Restless Legs Syndrome: New Evidence of Peripheral Mechanism

May 30, 2014

Further evidence that restless legs syndrome (RLS) could have a peripheral mechanistic component has come from a new Finnish study.

The study, published in the May 27 issue of Neurology, found a strong correlation between RLS symptoms and peripheral hypoxia. In addition, the hypoxia was reversed with the initiation of dopaminergic treatment, which also relieved symptoms.

The researchers, led by Aaro V. Salminen, MSc, Tampere University Hospital, Finland, conclude that these observations "increase the evidence for the involvement of peripheral factors in RLS pathophysiology," and "provide a new potential mechanism of action for dopaminergic therapy in suppressing RLS."

An accompanying editorial adds: "These findings support a strong association of peripheral tissue hypoxia with RLS/WED [Willis-Ekbom disease] symptoms and symptom severity, expanding our knowledge of potential peripheral leg vascular mechanisms operating during the active occurrence of RLS/WED symptoms."

Cause Unknown

In an interview with Medscape Medical News, Salminen explained that RLS was originally thought to be a peripheral disorder because the pain and restlessness occurred in the legs. But after the discovery that dopaminergic drugs relieved RLS symptoms, and dopaminergic drugs were thought to act centrally, the focus shifted to a central mechanism. More recently, new studies have revived beliefs that a peripheral mechanism may also be involved.

He noted: "Recent studies have suggested signs of hypoxia in peripheral tissues in patients with RLS, but we believe our study is the first one to have actually demonstrated peripheral hypoxia by measuring oxygen levels in the periphery."

"Our results are another step towards rejuvenating the peripheral hypothesis in RLS. This is a controversial area, but we are getting good feedback from the field," he added. "While most experts still believe a central mechanism is responsible for RLS, there is now a growing body of scientists who accept that peripheral effects could be a part of it."

Salminen said their results, if confirmed, could have major implications for the treatment of RLS. "If we can identify the site of action of the dopaminergic drugs, new medications could be developed that could treat the symptoms much more specifically."

The study involved 15 patients with RLS and 14 healthy controls. Participants were immobilized to provoke RLS symptoms, and then oxygen and carbon dioxide levels in the skin tissue of the chest and the legs were measured. Results showed that patients with RLS had lower partial pressure of oxygen in their legs but not on the chest.

Table. Partial Pressure of Oxygen (kPa) in Legs and Chest: Patients With RLS vs Controls

Measure Patients With RLS Controls P Value
Legs 5.54 7.19 .01
Chest 8.75 8.20 .35


More severe RLS correlated with high chest-to-foot oxygen gradient. Carbon dioxide levels did not differ between the groups.

Patients with RLS underwent the tests again after pramipexole therapy was started. Results showed that the drug relieved symptoms and corrected the peripheral hypoxia toward the levels observed in the controls (from 5.54 to 6.65 kPa).

Salminen commented: "Because we didn't see a difference in carbon dioxide levels, this suggests that the mechanism is not to do with peripheral blood flow. But there are probably other mechanisms at play — possibly iron-mediated oxygen transport."

While the study is exciting, he warned that it is very preliminary. "We believe that peripheral hypoxia is definitely involved in some way. But we haven't proven a causal effect in this study. We have just shown a correlation. And we only had small numbers — only 15 patients — so the results obviously need to be confirmed in further studies."

In their editorial, Erik K. St. Louis, MD, Mayo Clinic and Foundation, Rochester, Minnesota, and Jan Ulfberg, MD, Umeå University Hospital, Sweden, write: "Salminen et al have advanced our understanding of RLS/WED pathophysiology."

They add that future research will be necessary to distinguish whether peripheral leg tissue hypoxia is a primary mechanism or simply a downstream secondary alteration during RLS symptoms. In addition, more studies are necessary to determine whether relief of tissue hypoxia should become a main therapeutic focus in RLS and whether microvascular ischemia mediates chronic local or systemic tissue damage.

Neurology. 2014;82:1856-1861. Abstract Editorial


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