Restless legs syndrome (RLS, or Wittmaack-Ekbom's syndrome, which is not to be confused with Ekbom's syndrome) is a poorly understood and often misdiagnosed neurological disorder characterized by unpleasant or painful sensations in the body's extremities and an overwhelming urge to move them. Moving the limbs provides temporary relief for this chronic condition. Symptoms are often discernable in early childhood, and may become disabling in later life, particularly due to sleep deprivation.

Symptoms

The key symptoms of RLS are:

an urge to move the legs and sometimes arms, which can be irresistible when severe; this is usually associated with an abnormal sensation such as a "creepy" or "crawly" feeling, a tickle, an ache, or a discomfort that may be very difficult to put into words. These sensations generally occur inside the legs or arms (along the axis) in the calf or forearm area.
involuntary muscle movements (spasms or 'twitching')
excessive movement of the legs or arms when at rest,
aggravation of the discomfort during rest and at least temporary relief by movement,
a circadian rhythm of severity with symptoms being worse at the patient's usual bedtime.

Prevalence

Most sufferers think they are the only ones to be afflicted by this peculiar condition. Many people only have this problem when they try to sleep, but some people show symptoms during the day and pace or 'bounce' their legs. Some people get the symptoms on long car rides or during any long period of inactivity (like watching movies, attending dinners, etc.) The limbs may also start to twitch involuntarily, sometimes causing large limb excursions (flailing) especially during sleep. This is sometimes defined as a related syndrome, called Periodic limb movement disorder. It is not unknown for some people to be thrown out of bed by violent leg movements.

About 10 percent of adults in North America and Europe may experience RLS symptoms, according to the National Sleep Foundation, which reports that "lower prevalence has been found in India, Japan and Singapore," indicating that ethnic factors, including diet, may play a role in the prevalence of this syndrome.

Causes

There is a high incidence of familial cases, suggesting a genetic tendency. Secondary causes of RLS include antipsychotics, antidepressants, antihistamines (particularly those that cause drowsiness), serotonin reuptake inhibitors, and antinausea agents. As there seems to be a link between dopamine and RLS, drugs that interact with dopamine may also cause secondary RLS.

Treatment

Common medications include dopamine agonists (dopaminergic agents) such as levodopa, ropinirole, sinemet or pergolide, opioids such as propoxyphene or oxycodone, benzodiazepines (which improve quality of sleep), or anticonvulsants (patients who report pain may benefit most) such as gabapentin. In 2005, The Food and Drug Administration approved Requip (ropinirole) to treat moderate to severe Restless Legs Syndrome (RLS). The drug was first approved for Parkinson’s disease in 1997.

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Iron-deficient cells can cause restless legs syndrome
From Nutrition Health Review, 6/22/04

Iron-deficient cells in the brain are mixing up central nervous system signals to the legs and arms, causing the irresistible urge to move the arms and legs and "creepy-crawly" sensations that characterize restless legs (limbs) syndrome (RLS), a Penn State College of Medicine study reports.

"Our previous studies established a physical cause for RLS showing certain cells in the brain were iron-deficient," said James R. Connor, Ph.D., professor and vice chair for neurosurgery, at Penn State's Milton S. Hershey Medical Center. "We have now found a sequence of events that may connect that cellular iron deficiency to the uncontrollable movements of the disorder."

Xinsheng Wang, M.D., Ph.D., postdoctoral fellow in Dr. Connor's laboratory, presented the study at the Society for Neuroscience scientific meeting, held in San Diego in October 2004. RLS affects 5 to 10 percent of the U.S. population. The sensations are relieved only by movement, and they become worse as the sun goes down, causing many nights of sleeplessness for those with RLS and their partners.

In normal individuals, cells in a portion of the middle brain, called the substantia nigra, control the production of tyrosine hydroxylase (TH), an enzyme. The cells also determine how much TH is phosphorylated, or activated. The active enzyme regulates the production of dopamine, a substance in the brain that transmits messages from the brain and central nervous system to the body, giving it instructions for normal functioning.

Dr. Connor's team found that people with RLS had high levels of active TH. Although this should result in more dopamine being made, in fact, the proper regulation of dopamine production is possible only with both active TH and adequate levels of iron.

"We think the 'active form' has lost its feedback mechanism," Dr. Connor says. "The cell is getting a signal that more dopamine is needed so TH is made and shifted to the active form, but the activity is compromised because less iron is available. If the iron was present in sufficient amounts, the feedback process would signal the cells to stop or slow TH production."

"This shows us that developmental iron deficiency can be reversed, but that extended iron deficiency cannot be," Dr. Connor said.

In a second study using a human cell culture model, his team exposed PC12 cells, which create dopamine, to a substance that removes iron from cells. As more of the substance was added to the cells and, consequently more iron was removed, the expression of TH grew, connecting the cellular iron deficiency to elevated TH in human cells.

In a third study, brain tissues from eight individuals with RLS were compared with tissues from the brains of five healthy individuals. The brain tissue was acquired through the Restless Legs Syndrome Foundation's brain collection at the Harvard Brain Bank. The autopsy analysis of the brains of those with RLS showed that iron-deficient cells from the middle brain expressed high levels of TH compared with the non-RLS group.

"These results continue to support the idea that the brain dopaminergic system is altered in RLS and that the differences in the dopaminergic system are consistent with insufficient iron," Dr. Connor explained.

These findings explain why some patients with RLS find relief from taking dopaminergic drugs. Although these drugs have not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of RLS, they are used to calm tremors in those with Parkinson's disease. The dopaminergic agents replace dopamine in the brain and temporarily improve the nerve signal transmission to the body.

"Our next steps are to continue investigations of treatment strategies for RLS involving iron supplementation and dopamine agents to attempt to reach the normal balance between iron and dopamine in the brain," Dr. Connor stated.

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