ARTICLE IN BRIEF
Investigators reported that the severity of restless legs syndrome (RLS) symptoms is associated in a dose-dependent manner with peripheral hypoxia, suggesting that impaired delivery of oxygen to the periphery may play a role in the pathogenesis of RLS.
A team of Finnish researchers has found that peripheral hypoxia is associated with symptoms of restless legs syndrome (RLS) in a dose-dependent manner: the lower the oxygen partial pressure detected transcutaneously on the legs compared to that of the chest, the worse the RLS symptoms.
The results suggest that impaired delivery of oxygen to the periphery may play a role in the pathogenesis of RLS, a hypothesis strengthened by the team's observation that a standard dose of the dopamine agonist pramipexole simultaneously reversed the hypoxia while relieving RLS discomfort.
But while praising the study and its methods, a leading RLS researcher cautioned against jumping to the conclusion that the relationship between lowered oxygen levels in the legs and RLS symptoms is a causal one.
“It's a very good paper, carefully done,” said Richard Allen, PhD, associate professor of neurology and co-director of the Johns Hopkins Center for RLS. “But the conclusions overreach a bit. We've known for a while that there's something going on with hypoxic pathway activation. That is hardly surprising, because iron deficiency and hypoxia are closely related, and we already know there's an iron activation problem in RLS. So that doesn't mean that peripheral hypoxia is causing the leg movement.”
Aaro Salminen, a PhD student at the University of Tampere School of Medicine in Finland and first author of the study, said he agrees with Dr. Allen that a direct, causal relationship between RLS and peripheral hypoxia is only one possible explanation for the findings — but a reasonable explanation.
“Our results don't give any data on the direction of this connection,” Salminen said. But, he added, “Historically, research on RLS first focused on the periphery. Karl-Axel Ekbom, in Sweden, proposed a microvascular mechanism. But once it was discovered that dopaminergic drugs helped, the research shifted to the central nervous system. If it's shown that dopaminergic medications act in the periphery in RLS and not only in the CNS, we could develop new kinds of medications that could perhaps have smaller side effects than those currently available. Right now we don't really know the site of action of the dopaminergic drugs on RLS.”
STUDY METHODOLOGY, RESULTS
The case-control study, published electronically on April 30 in the journal Neurology, involved 15 RLS patients and 14 healthy controls. After two weeks off pramipexole therapy, RLS symptom severity was evaluated with the International Restless Legs Syndrome Study Group scale. Two sessions of the suggested immobilization test — a standard, objective measure in which patients are asked to keep their legs motionless for an hour — were performed while arterial oxyhemoglobin saturation was measured from the second toe of the foot. Transcutaneous carbon dioxide and oxygen signals were simultaneously recorded from both the chest and the sole of the foot.
During immobilization, the study found, RLS patients had lower partial pressure of oxygen in their legs (5.54kPa vs. 7.19kPa, p<0.01) but not on the chest (8.75kPa vs. 8.20kPa, p=0.355). Although carbon dioxide levels did not differ between the groups, more severe RLS symptoms correlated with a higher chest-to-foot oxygen gradient (p=0.692, p<0.01).
Two days after the first measurements were taken, pramipexole was re-continued at the RLS patients' previous dose, after which a second set of measurements were taken following the hour-long suggested immobilization test. By that time, the peripheral hypoxia had vanished in the RLS patients, along with their symptoms.
James R. Connor, PhD, vice-chair for neurosurgery research and director of the Center for Aging and Neurodegenerative Diseases at Penn State College of Medicine, has published a pair of studies, in 2011 and 2013, suggesting that the hypoxia-inducible factor pathway, which responds to decreases in oxygen, is active in the brains of people with RLS.
“Our original interest had been in iron deficiency,” Dr. Connor told Neurology Today. “We kind of backed into the hypoxia story. The data matched very nicely with an iron deficiency story. But looking at the data in a different way, we realized that it made a lot more sense from a hypoxia point of view. This new observation, that pramipexole corrected the hypoxia in the legs, is novel and interesting. It opens up potential new treatment targets.”
Still puzzling, however, is why Dr. Connor's studies have seen evidence of hypoxia-inducible factor pathway in the CNS, while the Finnish team's paper finds the hypoxia specifically in the legs.
“Why the limbs and not the chest area?” Dr. Connor mused. “I wouldn't have an explanation for that. We already knew there's something going on with the hypoxia pathway in the brain, but now it looks like it's also in the legs.”
Future studies should seek to determine whether experimentally increasing hypoxia in the legs will increase RLS symptoms, and whether the hypoxia is causally related to the increased risk of cardiovascular disease in RLS patients, according to Dr. Allen.
“It could be that the hypoxia is causing vascular compromise,” Dr. Allen said. “That may indicate where we should focus treatment.”
EXPERTS: ON THE ROLE OF PERIPHERAL HYPOXIA IN RESTLESS LEGS SYNDROME
•. Salminen AV, Rimpilä V, Polo O. Peripheral hypoxia in restless legs syndrome (Willis-Ekbom disease). Neurology. 2014; E-pub 2014 Apr 30.
•. Patton SM, Ponnuru P, Snyder AM, et al. Hypoxia-inducible factor pathway activation in restless legs syndrome patients. Eur J Neurol. 2011; 18:(11): 1329–35.
•. Patton SM, Cho YW, Chardy TW. Proteomic analysis of the cerebrospinal fluid of patients with restless legs syndrome/Willis-Ekbom disease. Fluids Barriers CNS. 2013; 10:(1): 20.
•. Allen RP, Barker PB, Horska A, et al. Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep. Neurology. 2013; 80:( 22): 2028–34.