Restless Legs Syndrome (RLS) in Patients (pts) with Polycythemia Vera (PV): Is Iron Deficiency (ID) the Only Culprit?

Background: RLS is a sensorimotor disorder that causes discomfort in the legs and the urge to move them. In its etiology, there are many conditions including ID. PV is a myeloproliferative neoplasia (MPN), and in pts with PV, ID may develop during the course of the disease. In one study, 29.6% of PV pts had RLS, which was thought to be associated with phlebotomy and ID (Med Oncol. 2010;27(1):105-7). Essential thrombocythemia (ET) is another MPN, in which ID is not typically observed. In our study, we sought to evaluate the frequency of RLS in PV and to search for possible factors other than ID that might have a role in the etiology of RLS among MPN pts.

Methods: Previously diagnosed pts with PV and ET, who admitted to our clinic between August and December 2021 were included. All PV pts were evaluated for the study regardless of their iron status. ET pts with ID were not included, since ET cases formed the non-ID MPN control group. Pts with a transferrin saturation below 20% and ferritin level below 20 µg/L were considered as cases with ID. Pts with comorbidities that may lead to RLS generation were excluded. Fasting plasma glucose, HbA1c values, urea, creatinine, thyroid function tests, vitamin B12, and magnesium values were measured. According to these parameters, pts with biochemical disorders that may affect the development of RLS were also excluded (Figure 1). In accordance with the PV and ET groups, pts with ID and healthy subjects (HS) were included as the positive and negative controls, respectively. Demographic characteristics, treatments, complete blood count (CBC) parameters, iron studies, and biochemical tests of the subjects were recorded. Neurological examination was performed in all cases, electromyography (EMG) was taken and evaluated for polyneuropathy. All subjects were questioned according to the RLS diagnostic criteria, and all subjects underwent Pittsburgh Sleep Quality Index (PSQI) tests.

Results: In the final analysis, 27 PV, 23 ET, and 22 ID pts and 23 HS were included (Figure 1). Pts in the ID group were significantly younger than other groups (p=0.025) (Table 1). The median follow-up duration of the ET pts was significantly higher than those of others (p=0.011). Other demographic features were comparable between groups (Table 1). No significant pathology was detected in the neurological examination in all subjects. RLS was detected in 25.9%, 34.8%, and 45.5% of PV, ET, and ID pts, respectively. While there was no difference between these groups in terms of the presence of RLS, RLS was not detected in HS. In pts with PV 66% had ID, and there were no significant differences in terms of CBC parameters, iron studies, biochemical parameters, and the JAK2V617F mutational status in PV and ET pts with and without RLS. In addition, polyneuropathy was detected in one ET patient by EMG and RLS was not detected in this patient. There was no significant difference between these groups regarding median PSQI scores, but the median PSQI score was found to be significantly higher in pts with RLS (p=0.001) (Table 1). When we investigated the relationship between cytoreductive treatments and RLS in PV and ET pts, we found that the frequency of RLS was higher in pts receiving interferon-alfa (IFN-a) and anagrelide (Table 2). In pts with PV and ET, IFN-a and anagrelide usage, and magnesium (Mg) levels were found to have an impact on RLS in univariate analysis, but only Mg levels was associated with RLS in multivariate analysis (Table 3).

Conclusion: In our study, the high prevalence of RLS in pts with ID and the absence of RLS among HS both indicate that our RLS questionnaire results are reliable. Although not all PV pts had ID, the prevalence of RLS was higher when compared to HS as was described previously (Med Oncol. 2010;27(1):105-7). In addition, although not significantly different, the frequency of RLS was higher in ET pts than that observed in PV cases. These results suggest that, RLS may occur during the course of the disease in MPN pts, due to factors independent of ID and other known RLS triggering conditions. In light of all these, further studies are needed to elucidate the etiology of RLS developing in pts with PV and ET.

No relevant conflicts of interest to declare.