Restless legs syndrome is a sensorimotor disorder characterized by a complaint of a strong, nearly irresistible urge to move the legs. The urge is often accompanied by unconfortable paresthesia felt deep in the legs, and such paresthesia and urge only occur or are worsened by rest and at the evening, while being at least in part relieved by walking and moving the legs. Symptoms of restless legs syndrome may greatly distress patients impeding falling asleep or causing awakenings or arousals, and are frequently associated with jerking or twitching movements of the legs and, especially during light sleep but sometimes also during relaxed wakefulness, by periodic limb movements in sleep (PLMS) or while awake (PLMW). Restless legs syndrome may occur secondary to other medical and neurological conditions, in particular during pregnancy and associated with uremia, but in most of the cases occurs as a primary condition, often familial. Five to 10% of the general population may be affected with restless legs syndrome of various degrees of severity. Restless legs syndrome occurs more frequently in women.
The pathogenesis of the disease is still unclear, but an important genetic determination is indicated by familial linkage and association studies that have disclosed several linkage loci and three variants in different genes that associated with restless legs syndrome. Aside from genetic factors, there is circumstantial evidence that restless legs syndrome is associated to some defect in the dopaminergic system and in iron regulation at the level of the central nervous system (CNS). The clearest evidence for dopamine system involvement is the pharmacological evidence acquired after the clinical observation of Akpinar of the beneficial effects of levodopa in restless legs syndrome. Evidence for an abnormality of iron metabolism also originated from clinical observations, and was substantiated by pathological and metabolic studies suggesting a deficient regulation of iron stores at the central nervous system level. These considerations are relevant to the treatment of restless legs syndrome, since the absence of a clear and unambiguous rationale for the pathogenesis of the disease had led to the proposal and adoption of haphazard treatment strategies. Following the establishment of international diagnostic criteria for restless legs syndrome and of validated scales of clinical severity; however, large controlled trials have been made possible. Consequently, practice parameters and guidelines for treatment of primary restless legs syndrome based on proofs of evidence have been formed and, as such, they will form the basis of our considerations for the treatment of restless legs syndrome here. All of these guidelines concur that dopaminergic agents are the drugs having the best evidence for activity in restless legs syndrome.
Nonpharmacological Treatment of Restless Legs Syndrome
Primarily opinion evidence has been presented concerning nonpharmacological treatment in restless legs syndrome. Behavioral options, including sleep hygiene, have been recommended by various authorities and included within the restless legs syndrome Foundation Medical Advisory Board treatment algorithm. Two modalities have undergone formal study: leg counter-pulsation and exercise. Enhanced external counter-pulsation was found to be effective in a small open series, but a tiny controlled trial was unable to confirm any benefit (ongoing studies may help resolve this conflict). An aerobic and leg strengthening exercise routine was found to be of benefit in a controlled trial, consistent with opinion that moderate levels of exercise may benefit restless legs syndrome. A small pilot study in hemodialysis patients also found benefit from a 16-week aerobic exercise program.
Surgical interventions [deep brain stimulation (DBS) for Parkinson’s disease, venous sclerotherapy, kidney transplant in restless legs syndrome secondary to uremia] have been reported for cases of secondary restless legs syndrome. The effect of deep brain stimulation has not been consistent; kidney transplantation seems to greatly benefit restless legs syndrome induced by uremia. Sclerotherapy and the association of restless legs syndrome and venous disease remain controversial.
On the basis of the findings to date, the final recommendations for treatment of restless legs syndrome are that dopaminergic agents have the best evidence for efficacy and, considering the issue of the fibrotic side effects of ergot derivatives, non-ergot derivatives have probably the best safety profile: pramipexole (0.25-0.75 mg), ropinirole (0.5-4 mg), and rotigotine (transdermal delivery 1-3 mg) all have clear proofs of efficacy in large sample studies. Pergolide (0.4-0.55 mg) and cabergoline (0.5-2 mg) are also definitely effective, but their use should be monitored for eventual multivalvular heart disease and pleuropericarditis. Levodopa / benserazide (mean dosage 159 / 40 mg at bedtime) is also definitely effective, but its use may be jeopardized by the frequency of the augmentation adverse effect, which greatly limits its long-term administration. Among all of the other interventions, only gabapentin (800-1800 mg / day) has definite proof of efficacy, albeit in a small sample of patients.
Adjunctive and Alternative Therapy of Restless Legs Syndrome
There has been minimal study and no reports of any complementary or alternative medicine (CAM) therapies in restless legs syndrome. One patient advocate, Jill Gunzel, has developed a Web site (http://members.cox.net) and published a book recommending a variety of techniques for managing restless legs syndrome with medications. There is one funded study ongoing at the University of Pennsylvania using valerian to treat restless legs syndrome.
An important aspect of adjunctive treatment is patient support. There are now a number of worldwide patient support and advocacy groups that have developed support networks and educational materials. The Restless Legs Syndrome Foundation (RLSF) was founded in 1993 and has an excellent Web site with both lay and professional materials free to download (www.rls.org).