripheral hypoperfusion observed on the plethysmography curve, with an abnormal photoplethysmography waveform).18 Abnormal breathing patterns were identified and labeled not Original Research
Figure 1. Placement of surface electrodes investigating respiratory muscles. Abdominal indicates electrode placement above rectus muscle. External oblique indicates electrode placement above external oblique muscles. DIA 5 diaphragm intercostals electrode placement; EMG 5 electromyography; RIC 5 right intercostals electrode placement. only according to AASM criteria, but also with a marking of “flow limitation” as defined in the literature.16,19 The appropriate therapeutic pressure was considered “reached” only after the elimination of the AASM-defined “hypopnea,” patterns of “flow limitation,”4,16,19 patterns of NREM-CAP with phases A2 and A3 in the sleep EEG recording,15 and the absence of PLMs. During the analysis, the pressure at which the apneas and hypopneas disappeared was noted on the score sheet, and the presence/absence of flow limitation, CAP, and PLM were also indicated. The CPAP associated with the disappearance of flow limitation and of PLMs was also noted. To confirm the disappearance of flow limitation and CAPs A2/A3, a minimum of 20 min of sleep at the same CPAP must have been obtained, and 30 min were requested to confirm the disappearance of PLM. When patients awoke and the pressure was lowered per protocol, a scoring similar to the one before the awakening was performed, and the same data were collected, with a similar requirement of having a minimum of 20 min of sleep at the same CPAP before confirming the absence of flow limitation, CAPs A2/A3, and PLM. PLMs were scored according to the recommendation of the AASM. After scoring had been performed, and after visually eliminating leg movement artifact, leg intervals were calculated for each subject using a proprietary computerized program; the mean and SD of all the events scored as PLMs in all the subjects were obtained from this program. The relationship between EMG bursts and inspiratory and expiratory EMG discharges was visually investigated and the temporal relationship between leg and abdominal muscle bursts was ascertained: to be considered “related,” the two EMG (leg and abdominal muscles) bursts must have overlapped (Fig 2). Once all the anonymous recordings were scored, the anonymous clinical data with the same research identifier number were placed on an Excel data sheet (Microsoft Corp); these data included age, sex, weight, height, and calculated BMI. journal.publications.chestnet.org
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Statistical Analyses To compare the presence/absence of the different variables studied, each CPAP increase was placed on an Excel sheet, and the four variables studied (AASM-defined apnea/hypopnea, flow limitation, CAPs with indication of arousal, and PLM) were scored independently. As mentioned, because sleep stages may vary and because confirming the absence of flow limitation and CAPs A2/A3 requires a minimum stable sleep recording, 20 min was used as the time base to confirm the presence/absence of the considered variable. A similar rule was used for scoring after an awakening associated with a drop in CPAP. Descriptive statistical analyses were performed, and skewness of data and kurtosis were determined to evaluate normal distribution. For each CPAP studied, the epochs in which AASMdefined apnea and hypopnea “recommended,” flow limitation, and CAPs A2 and A3 were noted as present were placed on independent score sheets. From these tabulations, a statistical comparison of the different variables studied and the measured CPAP was performed. Nonparametric statistics were used if necessary. All statistical analyses were performed using the SPSS statistical package, version 12.0 (SPSS Inc). All values are shown as mean ⫾ SD.
Results All successively monitored patients during a 7-month period who showed PLMs during nasal CPAP titration and who met the inclusion criteria were included in the study. Eighty-one patients were treated with nasal CPAP; the demographics are presented in Table 1. CHEST / 142 / 1 / JULY 2012
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Figure 2. Example of concomitant EMG discharges in leg and expiratory abdominal muscles. Two minutes of sleep recording is shown. The channels from top to bottom are EEG (channels 1 and 2); chin EMG (channel 3); electroocculogram (channels 4 and 5); EKG (channel 6); PPG (channel 7); left and right leg EMG (channels 8 and 9); intercostal muscles (channel 10); Dia (channel 11); ExOb (channel 12); neck microphone (channel 13); Sao2 (channel 14); flow obtained from CPAP equipment (channel 15); oral thermistor (channel 16); thoracic inductive plethysmography belt (channel 17); abdominal inductive plethysmography belt (channel 18). (Some monitored channels have been deleted to provide a better visual presentation of the respiratory muscle activity.) As can be seen, on both external oblique muscle and leg EMG recordings, there are simultaneous EMG discharges. The EMG discharges are not concomitant with the diaphragmatic EMG discharges, as can be seen on analysis of the EMG discharges on the “diaphragm and intercostals” channels (channels 10 and 11). Ctr 5 center; Dia 5 diaphragmatic muscle discharge; EKG 5 ECG; ExOb 5 external oblique muscle; L 5 left for chin & ECG, lower placement for left anterior tibialis, right anterior tibialis, RIC, diaphragmatic muscle discharge, and external oblique muscle; LAT 5 left anterior tibialis; PPG 5 photoplethysmogam; R 5 right; RAT 5 right anterior tibialis; Sao2 5 pulse oximetry; U 5 upper placement. See Figure 1 legend for expansion of other abbreviations.
PLMs Analyses The mean peak interval between two EMG leg discharges was 26 s (SD 5 5.1; range, 13-34 s) for the total group.4 Leg EMG discharges were associated with a sympathetic activation, as indicated by a downward movement of the finger plethysmography curve, in 95% ⫾ 3.1% of the leg movements. An associated change in the sleep EEG was also noted in 95% ⫾ 3.3% of the EMG bursts. These changes consisted of either a burst of high-amplitude EEG waves in the d frequency range; a mixture of high-amplitude, fasterfrequency, and lower-amplitude waves (u and a range); or fast-frequency low-amplitude waves (a and b range). These changes were of variable duration, as short as 1 s14 and at times longer than 3 s, and were indicative of an AASM arousal.17 Response to CPAP Appearance of PLMs: PLMs were present at a pressure of 5 cm H2O in 19 of 81 patients. PLMs appeared during sleep while receiving mostly low 114 Downloaded From: http://journal.publications.chestnet.org/ on 07/18/2012
CPAP, with PLMs noted when pressure was between 5 and 10 cm H2O in all subjects; apneas and hypopneas were always present in the recording when PLMs were noted. Disappearance of PLMs: PLMs were present in 72 subjects when AASM-defined hypopneas4 were eliminated. These subjects, however, still showed a pattern of “flow limitation” and the presence of CAP phases A2 and A3 during NREM sleep.14,15,17,19 The disappearance of “flow limitation” required higher Table 1—Demographics Variables Age, y Weight, kg Height, cm BMI, kg/m2
Patients With CPAP (N 5 81) 42.7 ⫾ 9.5 (19-64) 70.6 ⫾ 11.2 (43-89) 172.4 ⫾ 11.7 (147-198) 25.48 ⫾ 2.31 (19.4-28.1)
Data are presented as mean ⫾ SD (range). Of the total number of patients with CPAP, 33 (40.7%) were women. The statistical package used was SPSS, version 12.0. Original Research
pressure and was associated with the disappearance of PLMs. Nine subjects had simultaneous disappearance of apnea and hypopnea, flow limitation, indication of arousals using the CAP system, and PLMs, and 44 patients needed ⱖ 2 cm H2O of pressure to see the disappearance of flow limitation and PLMs. We did not note a difference in the disappearance of flow limitation, CAPs A2 and A3, and PLMs using our scoring criteria requirements of having at least 20 min of stable sleep without the presence of flow limitation and CAPs. When comparing the nasal CPAP necessary to eliminate AASM-defined “hypopneas” and the pressure necessary to eliminate PLM, we found a mean significant difference of 1.47 ⫾ 1.96 cm H2O (P 5 .02, two tailed). However, there was no significant difference in the pressure that eliminated flow limitation or CAPs A2 and A3 and PLMs. In the subjects in whom the disappearance of flow limitation and PLMs had already been observed, the drop of pressure with awakening led to a reappearance of PLMs, flow limitation, and CAPs A2 and A3. Position During Sleep: Sleep position was monitored continuously, and all patients spent between 92% and 100% (mean 95% ⫾ 3.5%) of their time during sleep in a supine position because of the CPAP titration protocol. Lateral sleeping, if present, was always short and was seen only in stage 1 NREM sleep. Relationship Between Sleep States and Appearance/ Disappearance of PLMs: PLMs were always first noted during NREM sleep stages 1 or 2, and rapid eye movement (REM) sleep was never noted during the time spent between sleep onset and the appearance of PLMs, but PLMs were noted during short-lived REM sleep bouts in 59% of cases; long, uninterrupted REM sleep periods were seen only after the disappearance of the PLM because the presence of PLMs was associated with a disruption of REM sleep. Return to Lower Nasal PAP During the PAP Titration: Per protocol, PAP drops were performed during an awakening of the patient (bathroom call 78% of the time); 61 of 81 subjects had reached an absence of PLMs at the time of this awakening. Return to lower pressure always led to a reappearance of abnormal breathing and to PLMs. In these 61 subjects, a mean of 58 min was spent increasing the CPAP back to the same level as before the awakening and bathroom trip, and the CPAP that eliminated flow limitation and PLMs was found to be the same as the one noted before the pressure decrease. The evaluation showed that at two different times during the night the same CPAP had to be reached to observe a disappearance of PLMs and an absence of flow limitation. In summary, titration of CPAP based on elimination of AASM-defined journal.publications.chestnet.org
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hypopneas4 was not sufficient to eliminate most of the PLMs observed during the PAP titration, and more pressure was needed to eliminate PLMs, flow limitation, and EEG disturbances related to abnormal breathing as demonstrated by the persistence of CAP phases A2 and A3.14,15,17,19 Recording of Expiratory Abdominal Muscles and Occurrence of PLMs Respiratory muscles were systematically monitored in all patients. The redundancy of expiratory muscle EMG recordings (right-left and several muscles) allowed continuous investigation of expiratory abdominal muscles; a concomitant increase in abdominal EMG discharge and PLMs was monitored (Figs 2, 3). These abdominal and leg EMG discharges were no longer seen once the nasal CPAP had reached a threshold at which flow limitation was not observed. Analysis of both leg and abdominal muscle EMGs showed that both EMG discharges began at the same time; there was a complete temporal concordance at the beginning of the EMG burst. Investigation of the C3/M2 and C4/M1 EEG recordings performed for each EMG burst at an analysis speed of 10 s indicated that there was no preceding arousal pattern before the occurrence of the abdominal-leg EMG burst. Abdominal and leg muscle bursts disappeared at the same time. Discussion PLMs have been noted in patients with different types of SDB, including Cheyne-Stokes breathing.10,11,20-24 In 1989, Fry et al10 were the first to show that PLMs could be noted not only during baseline diagnostic recording but also during nasal CPAP titration, emphasizing that the PLM count was higher in the nasal CPAP titration night than during the baseline night and that the PLM count had increased between the initial nasal CPAP titration and the follow-up performed months later, with the persistence of abnormal sleep; this finding was confirmed by others.23,24 Our study shows that PLMs do not disappear with the elimination of AASM-defined hypopnea, but with the elimination of flow limitation and the associated instability of NREM sleep. Why do PLMs appear and disappear with nasal CPAP titration? We can only offer suggestions because all necessary data are not available. One may argue that PLM induces “hypopnea” (ie, PLM would increase inspirations secondary leading to a compensatory physiologic pause related to the “hyperbreath” associated with some degree of CO2 depletion). Clearly, the “hypopnea” induced by such “hyperventilation” may not lead to a drop CHEST / 142 / 1 / JULY 2012
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Figure 3. Concomitant EMG discharges in leg and respiratory muscles. Compressed tracing of 5-min polysomnographic recording. The presence of a cyclic alternating pattern (CAP) with phases A2-A3 and the periodicity of the leg and expiratory EMG discharges are clearly shown. From the top, the first EEG leads show the CAP pattern reoccurring during the 5 min of recording; the two channels at the bottom (channels 19 and 20) show the EMG bursts monitored simultaneously in leg (channel 19) and external oblique (channel 20) muscles. The flow obtained from the CPAP equipment is presented on channel 12. PAP 5 positive airway pressure. See Figure 1 and 2 legends for expansion of other abbreviations.
of oxygen saturation of 4%, and the number of breaths needed to come back to normal breathing may require less than 10 s, particularly if the upper airway is better “opened” by CPAP. PLMs may then be seen without AASM-defined hypopnea, with a partially improved air exchange, but the absence of complete resolution of the upper airway narrowing will still lead to EEG disturbances and there will be a discrepancy between the scoring of AASM-defined hypopneas and the scoring of more subtle disturbances. There would not be the need to call upon expiratory muscle involvement to explain the finding of persistence of abnormal sleep and PLMs after treatment of AASMdefined apneas and hypopneas. But no “missed breath” is seen when flow limitation is noted and PLM occur, and there is still activation of different muscles, including leg muscles, that reoccurs periodically during the persistence of abnormal breathing. We found that the periodic EMG discharges monitored in the legs are also simultaneously seen in the abdominal muscles, and both EMG bursts disappear with optimal PAP pressure with the absence of flow limitation. We believe that this finding is relevant to our observation. An increase in both negative esophageal pressure and positive gastric pressure recorded measurements has been noted with CPAP above 8 to 10 cm H2O (Jed E. Black, MD, personal communication, January 2011); similarly, Lofaso et al,25 monitoring esophageal pressure and gastric pressure with airflow during nasal CPAP titration, and investigating the presence of expiratory abdominal muscle activity, showed that there is a “paradoxical rise” in gastric 116 Downloaded From: http://journal.publications.chestnet.org/ on 07/18/2012
pressure with a progressive increase in nasal CPAP, with a decrease in abdominal diameter. This abnormal rise in gastric pressure disappeared only when optimum PAP was reached.25 Also in subjects with untreated OSA, the Wisconsin group has well documented the presence of an expiratory component during hypopnea and apneas, indicating the presence of an expiratory involvement during upper airway obstruction during sleep.26,27 Such an observation was well confirmed by Stănescu et al,28 and both groups showed that such an expiratory component also existed in “heavy snorers,” as had already been suggested by the work of Sanders and Moore.29 The well-accepted concept of inspiratory upper-airway muscle tone decrease seen in OSA patients can be applied similarly to the pharyngeal constrictor muscles, and this decrease “destabilizes the airway.” One may, thus, suggest the presence of an expiratory muscle component during nasal CPAP titration and, as suggested by Lofaso et al25 data, this expiratory component disappears only when “optimum CPAP pressure” is reached. Why is such a component not noted more often? Perhaps because nasal CPAP titration is not commonly performed with esophageal pressure and gastric pressure, and even expiratory muscle recordings are not performed systematically; in addition, the patient group was nonobese, a fact that helped in the surface EMG monitoring and visualization of EMG surface signals. Why are PLMs not seen in every OSA patient? First, if a relationship exists between the presence of PLMs and expiratory muscle discharges (as suggested Original Research
by the temporal relationship of both recorded discharges), there must be a sufficient expiratory airflow limitation to induce active contraction of the expiratory muscles. As mentioned previously, Skatrud and Dempsey,26 Henke et al,27 and Stănescu et al28 demonstrated this involvement in untreated OSA and heavy snorer subjects whom they studied. The importance of this involvement, which is variable, may be related to the degree of expiratory limitation. Some of these subjects had PLMs from the very start of the recording (ie, before any effective treatment) and may have been similar to the OSA subjects reported previously. But some others did not, and the PLMs appeared only after the onset of CPAP treatment. Again, as previously documented, CPAP per se may induce “paradoxical rise in gastric pressure associated with changes in the diaphragmatic diameter”25 with increasing CPAP. Could the abdominal EMG bursts simply represent a more generalized motor system response with a more generalized EMG response, similar to the arm muscle activity that has been shown to accompany PLMs? Because we did not monitor arm EMGs, we cannot eliminate this possibility, but one may also raise the reverse possibility (ie, that activation of arms with PLMs may be related to the more important activation of the motor system because of the need for greater abdominal response). Further recordings will be needed, and direct intramuscle recording, with simultaneous gastric pressure measurement as used by Henke et al,27 may be needed. Acknowledgments Author contributions: Dr Guilleminault takes responsibility for the integrity of the data and the accuracy of data analysis. Dr Guilleminault: contributed to the study concept and design, subject recruitment, analysis of data, drafting of the manuscript, and study supervision. Dr Seo: contributed to the study design, subject recruitment, analysis of data, and preparation of manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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Original Research
Original Research SLEEP DISORDERS
Periodic Leg Movement, Nasal CPAP, and Expiratory Muscles Won Hee Seo, MD; and Christian Guilleminault, MD, DBiol
Background: Periodic leg movements (PLMs) may appear during nasal CPAP titration, persisting despite the elimination of hypopneas. Methods: Systematic recordings of expiratory abdominal muscles on the right and left sides with surface electromyographic (EMG) electrodes lateral to navel, and close from the lateral side of abdomen, were added during nasal CPAP titration for treatment of obstructive sleep apnea (OSA). Positive airway pressure was titrated during nocturnal polysomnography, based on analysis of the flow curve derived from the CPAP equipment and EEG analysis, including persistence of phases A2 and A3 of the cyclic alternating pattern (CAP). The requirement was to eliminate American Association of Sleep Medicine (AASM)-defined hypopnea and also flow limitation and abnormal EEG patterns. When CPAP reached valid results, it was lowered at the time of awakening by 2 or 3 cm H2O, and titration was performed again. Data collected during a 7-month period on adults with a prior diagnosis of OSA who had received treatment with nasal CPAP regardless of age and sex were rendered anonymous and were retrospectively rescored by a blinded investigator. Results: Eighty-one successively seen patients with PLMs during CPAP titration were investigated. Elimination of AASM-defined hypopnea was not sufficient to eliminate the PLMs observed during the titration; higher CPAP eliminated flow limitation and CAP phases A2 and A3 and persisting PLMs. PLMs were associated with simultaneous EMG bursts in expiratory abdominal muscles. Conclusions: The presence of PLMs during CPAP titration indicates the persistence of sleepdisordered breathing. PLMs during CPAP titration are related to the presence of abdominal expiratory muscle activity. CHEST 2012; 142(1):111–118 Abbreviations: AASM 5 American Association of Sleep Medicine; CAP 5 cyclic alternating pattern; EMG 5 electromyography; NREM 5 non-rapid eye movement; OSA 5 obstructive sleep apnea; PAP 5 positive airway pressure; PLM 5 periodic leg movement; PSG 5 polysomnography; REM 5 rapid eye movement; SDB 5 sleep-disordered breathing
limb movements (PLMs) during sleep are Periodic involuntary, repetitive, stereotypic, short-lasting, seg-
mental movements of the lower and sometimes upper extremities.1,2 Studies have indicated a wider variety of movements, including movements of the upper extremities, as part of PLMs during sleep.3 The presence of PLMs during sleep has been assessed by polysomnography (PSG) using two surface electrodes Manuscript received June 21, 2011; revision accepted December 7, 2011. Affiliations: From Stanford University Sleep Medicine Division, Stanford Outpatient Medical Center, Redwood City, CA. Funding/Support: The authors have reported to CHEST that no funding was received for this study. Correspondence to: Christian Guilleminault, MD, DBiol, Stanford University Sleep Medicine Division, Stanford Outpatient Medical Center, 450 Broadway M/C 5704, Redwood City, CA 94063; e-mail: [email protected]
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over both anterior tibialis muscles, and the scoring of PLMs is based on the amplitude of anterior tibialis electromyographic (EMG) discharges.4 PLMs may be associated with evidence of EEG changes of arousal and with changes in the plethysmographic curve obtained from the finger oximeter, which indicate sympathetic stimulation.5 PLMs during sleep may be seen with different sleep disorders,6-9 including sleep-disordered breathing (SDB),10,11 and PLMs may appear during nasal CPAP titration. About 2 years ago, to improve respiratory evaluation during sleep in patients during SDB diagnostic and nasal positive airway pressure (PAP) titration, systematic © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.11-1563 CHEST / 142 / 1 / JULY 2012
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recordings of extra EMG leads monitoring intercostaldiaphragmatic and expiratory abdominal muscles (rectus and external-oblique, right and left side) were added during PSG12,13 (Fig 1). Appropriate muscle contractions during inspiration and expiration were checked previously by asking subjects to perform respiratory maneuvers while awake and supine and during monitoring with esophageal manometry (esophageal pressure).12,13 In all further recordings, biocalibrations, including respiratory movements, nasal and buccal inspiration, and active expiration, were performed before sleep onset. We performed nasal CPAP titrations based on analysis of both a flow curve derived from the PAP equipment and EEG analysis, including the persistence of phases A2 and A3 of the cyclic alternating pattern (CAP), as reported previously in the literature.14,15 We requested that during the night, at the time of returning to bed after a bathroom break or a long awakening, pressure be lowered by several centimeters of water pressure (usually between 2 and 3 cm H2O) after reaching the optimal PAP pressure and that the titration be resumed from this lowered pressure, allowing confirmation of the most appropriate pressure for patient care. Optimal titration is based on the absence of American Association of Sleep Medicine (AASM)defined hypopnea4 and also on the elimination of “flow limitation” and the disappearance of phases A2 and A3 of the CAP.14-16 Performing a retrospective analysis on successively seen patients, we studied PLMs seen during nasal CPAP, including both “treatment-emergent” PLMs and those noted at the beginning of the titration, and we also investigated when the PLMs disappeared. We concomitantly measured respiratory muscle activity with surface electrodes and investigated their relation to PLMs.
Materials and Methods Research Protocol All data collected during a 7-month period on successively seen adult patients with a prior diagnosis of obstructive sleep apnea (OSA), demonstrated by PSG, who had received treatment with nasal CPAP regardless of age and sex, were rendered anonymous. An individual not involved in the research protocol identified patients reported to have had PLMs during nasal CPAP titration, eliminating patients with a history of restless leg syndrome or other neurologic or clinical syndromes with a reported association with PLMs during sleep, and obese patients. Each individual data set was then given a random identifier number for research purposes. The anonymous recording and clinical information constituted the research material. PSG recordings were rescored by only one individual blinded to clinical or prior PSG information; the anonymous clinical information was then provided with the research identifying number, and statistical analyses were 112 Downloaded From: http://journal.publications.chestnet.org/ on 07/18/2012
performed. Research comparison and evaluation of the anonymous data were approved by the Stanford institutional review board (approval number 15494). Polysomnography The overnight in-laboratory PSG included systematic monitoring of EEG (C3/A2, C4/A1, Fpz/A1-A2, O1-O2), electrooculography (right and left electrooculogram), chin and bilateral leg EMG, ECG (modified V2 lead), respiratory efforts (chest and abdominal respiratory-inductive-plethysmography effort belts, intercostals-diaphragmatic EMGs and abdominal expiratory muscles EMGs-right and left surface electrodes placed over rectus and oblique muscles [Fig 1]), oral thermistor, oxygen saturation (finger pulse oximetry with photoplethysmography sensor, producing also a plethysmography curve), body position, and neck microphone. The airflow curve was derived using Philips Respironics nasal CPAP equipment, using an algorithm developed by the company, with a tachometer and a pressure generator that analyzed airflow and provided a respiratory curve temporally synchronized with the other monitored variables placed on the computerized sleep recording system. Mask leaks, delivered pressure, and other measurements provided by the air pressure generator (Philips Respironics equipment) were also monitored with instrumental and biologic calibrations performed before sleep onset and at the end of data collection (the continuous video monitoring conducted during titration was not provided to the scorer). The minimum recording time was 7 h. Nasal PAP Calibration During the nocturnal recording, technologists were requested to reach the appropriate nasal CPAP as early as possible during the night, increasing pressures as fast as possible while maintaining sleep. The recommendation was to increase the nasal positive pressure by at least 1 cm H2O every 20 min if possible, until the nasal pressure curve presented a physiologic round inspiratory shape, and patterns not only of hypopneas but also of flow limitation (as described in the literature) did not exist. The sleep EEG was taken into consideration for confirming appropriate pressure, by looking for EEG evidence of AASM arousal but was also based on a 60-s absence of phases A2 and A3 of CAP.4,14,15 The presence of PLMs also led to an increase in pressure. Once the optimal pressure was reached, per protocol, the pressure was lowered in association with an awakening, and recording resumed at the lower pressure (2 to 3 cm H2O lower) following the same protocol. Because the supine position is considered to be the position with the greatest risk of breathing abnormalities during sleep and because patients, when introduced to nasal CPAP, most commonly use this position, nasal CPAP titrations were performed in this position with usage of one pillow elevating the head by about 8° to 10°. Data Analyses The same investigator, who was blinded to the clinical information, rescored all PSG recordings based on the following scoring criteria: wake and sleep stages were scored according to international manuals and criteria4,17 with EEG arousal (ⵑ 3 s)17 scored independently from respiratory events. The presence of CAP with phases A2 and A3 (associating a mixture of EEG synchronization and desynchronization during the phase A) was noted during the non-rapid eye movement (NREM) sleep titration.14,15 Oxygen desaturation readings were checked to verify the absence or deletion of artifacts (indicated by a sympatheticrelated peripheral hypoperfusion observed on the plethysmography curve, with an abnormal photoplethysmography waveform).18 Abnormal breathing patterns were identified and labeled not Original Research
Figure 1. Placement of surface electrodes investigating respiratory muscles. Abdominal indicates electrode placement above rectus muscle. External oblique indicates electrode placement above external oblique muscles. DIA 5 diaphragm intercostals electrode placement; EMG 5 electromyography; RIC 5 right intercostals electrode placement. only according to AASM criteria, but also with a marking of “flow limitation” as defined in the literature.16,19 The appropriate therapeutic pressure was considered “reached” only after the elimination of the AASM-defined “hypopnea,” patterns of “flow limitation,”4,16,19 patterns of NREM-CAP with phases A2 and A3 in the sleep EEG recording,15 and the absence of PLMs. During the analysis, the pressure at which the apneas and hypopneas disappeared was noted on the score sheet, and the presence/absence of flow limitation, CAP, and PLM were also indicated. The CPAP associated with the disappearance of flow limitation and of PLMs was also noted. To confirm the disappearance of flow limitation and CAPs A2/A3, a minimum of 20 min of sleep at the same CPAP must have been obtained, and 30 min were requested to confirm the disappearance of PLM. When patients awoke and the pressure was lowered per protocol, a scoring similar to the one before the awakening was performed, and the same data were collected, with a similar requirement of having a minimum of 20 min of sleep at the same CPAP before confirming the absence of flow limitation, CAPs A2/A3, and PLM. PLMs were scored according to the recommendation of the AASM. After scoring had been performed, and after visually eliminating leg movement artifact, leg intervals were calculated for each subject using a proprietary computerized program; the mean and SD of all the events scored as PLMs in all the subjects were obtained from this program. The relationship between EMG bursts and inspiratory and expiratory EMG discharges was visually investigated and the temporal relationship between leg and abdominal muscle bursts was ascertained: to be considered “related,” the two EMG (leg and abdominal muscles) bursts must have overlapped (Fig 2). Once all the anonymous recordings were scored, the anonymous clinical data with the same research identifier number were placed on an Excel data sheet (Microsoft Corp); these data included age, sex, weight, height, and calculated BMI. journal.publications.chestnet.org
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Statistical Analyses To compare the presence/absence of the different variables studied, each CPAP increase was placed on an Excel sheet, and the four variables studied (AASM-defined apnea/hypopnea, flow limitation, CAPs with indication of arousal, and PLM) were scored independently. As mentioned, because sleep stages may vary and because confirming the absence of flow limitation and CAPs A2/A3 requires a minimum stable sleep recording, 20 min was used as the time base to confirm the presence/absence of the considered variable. A similar rule was used for scoring after an awakening associated with a drop in CPAP. Descriptive statistical analyses were performed, and skewness of data and kurtosis were determined to evaluate normal distribution. For each CPAP studied, the epochs in which AASMdefined apnea and hypopnea “recommended,” flow limitation, and CAPs A2 and A3 were noted as present were placed on independent score sheets. From these tabulations, a statistical comparison of the different variables studied and the measured CPAP was performed. Nonparametric statistics were used if necessary. All statistical analyses were performed using the SPSS statistical package, version 12.0 (SPSS Inc). All values are shown as mean ⫾ SD.
Results All successively monitored patients during a 7-month period who showed PLMs during nasal CPAP titration and who met the inclusion criteria were included in the study. Eighty-one patients were treated with nasal CPAP; the demographics are presented in Table 1. CHEST / 142 / 1 / JULY 2012
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Figure 2. Example of concomitant EMG discharges in leg and expiratory abdominal muscles. Two minutes of sleep recording is shown. The channels from top to bottom are EEG (channels 1 and 2); chin EMG (channel 3); electroocculogram (channels 4 and 5); EKG (channel 6); PPG (channel 7); left and right leg EMG (channels 8 and 9); intercostal muscles (channel 10); Dia (channel 11); ExOb (channel 12); neck microphone (channel 13); Sao2 (channel 14); flow obtained from CPAP equipment (channel 15); oral thermistor (channel 16); thoracic inductive plethysmography belt (channel 17); abdominal inductive plethysmography belt (channel 18). (Some monitored channels have been deleted to provide a better visual presentation of the respiratory muscle activity.) As can be seen, on both external oblique muscle and leg EMG recordings, there are simultaneous EMG discharges. The EMG discharges are not concomitant with the diaphragmatic EMG discharges, as can be seen on analysis of the EMG discharges on the “diaphragm and intercostals” channels (channels 10 and 11). Ctr 5 center; Dia 5 diaphragmatic muscle discharge; EKG 5 ECG; ExOb 5 external oblique muscle; L 5 left for chin & ECG, lower placement for left anterior tibialis, right anterior tibialis, RIC, diaphragmatic muscle discharge, and external oblique muscle; LAT 5 left anterior tibialis; PPG 5 photoplethysmogam; R 5 right; RAT 5 right anterior tibialis; Sao2 5 pulse oximetry; U 5 upper placement. See Figure 1 legend for expansion of other abbreviations.
PLMs Analyses The mean peak interval between two EMG leg discharges was 26 s (SD 5 5.1; range, 13-34 s) for the total group.4 Leg EMG discharges were associated with a sympathetic activation, as indicated by a downward movement of the finger plethysmography curve, in 95% ⫾ 3.1% of the leg movements. An associated change in the sleep EEG was also noted in 95% ⫾ 3.3% of the EMG bursts. These changes consisted of either a burst of high-amplitude EEG waves in the d frequency range; a mixture of high-amplitude, fasterfrequency, and lower-amplitude waves (u and a range); or fast-frequency low-amplitude waves (a and b range). These changes were of variable duration, as short as 1 s14 and at times longer than 3 s, and were indicative of an AASM arousal.17 Response to CPAP Appearance of PLMs: PLMs were present at a pressure of 5 cm H2O in 19 of 81 patients. PLMs appeared during sleep while receiving mostly low 114 Downloaded From: http://journal.publications.chestnet.org/ on 07/18/2012
CPAP, with PLMs noted when pressure was between 5 and 10 cm H2O in all subjects; apneas and hypopneas were always present in the recording when PLMs were noted. Disappearance of PLMs: PLMs were present in 72 subjects when AASM-defined hypopneas4 were eliminated. These subjects, however, still showed a pattern of “flow limitation” and the presence of CAP phases A2 and A3 during NREM sleep.14,15,17,19 The disappearance of “flow limitation” required higher Table 1—Demographics Variables Age, y Weight, kg Height, cm BMI, kg/m2
Patients With CPAP (N 5 81) 42.7 ⫾ 9.5 (19-64) 70.6 ⫾ 11.2 (43-89) 172.4 ⫾ 11.7 (147-198) 25.48 ⫾ 2.31 (19.4-28.1)
Data are presented as mean ⫾ SD (range). Of the total number of patients with CPAP, 33 (40.7%) were women. The statistical package used was SPSS, version 12.0. Original Research
pressure and was associated with the disappearance of PLMs. Nine subjects had simultaneous disappearance of apnea and hypopnea, flow limitation, indication of arousals using the CAP system, and PLMs, and 44 patients needed ⱖ 2 cm H2O of pressure to see the disappearance of flow limitation and PLMs. We did not note a difference in the disappearance of flow limitation, CAPs A2 and A3, and PLMs using our scoring criteria requirements of having at least 20 min of stable sleep without the presence of flow limitation and CAPs. When comparing the nasal CPAP necessary to eliminate AASM-defined “hypopneas” and the pressure necessary to eliminate PLM, we found a mean significant difference of 1.47 ⫾ 1.96 cm H2O (P 5 .02, two tailed). However, there was no significant difference in the pressure that eliminated flow limitation or CAPs A2 and A3 and PLMs. In the subjects in whom the disappearance of flow limitation and PLMs had already been observed, the drop of pressure with awakening led to a reappearance of PLMs, flow limitation, and CAPs A2 and A3. Position During Sleep: Sleep position was monitored continuously, and all patients spent between 92% and 100% (mean 95% ⫾ 3.5%) of their time during sleep in a supine position because of the CPAP titration protocol. Lateral sleeping, if present, was always short and was seen only in stage 1 NREM sleep. Relationship Between Sleep States and Appearance/ Disappearance of PLMs: PLMs were always first noted during NREM sleep stages 1 or 2, and rapid eye movement (REM) sleep was never noted during the time spent between sleep onset and the appearance of PLMs, but PLMs were noted during short-lived REM sleep bouts in 59% of cases; long, uninterrupted REM sleep periods were seen only after the disappearance of the PLM because the presence of PLMs was associated with a disruption of REM sleep. Return to Lower Nasal PAP During the PAP Titration: Per protocol, PAP drops were performed during an awakening of the patient (bathroom call 78% of the time); 61 of 81 subjects had reached an absence of PLMs at the time of this awakening. Return to lower pressure always led to a reappearance of abnormal breathing and to PLMs. In these 61 subjects, a mean of 58 min was spent increasing the CPAP back to the same level as before the awakening and bathroom trip, and the CPAP that eliminated flow limitation and PLMs was found to be the same as the one noted before the pressure decrease. The evaluation showed that at two different times during the night the same CPAP had to be reached to observe a disappearance of PLMs and an absence of flow limitation. In summary, titration of CPAP based on elimination of AASM-defined journal.publications.chestnet.org
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hypopneas4 was not sufficient to eliminate most of the PLMs observed during the PAP titration, and more pressure was needed to eliminate PLMs, flow limitation, and EEG disturbances related to abnormal breathing as demonstrated by the persistence of CAP phases A2 and A3.14,15,17,19 Recording of Expiratory Abdominal Muscles and Occurrence of PLMs Respiratory muscles were systematically monitored in all patients. The redundancy of expiratory muscle EMG recordings (right-left and several muscles) allowed continuous investigation of expiratory abdominal muscles; a concomitant increase in abdominal EMG discharge and PLMs was monitored (Figs 2, 3). These abdominal and leg EMG discharges were no longer seen once the nasal CPAP had reached a threshold at which flow limitation was not observed. Analysis of both leg and abdominal muscle EMGs showed that both EMG discharges began at the same time; there was a complete temporal concordance at the beginning of the EMG burst. Investigation of the C3/M2 and C4/M1 EEG recordings performed for each EMG burst at an analysis speed of 10 s indicated that there was no preceding arousal pattern before the occurrence of the abdominal-leg EMG burst. Abdominal and leg muscle bursts disappeared at the same time. Discussion PLMs have been noted in patients with different types of SDB, including Cheyne-Stokes breathing.10,11,20-24 In 1989, Fry et al10 were the first to show that PLMs could be noted not only during baseline diagnostic recording but also during nasal CPAP titration, emphasizing that the PLM count was higher in the nasal CPAP titration night than during the baseline night and that the PLM count had increased between the initial nasal CPAP titration and the follow-up performed months later, with the persistence of abnormal sleep; this finding was confirmed by others.23,24 Our study shows that PLMs do not disappear with the elimination of AASM-defined hypopnea, but with the elimination of flow limitation and the associated instability of NREM sleep. Why do PLMs appear and disappear with nasal CPAP titration? We can only offer suggestions because all necessary data are not available. One may argue that PLM induces “hypopnea” (ie, PLM would increase inspirations secondary leading to a compensatory physiologic pause related to the “hyperbreath” associated with some degree of CO2 depletion). Clearly, the “hypopnea” induced by such “hyperventilation” may not lead to a drop CHEST / 142 / 1 / JULY 2012
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Figure 3. Concomitant EMG discharges in leg and respiratory muscles. Compressed tracing of 5-min polysomnographic recording. The presence of a cyclic alternating pattern (CAP) with phases A2-A3 and the periodicity of the leg and expiratory EMG discharges are clearly shown. From the top, the first EEG leads show the CAP pattern reoccurring during the 5 min of recording; the two channels at the bottom (channels 19 and 20) show the EMG bursts monitored simultaneously in leg (channel 19) and external oblique (channel 20) muscles. The flow obtained from the CPAP equipment is presented on channel 12. PAP 5 positive airway pressure. See Figure 1 and 2 legends for expansion of other abbreviations.
of oxygen saturation of 4%, and the number of breaths needed to come back to normal breathing may require less than 10 s, particularly if the upper airway is better “opened” by CPAP. PLMs may then be seen without AASM-defined hypopnea, with a partially improved air exchange, but the absence of complete resolution of the upper airway narrowing will still lead to EEG disturbances and there will be a discrepancy between the scoring of AASM-defined hypopneas and the scoring of more subtle disturbances. There would not be the need to call upon expiratory muscle involvement to explain the finding of persistence of abnormal sleep and PLMs after treatment of AASMdefined apneas and hypopneas. But no “missed breath” is seen when flow limitation is noted and PLM occur, and there is still activation of different muscles, including leg muscles, that reoccurs periodically during the persistence of abnormal breathing. We found that the periodic EMG discharges monitored in the legs are also simultaneously seen in the abdominal muscles, and both EMG bursts disappear with optimal PAP pressure with the absence of flow limitation. We believe that this finding is relevant to our observation. An increase in both negative esophageal pressure and positive gastric pressure recorded measurements has been noted with CPAP above 8 to 10 cm H2O (Jed E. Black, MD, personal communication, January 2011); similarly, Lofaso et al,25 monitoring esophageal pressure and gastric pressure with airflow during nasal CPAP titration, and investigating the presence of expiratory abdominal muscle activity, showed that there is a “paradoxical rise” in gastric 116 Downloaded From: http://journal.publications.chestnet.org/ on 07/18/2012
pressure with a progressive increase in nasal CPAP, with a decrease in abdominal diameter. This abnormal rise in gastric pressure disappeared only when optimum PAP was reached.25 Also in subjects with untreated OSA, the Wisconsin group has well documented the presence of an expiratory component during hypopnea and apneas, indicating the presence of an expiratory involvement during upper airway obstruction during sleep.26,27 Such an observation was well confirmed by Stănescu et al,28 and both groups showed that such an expiratory component also existed in “heavy snorers,” as had already been suggested by the work of Sanders and Moore.29 The well-accepted concept of inspiratory upper-airway muscle tone decrease seen in OSA patients can be applied similarly to the pharyngeal constrictor muscles, and this decrease “destabilizes the airway.” One may, thus, suggest the presence of an expiratory muscle component during nasal CPAP titration and, as suggested by Lofaso et al25 data, this expiratory component disappears only when “optimum CPAP pressure” is reached. Why is such a component not noted more often? Perhaps because nasal CPAP titration is not commonly performed with esophageal pressure and gastric pressure, and even expiratory muscle recordings are not performed systematically; in addition, the patient group was nonobese, a fact that helped in the surface EMG monitoring and visualization of EMG surface signals. Why are PLMs not seen in every OSA patient? First, if a relationship exists between the presence of PLMs and expiratory muscle discharges (as suggested Original Research
by the temporal relationship of both recorded discharges), there must be a sufficient expiratory airflow limitation to induce active contraction of the expiratory muscles. As mentioned previously, Skatrud and Dempsey,26 Henke et al,27 and Stănescu et al28 demonstrated this involvement in untreated OSA and heavy snorer subjects whom they studied. The importance of this involvement, which is variable, may be related to the degree of expiratory limitation. Some of these subjects had PLMs from the very start of the recording (ie, before any effective treatment) and may have been similar to the OSA subjects reported previously. But some others did not, and the PLMs appeared only after the onset of CPAP treatment. Again, as previously documented, CPAP per se may induce “paradoxical rise in gastric pressure associated with changes in the diaphragmatic diameter”25 with increasing CPAP. Could the abdominal EMG bursts simply represent a more generalized motor system response with a more generalized EMG response, similar to the arm muscle activity that has been shown to accompany PLMs? Because we did not monitor arm EMGs, we cannot eliminate this possibility, but one may also raise the reverse possibility (ie, that activation of arms with PLMs may be related to the more important activation of the motor system because of the need for greater abdominal response). Further recordings will be needed, and direct intramuscle recording, with simultaneous gastric pressure measurement as used by Henke et al,27 may be needed. Acknowledgments Author contributions: Dr Guilleminault takes responsibility for the integrity of the data and the accuracy of data analysis. Dr Guilleminault: contributed to the study concept and design, subject recruitment, analysis of data, drafting of the manuscript, and study supervision. Dr Seo: contributed to the study design, subject recruitment, analysis of data, and preparation of manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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