Neurology. 2004;62(9):1563-7. and Sleep Medicine. 2004;5(3):231-5.
Imagine that you're lying in bed, exhausted, but overwhelmed by an uncomfortable crawling sensation in your legs that is only relieved when you move them. Rather then getting the sleep you need, you spend the wee hours rubbing your legs or pacing the floor. For between 5 and 10 percent of Americans, this unwelcome scenario plays out nightly because they suffer from a sleep-related neurological disorder called restless leg syndrome (RLS).
People describe the strange sensations, which tend to worsen with age, as feeling as if they have ants or cola in their veins. With more severe disease, the feeling can occur not just at night but anytime someone is at rest, leading to interrupted movies and business meetings and miserable plane trips, as well as insomnia.
Fifteen years ago, people with RLS were never diagnosed, and even today it's estimated that 75 percent of people with RLS go undiagnosed. For those who are lucky enough to put a name to their symptoms, therapies are available. But an improved understanding of the causes of RLS may lead to better therapies.
More and more research suggests that a lack of iron—a mineral that helps courier oxygen to the cells so they can function—plays a role in the development of RLS. While iron supplements are already used to treat certain RLS patients, uncovering iron's exact role may provide new treatment options for a broader group.
Why Iron? "We know that iron deficiency is involved because every condition that produces iron deficiency, such as anemia or pregnancy, increases the risk of RLS dramatically," says Richard Allen, PhD, a diplomat on the American Board of Sleep Medicine and a founder of the Johns Hopkins Sleep Disorders Center. In fact, based on studies of hospital patients, about 40 percent of people with anemia had RLS and about 20 percent to 40 percent of pregnant women have RLS.
Another way researchers know that iron plays a role is iron-deficient patients' response to iron supplementation. "Then when the iron deficiency is corrected, the RLS often remits," Dr. Allen says.
For Some, It's a No-Brainer Some people with RLS, however, have normal iron levels. Researchers say that's not a reason to discount iron as an underlying cause of their RLS. Studies indicate that the problem is that the brains of RLS patients may not absorb iron normally.
In a post-mortem study of people with RLS published last summer in Neurology, James Connor, PhD, a professor and vice chair of neurosurgery at Penn State University in Hershey, Pennsylvania, and colleagues used magnetic resonance imaging (MRI) and analyzed brain tissue. They found that iron levels were low in brain cells in a particular area of the brain called the substantia nigra, and that there were not enough receptors to bind to a protein called transferrin that brings iron to and from the cells. Thus, RLS seems to result from a decreased ability of brain cells to acquire iron. This abnormality could be a genetic defect, Dr. Connor says.
"There are no consistent pathological changes in the RLS brain such as the plaques in Alzheimer's brains, so the RLS brain looks like a normal brain," Dr. Connor says. "But we've found a profile of iron deficiency in the brain."
Pump Up the Iron For now, doctors should test blood iron levels in their RLS patients. Although there are other ways to determine iron status, doctors usually measure blood levels of ferritin, a protein used to store iron, because ferritin levels best correlate with the symptoms of RLS. People with low ferritin levels may benefit from a 325 mg daily dose of a ferrous sulfate iron supplement, or other supplement that contains an equivalent amount of elemental iron. This should be taken along with vitamin C to improve absorption.
People may also benefit from eating iron-rich foods such as red meat and green leafy vegetables, though one also has to consider other health issues, such as heart disease, when eating red meat.
Dr. Allen says that people with RLS shouldn't take iron supplements without consulting a doctor because they may have hemochromatosis, a genetic condition that cause people to absorb too much iron. Iron supplements can also cause gastrointestinal upset, constipation and headaches.
In the future, iron supplementation may be a treatment option for more patients. In a study published in Sleep Medicine in May, Christopher Earley, MD, and colleagues at the Johns Hopkins Center for Restless Leg Syndrome reported treating people with RLS and normal iron levels—who presumably still have an iron deficit in the brain—with 1,000 mg of iron delivered via an IV. Because the IV infusion bypasses the gut, unlike oral iron, iron absorption is minimized and more iron is available to get into the brain.
The researchers found that the IV iron led to a complete remission of all RLS symptoms for between a few weeks and several months in 60 percent of the patients who were treated. "Even people with normal iron levels in the blood, if you give them IV iron, will show a reduction in RLS symptoms and even long-term relief," says Dr. Allen, who cautions that this treatment, and its side effects, need to be tested against a placebo before it can be accepted as valid.
Other Treatments While this IV iron treatment still needs further study, other treatments are being used widely. A class of drugs known as dopamine agonists, which is largely used for Parkinson's disease, appears to be very effective for RLS at low doses. According to Dr. Connor, an enzyme that makes the brain chemical dopamine is an iron-requiring enzyme, so iron deficiency changes the balance in the dopamine system. Dopamine agonists reduce symptoms by replacing the insufficient amounts of dopamine that are thought to induce RLS.
People with more severe symptoms may need other medications as well, such as a type of anticonvulsant that relieves neuropathic pain and pain relievers called opioids. Non-prescription therapies include exercising and limiting intake of caffeine, alcohol and tobacco. People also report that engaging in pre-bedtime activities that involve intense concentration, such as knitting or computer games or painting, or just taking a warm bath, can help.
These treatments don't work for everyone with RLS, however. According to Dr. Allen, about 10 to 15 percent of patients do not have relief with current treatment options.
Still, this is a promising time for RLS doctors, researchers and patients. For starters, studies have confirmed that patients have a genuine biological disorder. "It's helping patients know that there really is an underlying biological cause of RLS," Dr. Connor says. "Patients are armed with information and can go to their physician and say 'I want a serum ferritin check,' rather than leave the physicians office thinking that their RLS is all in their head."
Sources: Connor JR, Wang XS, Patton SM, Menzies SL, Troncoso JC, Earley CJ, Allen RP. Decreased transferrin receptor expression by neuromelanin cells in restless leg syndrome. Neurology. 2004;62(9):1563-7.
Earley CJ Heckler D, Allen RP. The treatment of restless leg syndrome with intravenous iron dextran. Sleep Medicine. 2004;5(3):231-5.
