Restless Legs Syndrome
Causes of RLS
Primary RLS The exact cause of primary RLS is unknown. However, there does appear to be a genetic component as approximately 40 to 50 percent of patients with primary RLS have a family history of the disorder and certain genetic variations are associated with the condition (Ferri 2012; Bradley 2008; Miletic 2011).
Although many think of primary RLS as a disease of the peripheral nervous system, studies suggest that the central nervous system may also be involved. Because RLS is akin to some other movement disorders the neurotransmitter dopamine, which helps facilitate uniform, controlled movements, has been theorized to be a possible causative factor. Indeed, altered dopamine signaling within the brain has been observed in several RLS studies, but results have been insufficient to draw firm conclusions (Clemens 2006; Cervenka 2006; Ruottinen 2000; Turjanski 1999; Eisensehr 2001). Additionally, alterations in dopamine signaling in the spinal cord have been observed, which lends further support to the hypothesis that dopamine is involved in RLS (Paulus 2006; Clemens 2006).
Secondary RLS Over twenty medical conditions are connected to secondary RLS (Miletic 2011).
Secondary RLS is a common complication of end-stage kidney disease. Estimates indicate that up to 60% of patients on dialysis have RLS (Walker 1995; Thorp 2001; Kavanagh 2004). People with diabetes or impaired glucose tolerance are more likely to have RLS, and RLS is a prominent part of diabetic peripheral neuropathy (Bosco 2009; O’Hare 1994; Lopes 2005; Merlino 2007). RLS may also be associated with Parkinson’s disease, another disorder associated with dopaminergic dysfunction in the nervous system. However, the link has not yet been clearly established (Guerreiro 2010; Gjerstad 2011). People with RLS also have an increased risk of developing high blood pressure, possibly due to overactivity of certain parts of the nervous system (Walters 2009; Batool-Anwar 2011).
Chronic venous disorders are a major contributor to secondary RLS (McDonagh 2007). In a 2007 study, researchers found that 36% of patients suffering from chronic venous disease also had RLS. In comparison, the control group only had a 19% occurrence of RLS. However, when the control participants who showed positive for RLS were studied more closely, it was noted that 91% of them had mild indications of venous problems (McDonagh 2007). In another study, participants with RLS who received medical treatment for chronic venous disease reported a 36% increase in quality of sleep and a 67% decrease in severity of symptoms (Tison 2005).
Role of Iron in RLS
One of the more commonly accepted hypotheses about the origins of RLS is that iron metabolism within the central nervous system plays a role (Miletic 2011; Connor 2008). As many as 25% of RLS patients have an iron deficiency (Rangarajan 2007), and iron supplementation was shown to relieve RLS symptoms in iron-deficient subjects (O’Keeffe 1994). Another study found that regular blood donors were more likely to develop RLS, particularly if they had reduced serum iron levels. Intravenous iron relieved RLS symptoms in this population (Birgegard 2010). Levels of ferritin (an iron storage protein) in the cerebro-spinal fluid (CSF) may also be reduced in patients with RLS (Earley 2000). Iron levels in the substantia nigra (a brain region in which dopamine is produced) may be particularly important as a study using MRI imaging found reduced iron concentrations in the substantia nigra of RLS patients (Allen 2001; Connor 2011). Other studies have further confirmed iron insufficiency in the substantia nigra as important for RLS. Also, people suffering from RLS often have abnormal levels of other proteins involved in iron handling (e.g., ferroportin and transferrin) (Connor 2003 and 2004).