Periodic limb movements during sleep (PLMS) refer to periodic episodes of repetitive, highly stereotyped involuntary movements of the lower extremities [1]. These movements may be associated with arousal, and although PLMS is not typically linked to insomnia, it can lead to fragmented sleep and excessive daytime sleepiness [1,2]. PLMS is observed in patients with various sleep-related disorders, including restless leg syndrome (RLS), rapid eye movement sleep behavior disorder (RBD), and obstructive sleep apnea (OSA) [3]. For instance, PLMS has been found in 80% of patients with RLS, 70% of those with RBD, and 19.7% of those with OSA [4-8].

The third edition of the International Classification of Sleep Disorders stipulates that a diagnosis of periodic limb movement disorder (PLMD) is appropriate when PLMS occurs at a frequency exceeding 15 times per hour and is accompanied by sleep disturbances or functional impairment, in the absence of other sleep disorders [9,10]. The prevalence of PLMD in the general population ranges from 3.9% to 11% [8,11,12]. PLMD may be indicative of autonomic system dysregulation and/or inflammation and has been associated with an increased risk of cardiovascular and cerebrovascular diseases [13]. Additionally, medical conditions such as diabetes and migraine have been linked to PLMD [14].

OSA is characterized by upper airway obstruction that leads to recurrent episodes of cessation or reduction of airflow during sleep [15]. A diagnosis of OSA is established when the apnea– hypopnea index (AHI) exceeds 5 events per hour [15]. While the hypoxic effect, arousal intensity, and other metrics can also be used to diagnose OSA, the AHI has been shown to correlate more strongly with cardiovascular outcomes [16,17]. Although OSA and PLMS exhibit a known association, the specifics of their relationship have yet to be fully elucidated [6]. However, a low arousal threshold is a common feature of both OSA and PLMS, which may suggest a connecting factor between the two conditions [18]. PLMS occurs more frequently in individuals with mild OSA compared to those without OSA, yet it is much less common in those with severe OSA than in individuals without the disorder [19,20].

OSA can be categorized into different subtypes based on sleeping position. The Cartwright classification defines positional obstructive sleep apnea (POSA) as occurring when the AHI in the supine position is at least twice as high as in the non-supine position [21]. POSA represents a large proportion of OSA cases. The position in which a patient sleeps can influence the effectiveness of treatments for POSA, such as continuous positive airway pressure (CPAP) therapy and surgical interventions [22,23]. While POSA may coexist with other sleep disorders, no direct link has been established between POSA and PLMS. Nevertheless, a Danish study examining sleep positions in relation to the degree of body movements—including those of the arms, thighs, and upper back—found that a preference for the lateral sleep position increased with age and body mass index (BMI). The study also noted that the extent of nocturnal body movements correlated with factors such as sex, age, BMI, and smoking status [24]. Given that age, sex, and BMI are recognized risk factors for OSA, the sleep positions of OSA patients might be associated with their patterns of nocturnal body movement. Furthermore, body weight unloading and positional changes can influence the threshold for spinal root muscle response. Consequently, associations have been observed between either PLMS or low spinal flexor reflex thresholds and increased spinal cord excitability in response to changes in position [25,26].

Although several studies have reported associations between OSA and PLMS [3,6,20], research comparing the prevalence and risk of PLMS with a control group that does not have OSA, based on OSA severity and POSA status, is lacking. Therefore, our main objectives were to compare the status of PLMS according to the severity of OSA and to evaluate the relationship between PLMS and POSA.

The study protocol was approved by the Institutional Review Committee of Seoul National University Hospital (Seoul, Republic of Korea; No. C-2007-179-1143), Seoul National University Bundang Hospital (Seongnam, Republic of Korea; No. B-2010/640-401), and Hallym University College of Medicine (Chuncheon, Republic of Korea; No. 2020-03-022). Written informed consent was waived because the data were collected in a de-identified manner.

A total of 7,745 participants who underwent diagnostic PSG were initially evaluated. After excluding those lacking data on age, sex, BMI, or PLMI, 6,140 participants remained for inclusion. For the analysis examining the correlation between PLMS and POSA, 5,078 patients with OSA were included after further exclusions (Fig. 1). Baseline characteristics of the participants, including mean age, sex, BMI, mean total sleep time, and mean AHI, are presented in Table 1. The proportion of POSA varied significantly among subgroups categorized by OSA severity.

We observed significant associations between the mean values of PLMI and PLMAI and the severity of OSA. Furthermore, the risk of PLMS was observed to decline as the severity of OSA increased. Specifically, the mean PLMI and PLMAI values decreased in conjunction with escalating OSA severity. The prevalence of PLMS also decreased as OSA severity increased. Notably, among all patients with OSA, the risk of PLMS was significantly elevated in the POSA group compared to the non-POSA group. However, in subgroup analysis, this difference was significant only for the severe OSA subgroup. In other words, this significantly increased risk was not observed in the mild or moderate OSA subgroups.

The reported prevalence of PLMS varies according to age, ethnicity, and comorbid disease status. In a Wisconsin sleep cohort from the United States, the PLMS rate was found to be 25.3% in the general population [33]. In two German cohorts and one Swiss cohort, the prevalence rates of PLMS were 32.4%, 36.4%, and 28.6%, respectively [28,29], with most participants being middle-aged and White. Other studies of white participants have shown that PLMS prevalence can be as high as 61% in older adults, while being only 5.6% in children [34,35]. A community-based study reported a PLMS prevalence of 4.3% among African-Americans, compared to 9.3% in white individuals [36]. In South Korea, the prevalence was 29.3% among older individuals (mean age, 68.3±5.6 years) [37] and 9.3% in the general population. These findings suggest that both age and ethnicity may influence the prevalence of PLMS. The rates of PLMS in patients with OSA have varied in published studies, with 14.8% and 14.1% reported in studies from the United States and Korea, respectively [6,20]. In the present study, the PLMS rate among patients with OSA was 9.4%, which is lower than those reported in previous studies. This discrepancy may be attributed to the specific characteristics of our participant group. We observed a decrease in PLMS as the severity of OSA increased. Specifically, the prevalence of PLMS in subgroups with escalating OSA severity was 13.1%, 11.4%, and 7.4%, respectively. These figures are lower than those reported in a prior Korean study, which found prevalence rates of 17%, 15%, and 12% for increasing OSA severity [20]. The differences observed may reflect variations in the characteristics of participants across studies.

In the present study, among patients with OSA, 70.2% also presented with POSA, which is comparable to the 75% prevalence reported in the HypnoLaus Sleep Cohort [29]. The link between POSA and PLMS is not well understood; however, three hypotheses can be proposed. First, a low arousal threshold might be a shared characteristic of both OSA and PLMS, given that it is a recognized risk factor for each condition [18]. Huang et al. [38] found that individuals with POSA exhibited a lower arousal threshold compared to the non-POSA group. Since the proportion of patients with POSA decreases with increasing OSA severity, this theory could account for the lower prevalence of PLMS observed in patients with severe OSA.

Second, enhanced spinal root reflex responses may contribute to the onset of PLMS. A study in the United States found that PLMS was more prevalent among patients with RLS who exhibited diminished spinal flexor reflexes and heightened spinal cord excitability [25]. Another study indicated that spinal and supraspinal mechanisms play a more pivotal role in PLMS than the peripheral motor efferent and sensory afferent pathways [39]. Therefore, frequent activations of the spinal cord, due to lowered thresholds influenced by changes in body weight distribution and position, may provoke PLMS [26]. Compared to lying in the supine position, standing has been shown to increase the threshold and diminish the posterior root muscle response, which is a monosynaptic reflex elicited by single-pulse, transcutaneous spinal cord stimulation [26]. In an earlier study, the response to a second stimulus was lower and the response thresholds were higher in the prone position compared to the supine position [40]. Consequently, adopting a supine sleeping posture in patients with POSA could lower the threshold, amplify the response to spinal cord stimulation, and ultimately trigger more PLMS episodes.

Finally, activation of the central pattern generator (CPG) may also play a role in PLMS. Patients with POSA tend to spend more time sleeping in the supine position [22], which can provoke involuntary movements of the lower extremities through the activation of the CPG [41,42]. Since PLMS can be triggered by CPG activation [43], an increase in supine sleep could be linked to a higher frequency of involuntary lower extremity movements resulting from this process. Consequently, POSA may exacerbate PLMS through a combined positional and CPG-related mechanism.

CPAP is considered the gold standard treatment for OSA [44,45]. A meta-analysis showed that CPAP use can reduce the AHI by up to 33.8 events per hour and lower systolic blood pressure by 2.4 mmHg [46]. This treatment has the potential to alleviate both airway obstruction and PLMS, contributing to several hypotheses. Retrospective studies investigating the impact of OSA treatment on PLMI have revealed that PLMI decreased following CPAP titration in patients with mild OSA, but increased in those with moderate to severe OSA [6,47,48]. Researchers have proposed that PLMI should be categorized into induced and spontaneous types [8,47]. Induced PLMI, which is related to residual respiratory events, may respond to CPAP treatment, while spontaneous PLMI, which occurs without an external stimulus, remains evident after CPAP titration [47,49]. This pattern was noted in both an earlier retrospective Korean study and the present research [50]. However, the Apnea Positive Pressure Long-term Efficacy Study found that CPAP titration did not significantly improve PLMI compared to sham CPAP [6]. That study differed from others in that it included a second CPAP titration 6 months after the initial one, while other investigations only compared data from the diagnostic PSG and CPAP titration status. Considering these disparate findings, future studies should incorporate long-term follow-up of patients with OSA to thoroughly assess the efficacy of CPAP treatment.

Our study had several limitations. First, the work was retrospective in nature; therefore, we cannot assert any causal relationship between PLMS and OSA. An event-synchronized analysis of a large cohort that considers all respiratory events and limb movements during sleep, along with sleep stages and positions, is warranted. Second, PSG was performed only once. While single-night studies are generally reliable for diagnosis, individual discrepancies between nights can be overlooked [51]. Third, we adjusted for only the demographic factors of age, sex, and BMI when evaluating the impact of OSA on PLMS. Factors such as antidepressant use, physical inactivity, and current smoking are also associated with PLMS, but these were not accounted for in our analysis [28]. Fourth, our study displayed an imbalance in group size, with the number of patients with severe OSA being three times higher than the other groups. Since patients with severe OSA tend to exhibit a lower incidence of PLMI, this disparity may have compromised our interpretation of PLMS prevalence in the general population. Further studies employing propensity score matching to adjust for OSA severity may be necessary to mitigate substantial errors in resulting conclusions. Finally, given the definitions of PLM-related parameters, respiratory events should be distinctly identified through event-synchronized analysis. Our retrospective analysis excluded respiratory event-related limb movements from the PLMS count; hence, we relied on auto-scoring for this variable. Although we used validated software, the lack of clear validation criteria for PLMS may have introduced some bias. Considering the risk of PLMS during rapid eye movement sleep, additional research focusing on PLMS throughout this sleep stage is also needed.

POSA may lead to an increased frequency of PLMS, particularly in patients with severe OSA. When PLMS is suspected, evaluating the patient’s POSA status and determining the severity of OSA are crucial steps. Such assessments can facilitate the selection of appropriate CPAP treatment.