RLS occurs in about 7 to 11 percent of individuals, and is two times more common in women than in men. For many people with the disorder, the symptoms are relatively mild, but for individuals with moderate to severe symptoms, it can be quite debilitating, mostly because of the sleep disturbance caused by the symptoms. About 3 percent of the population has RLS with symptoms significant enough to require medical management. RLS is a lifelong disorder and while symptoms may wax and wane over time, they rarely go away completely. Overall, the symptoms tend to worsen with age.
Restless legs syndrome can be primary, meaning that it is not associated with any other conditions, or it can be secondary to other conditions such as iron deficiency and end-stage renal disease. Secondary RLS can also occur in the third trimester of pregnancy. Primary RLS is associated with an earlier age of onset, and often with a positive family history of other family members having RLS. Although all of the mechanisms behind the development of RLS are not fully understood, both iron deficiency and abnormalities in the dopamine neurotransmitter system are involved.
Iron Abnormalities in Restless Legs Syndrome
The link between iron status and restless legs syndrome has been known for over 50 years, ever since the disorder was first described. The lower a person’s iron levels are, the more severe the symptoms of RLS. In order to understand how various blood tests measure and define different types of low iron levels/iron deficiency, some understanding of how the body stores and uses iron is required. Iron is stored in the liver as ferritin, and is released to make hemoglobin in new red blood cells, as required. Hemoglobin is a major component of red blood cells, and is required to carry oxygen in the blood. When the hemoglobin is low (measured by a blood test for hemoglobin or hematocrit), iron deficiency anemia occurs, with symptoms of fatigue, weakness, shortness of breath, headaches, and more. However, even when the hemoglobin is normal, iron deficiency can be present in the form of low ferritin, and this can lead to fatigue and other anemia-like symptoms. One limitation of ferritin as a measure of iron deficiency is that it can be elevated despite low iron stores, in the presence of inflammation.
Several studies have shown that giving iron supplementation can improve the symptoms of restless legs syndrome, and in fact, can do so even when individuals have normal hemoglobin and ferritin levels. This is thought to be because RLS is associated with low iron in the central nervous system, rather than low iron in the blood circulation. Although low iron in the blood will result in low iron in the central nervous system, with normal iron levels in the blood (normal ferritin and hemoglobin levels), there can still be low iron in the cerebrospinal fluid, which is a fluid found in the spine and brain. Furthermore, using MRI images, certain areas of the brain have been shown to have low iron in individuals with RLS. Faulty transport of iron across the blood brain barrier has been demonstrated in individuals with RLS, explaining why iron may be normal in the circulating blood, but low in the brain. How this low iron in the brain leads to RLS is not entirely understood, but there is some evidence linking it to the dopamine abnormalities in RLS, which are discussed in more detail below.
Studies of iron therapy for RLS have shown that oral iron therapy can improve symptoms in individuals with low ferritin. However, when ferritin is normal, intravenous iron treatment is required, probably because oral iron is very poorly absorbed. Studies of intravenous iron therapy for RLS (here, here and here) have shown that this treatment is safe and effective, and lasts at least 24 weeks, depending on the type of iron given and the dose.
Dopamine Abnormalities in Restless Legs Syndrome
Levodopa, a drug used to treat Parkinson’s disease, was found to treat symptoms of RLS, at least upon initial use of the drug. Levodopa is converted into dopamine in the body, and therefore it was thought that RLS resulted from a deficiency of dopamine, and thus was treatable with a medication that converts to dopamine. However, brain imaging studies have shown that dopamine is in fact increased in the brains of individuals with RLS. This increase causes the number of receptors for dopamine on neurons in the brain to decrease, something that is predicted given the way neurotransmitters act in the brain, and has been borne out with studies showing fewer dopamine receptors in the brains of individuals with RLS. Levels of dopamine change with the circadian rhythms and are lower in the evening and at night. The increase in dopamine in RLS is compensated for by a decrease in dopamine receptors, leading to an overall balance during the day, but at nighttime when dopamine levels are lower, there is an overall deficit of dopamine activity, leading to the symptoms of RLS.
In addition to levodopa, another type of drug called dopamine agonists are also used to treat RLS. These drugs include ropinirole and pramiprexole; they act by stimulating the dopamine receptors the same way that natural dopamine would. All of these medications have been found to cause something called augmentation, which is when symptoms improve at the beginning of treatment, but over time the symptoms worsen and start happening earlier in the day. This occurs because instead of treating the root cause of the disease, adding additional dopamine to a system that already has an excess of it is actually ends up creating a bigger imbalance over time, decreasing dopamine receptors further.
In addition to dopamine agonists, other pharmacuetical agents prescribed for RLS include gabapentin, opioids, and benzodiazepines. All of these options have a significant downside, either in the form of side effects (gabapentin), addiction (opioids and benzodiazepines), or augmentation/worsening of RLS (dopamine agonists). Intravenous iron treatment, as discussed above, may be a better option that is safer and also effective. There are also non-pharmacological treatment options that have been shown to ease symptoms in some individuals. These include moderate exercise, leg massage, hot baths or heating pads, and a regular sleep schedule and avoiding naps. Avoidance of lifestyle and diet factors that may worsen symptoms can also help–this includes avoidance of alcohol, nicotine, and caffeine. Finally, some medications can worsen RLS, and these should be avoided if possible: antidepressants, anti-psychotics, diphenhydramine (Dramamine), and dopamine antagonists used to treat nausea and vomiting, such as metoclopramide. In many individual combining non-pharmacological approaches with iron therapy may make symptoms manageable.
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