Restless Legs Syndrome


Research Into RLS

Investigators have made great strides in the understanding and treatment of RLS over the last two decades, to the relief of millions of victims. The fundamental etiology remains elusive, however, and a final common pathway has yet to be described. Sorting out the various secondary causes and effective treatments has proven to be a challenge. While investigators have begun looking more into secondary causes over the last few years, research continues to be directed mostly toward Primary RLS.

In 1982, Dr. S. Akpinar discovered that centrally acting dopamine stimulation could consistently relieve RLS symptoms. [19] Dopamine is a neurotransmitter responsible for transmitting signals between nerves in specific areas of the brain and spinal cord. Since then, dopamine dysfunction has been suspected to be the underlying cause of Primary RLS. According to Dr. Henning, “The implicit assumption of a causal relationship between RLS and possible dopamine pathology was quite appealing. Early research into the cause of RLS therefore focused on a possible dopaminergic abnormality.” [18] The concept that RLS involves defects in dopaminergic function is supported by the facts that:

  1. Most symptoms respond to treatment with dopaminergic agents and, conversely,
  2. Dopamine receptor antagonists that cross the blood-brain-barrier (BBB) exacerbate symptoms.

The fact that dopamine relieves RLS symptoms may in fact be sheer chance, and not because of linked biology. Extensive research has so far failed to unearth the cause of Primary RLS. Imaging studies have yielded conflicting results.” Some have detected a “modest reduction” in dopamine function. Other studies have failed to confirm these findings, showing equivocal or unclear evidence for the dopamine system.” [18] The strongest evidence for dopamine involvement in the pathophysiology of RLS remains pharmacological and not necessarily physiological. Dopamine research has recently shifted from evaluation of nigrostriatal pathways to diencephalospinal pathways. “Despite extensive research, scientific studies have not yet found convincing evidence to support a dopaminergic cause of Primary RLS.” [20]

Dr. Ekbom first noted that RLS is sometimes associated with iron deficiency in 1945. [2] It is postulated that iron deficiency or abnormal iron metabolism may decrease dopamine production, thus triggering RLS. [5] Investigations are now evaluating serum ferritin levels, focal iron distribution in the brain, and expression of iron-transporting proteins in the brain. Patients with low serum ferritin levels and RLS have been noted to have more severe symptoms and reduced sleep efficiency. Symptoms in these patients frequently improve with oral iron supplementation. Focal iron deficiency in the brainstem has been reported in RLS patients with normal serum iron levels. This deficiency is thought to be due to abnormal uptake and transport across the blood-brain barrier. [21]

Primary RLS is now believed by many investigators to be a sensorimotor disorder of the subcortical central nervous system involving dopamine function and iron metabolism. Research in these areas is ongoing. Investigators are currently utilizing techniques such as genetic and family studies, functional imaging studies (SPECT, PET, MRI, etc.), responses to medications, etc. [18] In his 2007 article, Dr R.P. Allen summarizes: “The only thing we know with reasonable certainty about RLS pathology is that iron deficiency is somehow involved in at least some cases of RLS. This iron deficiency appears to produce a dopamine dysfunction that may involve disruption of synaptic function, impairing circadian regulation of dopamine. This is reasonable given current data, but is based on limited studies and must be confirmed in future investigations. The putative dopamine dysfunction is presumably ameliorated by use of dopaminergic medications that often produce dramatic relief from symptoms of RLS…” [20]

Investigation into the identification and successful treatment of Secondary RLS is, unfortunately, in its infancy. We are continuing to delve into the relationship between RLS and venous disease. There is still a lot of work to do, but results thus far are encouraging.

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