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Medical Study
Clinical Presentation and Diagnosis of Restless Legs Syndrome
Posted 06/24/2005
Charles H. Adler, MD, PhD
Restless legs syndrome (RLS) was first described in the 1600s, but the term "restless legs" was coined in 1944 by Ekbom.[1] RLS is characterized by paresthesias or dysesthesias, an urge to move the limbs, and motor restlessness, with an onset of symptoms or exacerbation in the evening, and improvement with limb movement/walking around.[2] Regardless of its common occurrence (2% to 15% of the general population),[3,4] RLS is often underrecognized and misdiagnosed, which leads to significant physical and emotional disability. Although the exact etiology of idiopathic RLS is unknown, authorities postulate that it may be related to dopaminergic dysfunction, based on the favorable response of RLS to antiparkinsonian medications, such as levodopa and dopamine agonists.
Presenting Complaints
Patients may present with a constellation of complaints, including trouble falling asleep, trouble getting back to sleep, "a funny feeling in the legs," and a "creepy or crawly feeling in the legs." They find it difficult to explain what they experience; it is "indescribable." Universally, they characterize their symptoms as occurring mainly when they sit for prolonged periods of time (eg, on an airplane, during a long car ride, or in the theater) or when they are supine, and they note exacerbation with nightfall. The paresthesias or dysesthesias predominantly involve the legs, but many patients also have symptoms in the arms or trunk. Symptoms are usually bilateral and usually occur simultaneously.
Some patients have difficulty immediately after getting into bed, delaying the onset of sleep, whereas others are able to fall asleep but are then awakened and have difficulty getting back to sleep. Patients with RLS experience both an urge to move and a sense of relief with movement. Symptoms are often best alleviated by walking or pacing the floors. However, this disruption of sleep can lead to excessive daytime sleepiness as well as depression and anxiety, and may have a significant negative impact on quality of life.
Many, but not all, patients with RLS also experience periodic limb movements of sleep (PLMS).[5] These are stereotyped, repetitive flexion movements of the legs more than arms, which may (or may not) arouse patients from sleep, and when severe, can interfere with the bed partner's ability to sleep. Often, the patient is unaware of these movements, and they are brought to the physician's attention by the bed partner. Some patients will also exhibit involuntary limb movements (or dyskinesias) when awake, usually when seated or supine. The sleep patterns of patients with PLMS may be quite disturbed with frequent nocturnal awakenings leading to poor quality of sleep and moderate-to-severe excessive daytime sleepiness and fatigue. These symptoms also have a direct negative impact on quality of life.
Epidemiology of RLS
Epidemiologic studies estimate that the prevalence of RLS ranges from 2% to 15% of the general population.[3,4] In many studies, the mean age of patients with RLS falls within middle age (40-60); however, onset can occur from infancy to old age. Although the onset of symptoms may arise before 30 years old, most individuals do not seek medical attention until they reach their mid-30s and many are not appropriately diagnosed until their 50s.
Typically, RLS is gradually progressive over time, and the remission rate is generally low. Studies of heredity and RLS reveal a family history of RLS in 25% to 92% of patients, and a link to chromosomes 12[6] and 14[6,7] has been recently reported. Because other family members may have these symptoms, patients often do not recognize their importance when they see their physicians, and consequently they may not mention them.
Pathophysiology
Most cases of RLS are thought to be primary, or idiopathic. The pathophysiology of RLS remains unclear.[8] Given the response of RLS to dopaminergic medications, such as levodopa and dopamine agonists, it is postulated that a dopaminergic abnormality is the mechanism underlying RLS. However, some neuroimaging studies have revealed contradictory findings, and although some studies have found a more frequent occurrence of RLS in patients with Parkinson's disease (PD),[9,10] no pathophysiologic data support a relationship between RLS and PD.[11]
Another possible pathophysiologic mechanism relates to iron deficiency. Studies have shown a reduction in iron in the central nervous system in those with RLS, improvement with iron replacement therapy, and because iron is an important cofactor in dopamine synthesis, the 2 mechanisms may be related.[12,13] To date, the only significant findings from pathologic examination of patients with RLS is evidence for iron deficiency in the substantia nigra,[14] but there is no evidence of PD or dopamine neuron pathology.[15]
Whereas most cases of RLS are primary in cause, a number of secondary causes also exist. These include iron deficiency, renal failure, and pregnancy.[14-16] All patients with RLS should have serum ferritin levels checked, and if low (< 50 mcg/dL), they should be considered for treatment with iron replacement therapy. Frequent blood donors should also be aware that symptoms of RLS have been reported following blood donation.[16] Pregnancy has been associated with the development of RLS, which may be secondary to folate deficiency. One study found that as many as 26% of pregnant women had symptoms of RLS.[17] In most cases, RLS resolves postpartum. Renal failure with uremia, especially those cases needing hemodialysis, also is commonly associated with RLS.[18] All patients with RLS should have blood urea nitrogen and creatinine levels checked.
Examination of patients with RLS should include an evaluation for neuropathy and varicose veins, which can be associated with secondary RLS. If the examination suggests peripheral neuropathy, then further testing with nerve conduction and electromyography (EMG) can be considered; evaluation for causes of neuropathy, such as diabetes, also should be considered. Finally, drug-induced RLS must always be considered. Medications, such as dopamine antagonists (neuroleptics and metoclopramide), tricyclic antidepressants, some selective serotonin reuptake inhibitors, lithium, and H2 blockers, may cause or exacerbate RLS and should be discontinued if possible to see whether symptoms resolve. Although not necessarily causative, anecdotal reports suggest that caffeine or alcohol may exacerbate RLS symptoms.
Some have suggested that RLS is more common in patients with PD.[10] The available data are inconclusive, although PD patients certainly can have RLS, there is no evidence linking RLS to PD or the development of PD. However, the fact that dopaminergic agents are effective in treating both disorders continues to support investigating a possible link between the disorders.
Making the Diagnosis
In order to make a diagnosis of RLS, patients should meet the criteria recently put forth by the International RLS Study Group and the National Institutes of Health (NIH).[2] These include (1) an urge to move the legs, (2) temporary relief with movement, (3) onset or worsening of symptoms with rest or inactivity, and (4) worsening or onset of symptoms in the evening or night.
There is no diagnostic test for RLS; the diagnosis is based on subjective symptoms. If concurrent PLMS is of concern, then a sleep study can be performed to evaluate the patient for leg movements during sleep. The International RLS Study Group Rating Scale can be used to quantitate the degree of RLS and follow the patient longitudinally. This measure comprises 10 questions, each rated on a 0-4 scale to a maximum score of 40.[19]
As discussed, patients presenting with RLS should be asked about a family history of RLS. (Did a parent always get up and walk around all night? Does a child move around a lot when asleep?) In addition, a comprehensive review of current and previous medication use should be taken. All RLS patients should be examined for varicose veins and evaluated for peripheral neuropathy and myelopathy. Laboratory evaluation should include a blood count, blood urea nitrogen, creatinine, fasting blood glucose, thyroid-stimulating hormone, ferritin, and folate levels, with further laboratory testing if the patient is found to have neuropathy. In some cases, it may be valuable to obtain EMGs and nerve conduction studies to further evaluate for peripheral neuropathy.
In most cases, polysomnography is not necessary because the history will be clear enough to suggest a diagnosis of RLS and allow consideration of pharmacologic intervention. However, if the symptoms are not clear-cut, the diagnosis is unclear, or treatment has proven ineffective, polysomnography can be valuable for documenting PLMS, as well as the degree of sleep disturbance experienced by the patient. Polysomnography will not diagnose RLS, which is based on the subjective criteria outlined above, but it will determine the presence of PLMS (found in ~80% of patients with RLS) or another sleep disorder that may be causing the complaints.
References
1. Ekbom KA. Restless legs syndrome. Neurology. 1960;10:868-873. Abstract
2. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-119. Abstract
3. Phillips B, Young T, Finn L, Asher K, Hening WA, Purvis C. Epidemiology of restless legs symptoms in adults. Arch Intern Med. 2000;160:2137-2141. Abstract
4. Zucconi M, Ferini-Strambi L. Epidemiology and clinical findings of restless legs syndrome. Sleep Med. 2004;5:293-299. Abstract
5. Plazzi G, Vetrugno R, Meletti S, Provini F. Motor pattern of periodic limb movements in sleep in idiopathic RLS patients. Sleep Med. 2002;3(suppl):S31-S34. Abstract
6. Desautels A, Turecki G, Montplaisir J, Sequeira A, Verner A, Rouleau GA. Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am J Hum Genet. 2001;69:1266-1270. Abstract
7. Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain. 2003;126(pt6):1485-1492.
8. Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med. 2004;5:385-391. Abstract
9. Krishnan PR, Bhatia M, Behari M. Restless legs syndrome in Parkinson's disease: a case-controlled study. Mov Disord. 2003;18:181-185. Abstract
10. Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson disease and restless legs syndrome. Arch Neurol. 2002;59:421-424. Abstract
11. Garcia-Borreguero D, Odin P, Serrano C. Restless legs syndrome and PD: a review of the evidence for a possible association. Neurology. 2003;61(suppl3):S49-S55.
12. Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology. 2000;54:1698-1700. Abstract
13. Earley CJ, Heckler D, Allen RP. The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med. 2004;5:231-235. Abstract
14. Connor JR, Wang XS, Patton SM, et al. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology. 2004;62:1563-1567. Abstract
15. Pittock SJ, Parrett T, Adler CH, Parisi JE, Dickson DW, Ahlskog JE. Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology. Mov Disord. 2004;19:695-699. Abstract
16. Silber MH, Richardson JW. Multiple blood donations associated with iron deficiency in patients with restless legs syndrome. Mayo Clin Proc. 2003;78:52-54. Abstract
17. Manconi M, Govoni V, De Vito A, et al. Restless legs syndrome and pregnancy. Neurology. 2004;63:1065-1069. Abstract
18. Kavanagh D, Siddiqui S, Geddes CC. Restless legs syndrome in patients on dialysis. Am J Kidney Dis. 2004;43:763-771. Abstract
19. Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4:121-132. Abstract
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