After a night of socializing with friends when he was in his late teens, Gene Stalnecker remembers experiencing a bizarre sensation in his legs. "I had no clue what was wrong, but I couldn't relax my legs, especially my calves," he says. The sensation became more and more persistent at night, and by the time he reached his mid-20s he could barely calm his calves—and he dreaded bedtime.

After years of being misdiagnosed—with leg cramps, periodic limb movements, and even multiple sclerosis—Stalnecker finally got an answer from his primary care physician: He had restless legs syndrome, or Willis-Ekbom disease (RLS/WED), a disorder that affects one in 10 Americans, according to the National Sleep Foundation. This sleep-related movement disorder causes an overwhelming and unpleasant urge to move the legs when they are at rest. Once patients move their legs, the urge often diminishes. First identified in the late 1600s, RLS/WED continues to baffle researchers.

The root of the disorder is discomfort—a discomfort so intense, you have to move to get relief. The urge is so strong, in fact, that about one-third of those affected seek medical attention. "When you have RLS, it's like your legs are disconnected from you and constantly yelling, 'Hey! We're here! Make us move!'" says Stalnecker. (See "How RLS/WED is Diagnosed" below for specific diagnostic criteria).

Clues to a Cause

For the past 20 years, researchers have been teasing out the many facets of RLS/WED. While they still haven't pinpointed the exact cause, they have uncovered several clues.

For starters, the condition takes two forms: Primary RLS/WED may have a genetic link and has no identifiable cause, while secondary RLS/WED stems from an underlying medical condition such as varicose veins, chronic kidney failure, or peripheral neuropathy (damage to the peripheral nerves, which causes numbness and pain in the hands and feet).

Secondly, both dopamine, a neurotransmitter that affects both the reward centers in the brain and motor control, and iron levels are involved, although it's unclear how the two are related, says Michael H. Silber, MD, a professor of neurology at the Mayo Clinic College of Medicine in Rochester, MN, and a Fellow of the American Academy of Neurology (FAAN). "The most accepted hypothesis is that severely affected patients have fewer dopamine receptors, which may be caused by reduced iron. And some evidence indicates that fewer receptors may reflect a problem with iron absorption across the blood-brain barrier."

Additionally, the release of dopamine follows a daily internal clock, or circadian rhythm, with a low point late in the day and a relatively high point in the morning. In people with RLS/WED, this rhythm may be dysfunctional, and the lower-than-normal signal in the evening may be what intensifies the urge to move the legs, says Arthur S. Walters, MD, FAAN, a professor of neurology and associate director of sleep medicine at Vanderbilt University School of Medicine in Nashville, TN.

Long-Term Consequences

The unpleasant sensations caused by RLS/WED keep many people from falling asleep or wake them up throughout the night, which can trigger a cascade of other problems. Insufficient sleep suppresses activity in the brain's frontal lobes, areas that govern decision making and impulse control, according to the National Institutes of Health. As a result, sleep-deprived people don't have the mental clarity to make good decisions.

Plus, there's robust evidence that sleep deprivation over time can affect overall health and longevity. In fact, in a study of nearly 20,000 men published online in the journal Neurology in 2013, Harvard researchers found that those with the syndrome had a 30 percent higher risk of early death than those without it. The more frequent the symptoms, the greater the risk of premature death. While this type of observational study does not prove cause and effect, it does uncover a potential link between RLS/WED and mortality. That makes sense, says Dr. Walters, since studies link RLS/WED with many other conditions, including depression, high blood pressure, and heart disease.

"We don't know if RLS is a marker for heart disease or a cause. We're worried it's a cause because the periodic limb movements in sleep that often occur with restless legs can affect blood pressure," says Richard P. Allen, PhD, an associate professor of neurology at Johns Hopkins University School of Medicine in Baltimore, MD, and a member of the AAN. "Every time you have a movement, you're getting a fairly significant increase in blood pressure—and you're doing that up to 1,000 times a night."

For Stalnecker, there were other consequences as well. For example, he found that eating sugar offered some relief, so he began to scarf down two donuts each day during his morning commute, which ultimately led to weight gain and diabetes. "When I went to my general practitioner, she tried to address my diabetes and heart problems. But I told her, 'We can't get anywhere until the RLS is under control.'"

Pumping Iron

Treating RLS/WED isn't an exact science, but experts agree that a critical part of the protocol is to boost iron stores, either through iron supplements or intravenously.

In fact, a study published in the journal Sleep Medicine in 2011 found that giving 1,000 mg of intravenous iron to RLS/WED patients with "normal" iron stores improved symptoms for nearly 50 percent of them. For 20 percent of patients, intravenous iron almost completely resolved their symptoms.

Physicians aim for a ferritin level of anywhere from 50 to 150 micrograms (mcg) per liter or higher in their patients, depending on a variety of factors; the normal level is 18 to 20 mcg per liter. Ferritin is a protein that stores and transports iron; low serum levels of ferritin are the most sensitive measure of iron deficiency. "Even if there's enough iron in the blood, it has to transfer to the brain to correct any deficits," explains Dr. Walters. "Unfortunately, oral iron doesn't cross the blood-brain barrier very well, so even if we start a patient on iron therapy, we usually prescribe medication simultaneously. In severe cases, and after no response to other medications, we may even start the patient on intravenous iron."

What Dopamine Does

In addition to iron, physicians often prescribe a dopamine agonist such as levo-dopa, pramipexole (Mirapex), ropinirole (Requip), and the long-acting dopamine patch rotigotine (Neupro). Scientists do not fully understand why medications that increase the amount of dopamine in the brain can calm restless legs, says Dr. Allen, but dopamine-boosting drugs can effectively reduce symptoms in up to 90 percent of RLS/WED patients.

However, the drawbacks may be significant. Since these drugs flood the brain's pleasure centers with dopamine, patients may struggle with compulsive behaviors such as obsessive shopping, eating, gambling, and sex addiction; a 2010 Journal of Neurological Sciences study of 94 patients with RLS/WED who were treated with standard-dose dopamine agonists found that 12.4 percent developed compulsive behavior.

When Stalnecker took dopamine agonists, he didn't develop compulsive behavior, but he didn't feel like himself, either. "I was obsessed with anything that captured my interest, my brain was racing all the time, and I could not tolerate being still," he says.

Over time, the majority of patients on dopamine agonists also begin to experience RLS/WED symptoms earlier in the day and in different parts of the body—a phenomenon called augmentation, which affects as many as 80 to 90 percent of patients, says Dr. Allen. At that point, he says, many doctors will increase the dose or add another dopamine medication, and that inadvertently exacerbates the disease. And when patients try to go off the meds too quickly, they can experience serious withdrawal symptoms.

When Drug Choices Narrow

Once symptoms start appearing earlier in the day, options for effective drugs become more limited, says Dr. Silber. Doctors may try to split or increase the dose (while staying within the maximum recommended amounts), switch from an oral dopamine agonist to a long-acting dopamine patch, or eliminate dopamine agonists altogether and start a new class of medications. In fact, recent research has some physicians questioning whether other drugs should be considered as a first line of defense in the treatment of RLS/WED.

In a 2014 study published in the New England Journal of Medicine, for instance, Dr. Allen and colleagues compared the neuropathy and anti-seizure drug pregabalin (Lyrica) to the dopamine agonist pramipexole and found that Lyrica was as effective, if not more effective, at reducing the severity of RLS/WED symptoms over a one-year-period, without the risk of augmentation.

Scientists know that pregabalin and other drugs in the same class—referred to as alpha-2-delta drugs—affect the pain centers of the brain and help stabilize the electrical activity of nerve cells. Of course, like any medication, these drugs can also have side effects, which include dizziness, depression, and weight gain.

The Opioid Option

"For patients with severe RLS that doesn't respond to other medications, opiates are very effective," says Dr. Walters. "And we can sometimes use a much lower dose than what we use to treat pain."

Although these medications—which include methadone, morphine, and oxycodone—can be highly addictive, a 2011 analysis published in Sleep Medicine showed that 85 percent of RLS/WED patients who started on methadone were still taking it two to 10 years later, compared to fewer than 20 percent of those who started on a dopamine drug. Turns out, the opioid medications were more effective than dopamine agonists for long-term use, particularly since they carry no risk of augmentation. What's more, research shows that for most RLS/WED patients, addiction and tolerance are not a significant problem, even among those who are on long-term opioid therapy—provided they do not have a prior history of drug or alcohol abuse, according to Dr. Walters.

Drug-Free Strategies

But drugs aren't the only way to calm jittery legs. In fact, the vast majority of patients also experiment with non-drug treatments to manage the condition.

Anything that produces stimulus may reduce the patient's focus on their symptoms, says Dr. Allen. In fact, something as simple as doing a crossword puzzle may be enough of a distraction. Moderate exercise can also improve symptoms, but heavy exercise late in the day tends to make things worse, he says.

Other tips for managing RLS/WED include avoiding coffee and alcohol, which can exacerbate symptoms, and taking a thorough inventory of all medications, since drugs like antidepressants and antihistamines may worsen RLS symptoms.

Relief at Last

Researchers are still decades away from understanding the complexities of RLS/WED—why, for instance, it comes on like gangbusters for some and then temporarily disappears for weeks or months, while others deal with it for decades at a seemingly constant rate. They also do not understand why people who develop RLS/WED earlier in life are more likely to have long-lasting symptoms, nor why dopamine agonists ultimately lead to augmentation.

"RLS is a deep, agonizing sensation that can drive you crazy every night of your life," says Stalnecker, who created a support group on Facebook to help patients understand dopamine agonists and manage augmentation. "When you're on these drugs for a long period of time, your brain is never the same. That's something even the best doctors don't understand," he says.

In December 2013, Stalnecker skipped his nightly dose of Mirapex, knowing he would go through withdrawal, then made an appointment at Johns Hopkins University to see a physician skilled in treating augmentation. Within a month—and after starting a very low dose of physician-prescribed methadone—his symptoms stopped.

"Now, a year and a half later, I'm nearly free of RLS," he says. "I still have lingering problems from the dopamine agonists, including fatigue and depression, but to be free of those invisible chains is something that you need to experience to appreciate."

For More Information

• Restless Legs Syndrome Foundation
• Restless legs syndrome fact sheet at National Institute of Neurological Disorders and Stroke
• Restless legs syndrome at National Sleep Foundation

4 Risk Factors

Researchers don't understand what causes restless legs syndrome/Willis-Ekbom disease, but they have identified four factors that seem to increase the risk.

1. AGE. The syndrome affects 10 percent of people 65 and older, compared with only 5 percent of the general population.
2. SEX. Women are more likely to experience the condition than men, but the sex connection seems to be tied to pregnancy. If a woman has never been pregnant, her risk is the same as a man's.
3. LOW IRON. Diminished iron in the brain is implicated in the syndrome.
4. FAMILY HISTORY. People with a family history of the disease are at greater risk.

How RLS/WED is Diagnosed

Doctors look for these five diagnostic criteria, according to the International Restless Legs Syndrome Study Group.

1. An urge to move the legs, which is usually, but not always, accompanied by uncomfortable and unpleasant sensations.
2. The urge to move the legs and the accompanying sensations start or worsen during rest or inactivity.
3. The urge and sensations are partially or totally relieved by movement such as walking or stretching.
4. The urge and sensations only occur or are worse in the evening or at night.
5. The first four symptoms cannot be attributed to another medical condition such as leg cramps, positional discomfort, muscle pain, swelling of the legs (edema), blood pooling in the leg veins, or habitual foot tapping.