|Year : 2022 | Volume
| Issue : 1 | Page : 35-39
Periodic legs movements in sleep persisting after positive airway pressure titration is significantly associated with cardiovascular diseases
Aygul Mahmudova, Hatice Kurucu, Gulcin Benbir Şenel, Derya Karadeniz
Department of Neurology, Cerrahpasa Faculty of Medicine, Istanbul, Turkey
|Date of Submission||10-Aug-2021|
|Date of Decision||04-Jan-2022|
|Date of Acceptance||09-Jan-2022|
|Date of Web Publication||31-Mar-2022|
Cerrahpaşa, Koca Mustafapaşa Cd No: 53, Fatih, İstanbul 34098
Source of Support: None, Conflict of Interest: None
Purpose: Obstructive sleep apnea syndrome (OSAS) and periodic limb movement disorder in sleep (PLMS) are highly prevalent diseases of sleep and both are associated with a negative cardiovascular outcome. The purpose of this study was to investigate the presence of PLMS in patients with OSAS in positive airway pressure (PAP) titration and examine its relation to cardiovascular diseases. Materials and Methods: All patients who were diagnosed as having OSAS after one-night polysomnographic (PSG) recording during a 1-year period and were been treated successfully through PAP titration PSG were investigated retrospectively. Results: Out of 460 medical files investigated, 300 patients were included in the study (204 males, 68%) with a mean age of 54.2 ± 10.6 years. A comparison between patients with a PLMS index >15/h and PLMS index <15/h revealed that cardiac diseases (P = 0.040), hypertension (HT) (P = 0.006), and hyperlipidemia (P = 0.019) were all more common if patients had a PLMS index >15/h. Furthermore, a significant correlation was detected between the PLMS index and cardiac diseases (ß = 39.908, P = 0.012) and HT (ß = 32.884, P = 0.021). Conclusions: The risk of cardiovascular diseases is markedly increased in patients with OSAS with PLMS, and this was positively correlated with the PLMS index. Physicians should be aware that PLMS persisting after PAP titration might prevent the efficiency of PAP therapy in OSAS, especially in preventing cardiovascular complications.
Keywords: Cardiovascular disease, obstructive sleep apnea, periodic limb movement, positive airway pressure therapy
|How to cite this article:|
Mahmudova A, Kurucu H, Şenel GB, Karadeniz D. Periodic legs movements in sleep persisting after positive airway pressure titration is significantly associated with cardiovascular diseases. Neurol Sci Neurophysiol 2022;39:35-9
|How to cite this URL:|
Mahmudova A, Kurucu H, Şenel GB, Karadeniz D. Periodic legs movements in sleep persisting after positive airway pressure titration is significantly associated with cardiovascular diseases. Neurol Sci Neurophysiol [serial online] 2022 [cited 2022 Jun 28];39:35-9. Available from: http://www.nsnjournal.org/text.asp?2022/39/1/35/342364
| Introduction|| |
Obstructive sleep apnea syndrome (OSAS) is a very common sleep disorder with an incidence of 2%–4% in males and 1%–2% in females. It is now well-known that OSAS is associated with a higher risk for cardiovascular diseases and increased mortality, possibly through recurrent episodes of nocturnal hypoxia, arousals, and sympathetic activation. The gold standard treatment of OSAS is noninvasive positive airway pressure (PAP) therapy, which is proved to be very effective in relieving symptoms related to OSAS and lowering the risk for cardiovascular events. In patients with OSAS, periodic limb movement disorder in sleep (PLMS) is commonly observed, mostly associated with abnormal respiratory events.,
PLMS is characterized by stereotypic, periodic movements in the legs and/or arms, which is another cause of fragmented sleep, bioelectric arousals, and sympathetic activation. Although PLMS secondary to OSAS vanishes when treated, it persists in a considerable percentage of patients, even after PAP therapy. In one of our previous studies, we showed that PLMS was associated with a poorer prognosis in patients with ischemic stroke, especially if arousal reactions were related to PLMS. However, in the case of concurrent diagnoses of OSAS and PLMS, the current literature falls short of sufficient evidence for their effect on cardiovascular diseases. Previously, in one individual limited study, it was observed that increased basal sympathetic activity had a negative outcome on cardiovascular events in patients with both PLMS and OSAS. In this study, we aimed to investigate the presence of PLMS in patients with OSAS after PAP therapy and its association with cardiovascular diseases.
| Materials and Methods|| |
In this retrospective study, we analyzed the medical data of all patients who had undergone one-night polysomnographic (PSG) recordings in our sleep laboratory over a 1-year period and were diagnosed as having OSAS in diagnostic investigations, followed by successful treatment with one-night PAP therapy. The inclusion criteria were defined as age between 25 and 75 years, having a PLMS index equal to or higher than 15 per h in diagnostic PSG, and having an index of abnormal respiratory events of fewer than 5 per h. Demographic data of patients meeting the inclusion criteria were noted in detail, including age, sex, body mass index, smoking, alcohol or substance intake, comorbid systemic and neurologic conditions, and laboratory data, especially ferritin levels. The exclusion criteria were being diagnosed with having a sleep-related breathing disorder other than OSAS, use of medications known to trigger or cause PLMS, and having developed complex sleep apnea syndrome with titration PSG. PSG recordings were performed and scored according to the latest version of the American Academy of Sleep Medicine manual for the scoring of sleep and associated events. For the diagnosis of sleep disorders, the latest version of the International Classification of Sleep Disorders was used. Our study was approved by the Local Ethics Committee (Permission number: 2017-99518).
Statistical analysis was performed using the SPSS 24.0 program. Descriptive parameters with normal distribution were analyzed using the Kolmogorov–Smirnov test, and numerical data were assessed using Student's t-test. Risk factor analysis to define the predictive value of parameters was defined using logistic regression and Pearson's correlation analysis. The level of statistical significance was set at a P < 0.05 with a confidence interval of 95%.
| Results|| |
A total of 460 medical files were investigated and 300 patients were suitable for inclusion in the study. The study group consisted of 204 (68%) males and 96 (32%) females with a mean age of 54.2 ± 10.6 years. The mean body mass index was calculated as 30.9 ± 5.1 kg/m2. Smoking was present in 28.7% of our study population. Among the PSG data, the mean respiratory disturbance index (RDI) on the diagnostic night was 40.2 ± 22.9/h. On the PAP night, in addition to a significant decrease in RDI (P < 0.001), the total duration of wakefulness and superficial nonrapid eye movement (NREM) sleep stages were significantly decreased (P = 0.009 and P < 0.001, respectively), and deep NREM sleep and REM sleep durations were significantly increased (P < 0.001).
In diagnostic PSG, in 131 (43.7%) of all the patients, the PLMS index PLMSI was equal to or higher than 15 per h, with a mean PLMSI of 41.9 ± 30.2 per h. The demographic parameters [Figure 1]a and the associated diseases [Figure 1]b in patients with a PLMSI higher or lower than 15/hr at diagnostic PSG were all similar. On the second night, when PAP titration was performed successfully, 112 (37%) patients had a persisting PLMSI of >15/h. Of these patients, 72 (64.3%) were males and 28 (35.7%) were females. The mean age of these 112 patients was calculated as 57.2 ± 9.1 years. The mean persisting PLMSI was calculated as 47.9 + 31.6/h on the titration night, which showed no significant difference compared with those on the diagnostic night (P = 0.462). Demographic data including age, sex, and body mass index in this subgroup of patients (with a persisting PLMSI >15/h at titration night) were similar to those in the general study population. Nevertheless, the mean age in this subgroup of patients with a persisting PLMSI of >15/h was higher than those with a persisting PLMSI of <15/h (t = 3.793, P < 0.001). In the PSG data, the mean durations of superficial NREM sleep stages were significantly longer (t = 2.776, P = 0.007; and t = 2.644, P = 0.009, consecutively) and the duration of the deep NREM sleep stage was significantly shorter (t = −3.277, P = 0.002) in patients with a persisting PLMSI of >15/h on the titration night, even if OSAS was successfully treated.
Eighty-eight (29.3%) patients were diagnosed as having Willis-Ekbom disease/restless legs syndrome (WED/RLS). The mean ferritin level was calculated as 99.8 ± 224.1 ng/mL; 64.6% had a ferritin level <75 ng/mL. In patients with a persisting PLMSI of >15/h on the titration night, 36.6% had WED/RLS and 56.8% of these had low ferritin levels (<75 ng/mL). The presence of WED/RLS was significantly higher in patients with a persisting PLMSI of >15/h at titration night (P = 0.022), although the low levels of ferritin failed to show a statistically significant difference in this subgroup of patients [P = 0.087; [Figure 2]a].
|Figure 1: The demographical (a) and clinical (b) characteristics of the patients with an index of periodic leg movements in sleep <15/hr versus >15/hr at diagnostic PSG (for all, P>0.05)|
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|Figure 2: The demographical (a) and clinical (b) characteristics of the patients with an index of persisting periodic leg movements in sleep <15/hr versus >15/hr|
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Analysis of systemic and/or neurologic comorbidities in patients with OSAS revealed that 60% of patients had a cardiovascular pathology such as myocardial infarction or congestive heart failure or arrhythmias, 51.7% had hypertension (HT), 21.3% had type 2 diabetes mellitus (DM), 19.3% had hyperlipidemia (HL), and 4.7% had ischemic type cerebrovascular events. Among other diseases, 5 (1.7%) patients had amyotrophic lateral sclerosis, 3 (1%) had multiple sclerosis, and 13 (4.3%) patients had Parkinson's disease. None of the patients were recorded as having rheumatologic and/or musculoskeletal diseases.
When patients with a persisting PLMSI of >15/h on the titration night were analyzed, 69.6% had a cardiovascular pathology such as myocardial infarction or congestive heart failure or arrhythmias, 59.8% had HT, 25.9% had type 2 DM, 25% had HL, and 7.1% had ischemic type cerebrovascular events. The difference in associated systemic and/or neurologic comorbidities between the general study population and patients with a PLMSI of >15/h showed no statistically significant differences [Figure 2]b. On the other hand, when patients with a persisting PLMSI of >15/h on the titration night were compared with patients with a persisting PLMSI of <15/h on the titration night, it was observed that cardiac diseases (P = 0.040), HT (P = 0.006), and HL (P = 0.019) were all more common if patients had a persisting PLMSI of >15/h. Furthermore, a significant correlation was detected between the index of persisting PLMS and cardiac diseases (ß = 39.908, P = 0.012) and HT (ß = 32.884, P = 0.021); the higher the persisting PLMSI, the more common was the cardiac diseases and HT [Table 1].
|Table 1: The correlation analysis of the persisting periodic leg movements in sleep>15/h at titration night|
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| Discussion|| |
PLMS is a highly prevalent disorder, reported in around 4% of the general population. Its prevalence, on the other hand, is known to increase vastly in combination with OSAS, up to about 40%., Similarly, in our study, persisting PLMS was present in 37% of patients with OSAS. The prevalence of PLMS was reported to increase with age in several studies.,,,, We also observed that among the patients with a persisting PLMSI (>15/h), higher age was associated with a higher index of persisting PLMS.
As is already well-known, noninvasive PAP therapy is the gold standard treatment for OSAS, which normalizes abnormal respiratory events during sleep, abolishing OSAS-related symptoms, and OSAS-related cardiovascular risks. In our study, we included all patients who had an effective PAP titration night with an RDI dropping to fewer than 5 per h. We observed that durations of wakefulness and superficial NREM sleep stages were significantly decreased and deep NREM and REM sleep stages were significantly increased, supporting the achievement of an effective PAP treatment together with the decrease in RDI. These beneficial effects of PAP therapy on sleep architecture and sleep quality are also well-known., On the other hand, in the subgroup analysis of patients with an efficient PAP titration night, those with a persisting PLMSI of >15/h had longer durations of superficial NREM sleep stages and shorter duration of the deep NREM sleep stage than in patients with a persisting PLMSI of <15/h on the titration night. This finding supports the deteriorating effects of PLMS on sleep quality, which persisted even if OSAS was successfully treated. These observations presented here highlight that physicians should be alert for PLMS persisting after PAP therapy, which may prevent the beneficial effects of PAP therapy of OSAS.
Sympathetic autonomic hyperactivity triggered by abnormal respiratory events leads to an increased risk for cardiovascular diseases and HT in OSAS, and this may also be the case for PLMS associated with arousal reactions. An increased sympathetic tone was previously reported in association with PLMS. In addition, sympathetic hyperactivity triggered by PLMS was also suggested to be associated with an increased risk for cardiovascular events. Furthermore, persisting PLMS even after PAP therapy was investigated in one recent study, and it was reported that PLMS had hazardous influences on the cardiovascular system by causing autonomic dysregulation, as shown by heart rate variability measurements, irrespective of abnormal respiratory events. In this study, we demonstrated that the prevalence of cardiovascular diseases was markedly increased in patients with persisting PLMS, and a significant positive correlation was found with the index of persisting PLMS and the presence of cardiovascular diseases. The lack of significant differences between patients with and without PLMS in diagnostic PSG in terms of cardiovascular comorbidities increases the importance of the relationship between persisting PLMS on the titration night and cardiovascular diseases.
Although this study clearly suggests that PLMS persisting after PAP therapy may prevent the efficiency of PAP therapy in OSAS, some limitations in this paper are evident due to its retrospective design, which can be addressed in future studies. Persisting PLMS documented after 3 months of PAP therapy, instead of on the PAP titration night, and monitoring compliance with PAP therapy should be analyzed prospectively for a better understanding of the hazardous effects of PLMS. This limitation was counteracted by the use of large numbers of patients. Furthermore, the causal relationship between persisting PLMS and cardiovascular diseases could not be determined in this cross-sectional study. Similarly, the causal relationship between PLMS and other secondary causes could not be evaluated accurately because of the retrospective design of the study. Finally, we did not perform spectral analysis of PLMS, whether it was associated with cortical, bioelectric, or autonomic arousal reactions, to determine a link between the presence of persisting PLMS and cardiovascular diseases. Nevertheless, we state that prospective designs in patients with a persisting PLMSI of >15/h and those with a persisting PLMSI of <15/h, whether or not in association with OSAS, should be performed for the delineation of the long-term effects of persisting PLMS on the cardiovascular system.
| Conclusions|| |
The results of this study emphasize that PLMS persisting even after PAP therapy in patients with OSAS deserves attention due to its hazardous effects on the cardiovascular system. For this reason, persisting PLMS should be evaluated carefully and scored in patients with OSAS during PAP therapy, to eliminate negative cardiovascular influences.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: A population health perspective. Am J Respir Crit Care Med 2002;165:1217-39.
Destors M, Tamisier R, Baguet JP, Levy P, Pepin JL. Cardiovascular morbidity associated with obstructive sleep apnea syndrome. Rev Mal Respir 2014;31:375-85.
Jean-Louis G, Zizi F, Clark LT, Brown CD, McFarlane SI. Obstructive sleep apnea and cardiovascular disease: Role of the metabolic syndrome and its components. J Clin Sleep Med 2008;4:261-72.
Baran AS, Richert AC, Douglass AB, May W, Ansarin K. Change in periodic limb movement index during treatment of obstructive sleep apnea with continuous positive airway pressure. Sleep 2003;26:717-20.
Haba-Rubio J, Staner L, Krieger J, Macher JP. Periodic limb movements and sleepiness in obstructive sleep apnea patients. Sleep Med 2005;6:225-9.
Hornyak M, Feige B, Riemann D, Voderholzer U. Periodic leg movements in sleep and periodic limb movement disorder: Prevalence, clinical significance and treatment. Sleep Med Rev 2006;10:169-77.
Benbir G, Karadeniz D. Influence of periodic leg movements in sleep on stroke outcome.Sleep Biol Rhythms 2013;11:194-9.
Wu MN, Lai CL, Liu CK, Yen CW, Liou LM, Hsieh CF, et al.
Basal sympathetic predominance in periodic limb movements in sleep with obstructive sleep apnea. J Sleep Res 2015;24:722-9.
American Academy of Sleep Medicine. International Classification of Sleep Disorders: Diagnostic and Coding Manual. 3rd
ed. American Academy of Sleep Medicine; 2014.
Daroff RB. The International Classification of Sleep Disorders: Diagnostic and Coding Manual. Neurology; 2012.
Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002;53:547-54.
Fry JM, DiPhillipo MA, Pressman MR. Periodic leg movements in sleep following treatment of obstructive sleep apnea with nasal continuous positive airway pressure. Chest 1989;96:89-91.
Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell R, Kaplan O. Periodic limb movements in sleep in community-dwelling elderly. Sleep 1991;14:496-500.
Coleman RM, Pollak CP, Weitzman ED. Periodic movements in sleep (nocturnal myoclonus): Relation to sleep disorders. Ann Neurol 1980;8:416-21.
Hornyak M, Trenkwalder C. Restless legs syndrome and periodic limb movement disorder in the elderly. J Psychosom Res 2004;56:543-8.
Hornyak M, Kopasz M, Feige B, Riemann D, Voderholzer U. Variability of periodic leg movements in various sleep disorders: İmplications for clinical and pathophysiologic studies. Sleep 2005;28:331-5.
Koo BB, Blackwell T, Ancoli-Israel S, Stone KL, Stefanick ML, Redline S, et al.
Association of incident cardiovascular disease with periodic limb movements during sleep in older men: Outcomes of sleep disorders in older men (MrOS) study. Circulation 2011;124:1223-31.
Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med 2001;163:344-8.
Brillante R, Cossa G, Liu PY, Laks L. Rapid eye movement and slow-wave sleep rebound after one night of continuous positive airway pressure for obstructive sleep apnoea. Respirology 2012;17:547-53.
Fietze I, Quispe-Bravo S, Hänsch T, Röttig J, Baumann G, Witt C. Arousals and sleep stages in patients with obstructive sleep apnoea syndrome: Changes under nCPAP treatment. J Sleep Res 1997;6:128-33.
Dursunoğlu N, Dursunoğlu D, Cuhadaroğlu C, Kiliçaslan Z. Acute effects of automated continuous positive airway pressure on blood pressure in patients with sleep apnea and hypertension. Respiration 2005;72:150-5.
Guggisberg AG, Hess CW, Mathis J. The significance of the sympathetic nervous system in the pathophysiology of periodic leg movements in sleep. Sleep 2007;30:755-66.
Walters AS, Rye DB.
Review of the relationship of restless legs syndrome and periodic limb movements in sleep to hypertension, heart disease and stroke. Sleep 2009;32:589-97.
[Figure 1], [Figure 2]