Neuropeptides in Patients with Restless Legs Syndrome

By Daniel A. Barone, MD, FAASM, FANA

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: The diurnal onset of restless legs syndrome (RLS) has been replicated in a mouse model using central instillation of the main melanocortin agonist, α-MSH, which stimulates excessive locomotion and grooming in rodents as well as a state of hyperalgesia. The actions of β-endorphin (β-EDP) oppose those of α-MSH, since β-EDP promotes passivity and analgesia. In this study, these prohormones were measured in plasma and cerebrospinal fluid in patients with RLS and compared to controls. Patients with RLS had elevated levels of α-MSH and lower levels of β-EDP compared to the control group.

SOURCE: Koo BB, Abdelfattah A, Eysa A, Lu L. The melanocortin and endorphin neuropeptides in patients with restless legs syndrome. Ann Neurol 2024; Feb 3. doi: 10.1002/ana.26876. [Online ahead of print].

Restless legs syndrome (RLS) is a common disorder characterized by an unrelenting urge to move the legs (although there are cases of symptoms involving the hands and trunk), usually occurring at night, when patients are lying down to sleep. These urges prevent the onset of sleep vis-à-vis a need to move or walk during times of rest. RLS is the most common neurologically based sleep disorder, with a prevalence of 7.2% in North American and European populations. Despite this, treatment options for RLS are limited, and medications commonly used (i.e., dopamine agonists) actually may cause a paradoxical worsening of RLS over months to years through a phenomenon called augmentation.

The fact that there is a circadian aspect to RLS (urges to move and sensory discomfort usually arise at night) suggests that a biological substance with diurnal release may underlie the symptoms. Hormones of the melanocortin (MC) system are produced in the hypothalamic arcuate nucleus, are released diurnally, affect movement and hyperalgesia, and are, therefore, thought to have some involvement in RLS. The authors of this current publication aimed to assess plasma and cerebrospinal fluid (CSF) α-melanocyte-stimulating hormone (α-MSH) and β-endorphin levels in RLS patients and controls.

The study included 42 untreated moderate-to-severe RLS patients and 44 matched controls; RLS severity was assessed by the International RLS Study Group Severity Scale. All participants underwent venipuncture and lumbar puncture at various time points to analyze levels of proopiomelanocortin (POMC), adrenocorticotropin hormone (ACTH), α-MSH, β-MSH, and β-endorphin. RLS participants were 52.7 ± 12.0 years of age and 61.9% were women; controls were of similar age and sex. Plasma ACTH, α-MSH, and β-endorphin were similar between the two groups. Plasma POMC was significantly greater in RLS patients than in controls (P = 0.048). CSF ACTH was similar between the two groups. CSF α-MSH was significantly higher in painful than in nonpainful RLS or controls (P = 0.03). CSF α-MSH was higher in RLS than controls (P = 0.062). CSF β-endorphin was lowest in painful RLS, intermediate in nonpainful RLS, and highest in controls (P = 0.049).

The ratio of the sum of CSF α- and β-MSH to CSF β-endorphin was highest, intermediate, and lowest in painful RLS, nonpainful RLS, and controls, respectively (P = 0.007). In summary, CSF β-MSH increased and CSF β-endorphin decreased in RLS patients with painful symptoms.

COMMENTARY

This well-done study is extremely important to the fields of general neurology, movement disorders, and sleep medicine. It represents the first time a potential explanation has been proposed regarding the underlying cause of the sensorimotor disturbances in patients with RLS. As the authors pointed out, much remains to be discovered, but this is a significant step forward. Future studies are needed with a focus on how the MC system interacts with iron and dopamine systems in RLS patients.

Despite the scientific rigor of this study, for which the authors should be commended, there are important limitations to note. Aside from what was mentioned by the authors (i.e., small sample size, high number of statistical comparisons potentially leading to type I error), there was a lack of formal sleep testing. It is quite possible that occult obstructive sleep apnea may have affected the results; moreover, many patients with RLS also will demonstrate periodic limb movements of sleep, which could, theoretically, affect the findings.

There is great complexity in the RLS phenotype, insofar as the expression of the disease is influenced by numerous genetic factors and different behavioral traits, such as anxiety, poor sleep, and impulsivity. This study by Koo et al opens the door to further research and provides both clinicians and patients with hope that this potentially life-altering condition will have more effective treatments and be “put to bed” one day.