PLMS has thus far been regarded as mostly an incidental concomitant phenomenon found in PSG monitoring in OSA patients since patients rarely present with isolated complaints of PLMS due to the lack of attendant leg discomfort as in RLS. However, this is no coincidence: current literature supports the view that PLMS is more common in OSA patients than in the general population. Taking PLMI ≥ 5 as the standard, Canada and the United States reported that the prevalence of PLMS in OSA patients is 48%11 and 33%27, respectively, compared to a prevalence of 4–11% in all adults28. Our study included only the Chinese population, where the prevalence was found to be 22.1% using the same PLMI ≥ 5 standard, or 16.1% using the newer PLMI ≥ 15 standard. Along with another study that recorded a prevalence of 20.1% in Taiwan29, this suggests that the occurrence of PLMS in the Chinese OSA population may be lower than that in the North American population.
In the OSA-PLMS group, the sleep efficiency of the patients appeared to be lower than that in the OSA-only group. In terms of the sleep structure, patients in the OSA-PLMS group displayed a higher proportion of stage N1 sleep and lower proportion of stage N2 sleep stage (Table 2). As is consistent with the literature6,7, this points to the disruption of sleep structure due to the periodic limb motor movements in OSA patients combined with PLMS. The potential mechanisms of such disruption can be manifold. Some studies have found that PLM is often accompanied by frequent EEG arousals30, which regardless of their causes, prevent deeper, more stable stages of sleep. Furthermore, among OSA patients, about one-third are clinically characterized by a low respiratory arousal threshold31, which is a key factor associated with increased ventilatory instability and more severe OSA 32. As shown by both our data and the MrOS external dataset, OSA-PLMS patients demonstrate an elevated tendency to have a low arousal threshold. Low arousal threshold leads to premature airflow recovery and limits the accumulation of respiratory stimuli required to activate pharyngeal dilators 33. Transient hyperventilation response after awakening causes blood CO₂ levels to continue to decline after the end of apnea events, aggravating ventilatory instability and perpetuates the cycle of repetitive arousals, leading to sleep disruption17,32. Indeed, this mechanism of low arousal threshold could offer an explanation for the increased arousals and reduced sleep efficiency in OSA-PLMS patients seen in some studies6,7, bridging the gap between the ostensibly unrelated symptoms of PLMS and OSA. Crucially, this negative effect is further compounded by the more recent finding that put into doubt the traditional belief that arousals are necessary for re-opening of the obstructed airway18,33, that is, arousals are not a “protective” mechanism as traditionally suggested and low ArTH contributes to the pathogenesis of severe OSA34.
In our study, the methodology adopted to identify patients with low ArTH was a prediction tool developed by Edwards et al. 21, whose study validated this prediction tool against the gold standard epiglottic ArTH measurement in 146 patients. The tool achieved a reasonably high sensitivity (80.4%) and specificity (88.0%), and its robustness is further affirmed through its adoption by many recent studies 35–39. This made possible the retrospective data collection and external dataset validation on a much larger sample of patients than the arguably more accurate invasive epiglottic measurement could. In our sample, 46.6% of patients in the OSA-PLMS group were of the low arousal threshold phenotype, compared to 19.7% in the OSA-only group (p < 0.001, Table 3). Using multivariate logistic regression, this difference is estimated to represent an odds ratio of 5.51 (3.35–9.05, p < 0.001) for patients with low ArTH. This relationship between low ArTH and PLMS is further validated using the MrOS database (N = 2232) where the odds ratio was calculated at 1.46 (1.18–1.81, p < 0.001). The MrOS cohort had a median age of 76.3 years, while the median age in our study was 45 years. This suggests that low arousal threshold is not only a risk factor for OSA but also and plays an important role in predisposing OSA patients to PLMS in all age groups.
Despite its muted significance in patient complaints, PLMS combined with OSA represents notable cardiovascular and cerebrovascular risks. One multisite, longitudinal study by A. Zinchuk et al. of 1247 US veterans assessed the relationship between OSA phenotype and cardiovascular outcomes. Based on the polysomnographic features, seven phenotypes were identified among the OSA patients using cluster analysis, namely, “mild”, “periodic limb movements of sleep (PLMS)”, “NREM and arousal”, “REM and hypoxia”, “hypopnea and hypoxia”, “arousal and poor sleep” and “combined severe”. Astonishingly, membership to the “PLMS (N = 119)” cluster was shown to be an even better predictor than AHI categories (AHI ≥ 30 vs AHI < 15 ) in predicting cardiovascular outcomes, and the PLMS cluster carries the highest risks of negative cardiovascular outcomes (OR = 2.02, 1.32–3.08) among the six clusters12. In our study, we found that the prevalence of hypertension, arrhythmia, diabetes mellitus, and stroke in the OSA-PLMS group was higher than that in the OSA-only group. Similarly, a study by Koo BB et al demonstrated the relationship between PLMS and CVD in the MrOS sleep study cohort40. Besides cardiovascular risks, recent research has observed associations between PLMS and attention-deficit/hyperactivity disorder (ADHD)41, as well as depression42.
Such strong links between PLMS and heightened risks of cardiovascular and psychological disorders point to either the direct effect of this motor disorder or, more likely, the presence of a more sinister mechanism underlying both PLMS and cardiovascular risks. Currently, several hypotheses exist to explain this relationship. One hypothesis implicated the repetitive abnormal autonomic response to PLMS30. In a study by W. Cassel et al., increased lability in blood pressure was recorded during leg movements compared to controls. The study also observed a temporal relationship between the onset of PLM and blood pressure elevations43. Another study by Carolina Lombardi et al. also demonstrated an increment of blood pressure equal to 2.64 mm Hg in patients with significant PLMS when compared to patients without significant PLMS (p = 0.044)44. Yet, from the OSA perspective, a correlation has been repeatedly shown between hypertension and sleep disruption. Thus, in light of the relationship we have shown between low ArTH and PLMS, we postulate that a central mechanism underlying the low arousal threshold could bridge the missing link between PLMS and hypertension, through the transient moderation of the autonomic nervous system (as in the former study by W. Cassel et al.,) and the process of sleep disruption in the longer term (as in the latter study by Carolina Lombardi et al., also see12). Regardless of the cause of such risks, current evidence highlights the importance of early intervention in patients with OSA complicated by PLMS to reduce their risks of cardiovascular events and psychological disorders.
Inadequacy of current approaches to the management of OSA-PLMS patients
There has been a lack of research attention to the specific treatment of PLMS. On the one hand, the clinical symptoms of this group of patients are not obvious or bothersome to patients, due to the absence of strong discomfort as in RLS; on the other hand, the currently used treatments and medications lack robust research trials of effectiveness. Evidently, the underlying link between PLMS and a whole host of comorbidities warrant further investigation into this clinical disorder, despite its lack of frank clinical symptoms. In PLMS patients who are often treated by CPAP for their concomitant OSA, studies have shown that CPAP treatment has no clear impact on the severity of PLMS6,13. The current treatment approaches of PLMS mainly “borrow” from the pharmacological treatments of RLS, where the current guideline presents a “standard” level of recommendation for pramipexole and ropinirole and a “guideline” level of recommendation for levodopa with dopa decarboxylase inhibitor, opioids, gabapentin enacarbil in the treatment of RLS45. These drugs reduce PLMS but usually do not eliminate them, which may continue to be directly or indirectly a risk for cardiovascular diseases46.
From the OSA perspective, the mainstay of the current management approach is the use of Continuous Positive Airway Pressure (CPAP) therapy. However, the treatment efficacy of CPAP in the subgroup of combined OSA-PLM patients leaves much to be desired. A study has shown that patients with combined PLMS demonstrate poorer adherence to CPAP treatment14. Interestingly, A. Zinchuk et al. found a markedly poorer adherence to long-term CPAP therapy in the nonobese (BMI < 30) OSA patients with low ArTH when compared to patients with high ArTH47. In our study, we demonstrated a strong correlation between low arousal threshold and PLMS. This might suggest that these two subgroups of CPAP non-complying patients with low ArTH and PLMS are highly overlapping or even mechanistically linked by a common etiology. Given its accompanying cardiovascular risks in these patients, we call for more attention to this low ArTH – PLMS subgroup of OSA.
Pharmacological approaches that raise the arousal threshold may simultaneously improve PLMS, OSA, and CPAP adherence in this cohort. Indeed, one of the foci of research has been the drug therapy for OSA targeting low arousal thresholds. A pilot experiment shows that the application of 3 mg of eszopiclone improved AHI (25 times/h vs 14 times/h) and sleep quality in patients with low arousal thresholds, without worsening hypoxemia48. In our study, the OSA-PLMS group has a high proportion of low arousal thresholds, and it can be envisaged that the use of this class of drugs in the treatment of OSA may be effective in this population.
This retrospective study is purely observational, and the findings could only establish a correlation between PLMS and low arousal threshold, while further research is needed to establish the direction of causality. Admittedly, to enable the collection of a large dataset to make possible the analysis of such subtle clinical correlations, the gold standard epiglottic ArTH measurement would be extremely difficult, if not impossible. As such, the classification of low arousal threshold in this study was based on a validated clinical prediction tool, which in turn, brings the additional utility in terms of potential applications in community screening of OSA patients and their phenotypes. This also enables the validation of our findings in the widely analysed and validated MrOS cohort. It should also be noted that most patients had only one session of PSG, which could be susceptible to the influence of the “first night effect”.