Diagnostic approach

A high index of suspicion is required, especially when treating conditions associated with RLS.

History: The history is crucial because of the highly variable ways in which patients may present. A significant number of RLS patients will also have other sleep disorders. Most important is the issue of sleep-disordered breathing, which includes obstructive sleep apnea (OSA) and upper airway resistance syndrome (UAR), a milder form of OSA. Many patients also have periodic limb movements of sleep (PLMS). OSA, UAR, and PLMS can result in sleep fragmentation, which affects the quality and amount of sleep. These disorders may present as excessive daytime somnolence or fatigue. In children, they may present as hyperactivity and/or inattention.


Continue Reading

Examination: There are no specific findings attributable to RLS, although some associated conditions have characteristic findings. The examination should include muscle stretch reflexes (deep tendon reflexes), gait, sensory function (light touch, pinprick perception, presence of “stocking-glove pattern,” vibration, and joint-position sense). Check the mobility of the spine with the straight leg raising test and the distal circulation by palpation of the dorsalis pedis and posterior tibial arteries. 

Laboratory studies: An appropriate laboratory screening should encompass basic screening tests. Depending on the circumstances, some patients should undergo supplemental testing.

Treatment

The first decision point in therapy is necessity for treatment. Some patients with very mild and/or intermittent symptoms do not require immediate treatment. Educating the patient is essential so that if the RLS worsens, he or she may seek re-evaluation.

Conservative measures: Patients may benefit to some degree from good sleep hygiene; avoidance of caffeine, tobacco, and alcohol in the afternoon and evening; afternoon exercise; pastimes that promote mental activity, such as puzzles, video/computer games, etc.; limited use of medications that cause or exacerbate RLS, especially in the evening; hot baths; and massage.

Treatment of underlying causes: Frequently, treatment of an underlying cause will lead to improvement in both the underlying condition and the RLS. Correction of anemia, depressed ferritin or folate levels, or hypomagnesemia may decrease symptoms. A smoking-cessation program is a valuable adjunctive therapy. Lyme disease requires appropriate antibiotics. Many of the treatments for PD are commonly used in the management of RLS. A preliminary open-label study of magnesium showed possible benefit.11 

Pharmacologic approaches: When nonpharmacologic treatments do not control the symptoms, consider medication.

Dopamine agonists: These are the initial drugs of choice. Both ropinirole (Requip) and pramipexole (Mirapex) appear to be effective. Start with the lowest dose about one-and-a-half to two hours before bedtime, and increase the dose about every three days, as tolerated and needed. Patients may experience orthostatic hypotension, hallucinations, dyskinesias, dizziness, and even insomnia.

Older dopamine agonists include bromocriptine (Parlodel), available in 2.5- and 5-mg formulations, and pergolide, in 0.05-, 0.25-, and 1-mg doses. Pergolide may cause fibrosis of cardiac valves, pericardium, pleura, as well as the peritoneum and the retroperitoneum.  Both bromocriptine and pergolide can cause sedation, headaches, hallucinations, and sudden sleep. 

Dopamine precursors: Carbidopa in combination with levodopa (Sinemet, Sinemet CR) is a very effective treatment for RLS. The shorter-acting form, which works more quickly, is useful when the patient only has difficulty falling asleep or problems with prolonged activities, such as going to the theater or a long dinner. When the patient also has difficulty maintaining sleep because of nocturnal awakening, the extended-release (CR) formulation is preferable. Both forms may result in “augmentation,” a phenomenon in which the patient experiences symptoms progressively earlier in the day. Augmentation is probably of less concern when the patient uses the medication only on an intermittent basis.  

Anticonvulsants: As a group, these seem to be somewhat less effective than the dopamine agonists and precursors. The initial dose of gabapentin (Neurontin) should be low, especially in the elderly. Younger patients may start with 100 or 300 mg, but the elderly should begin with 100 mg one to two hours before retiring. The maximum dose depends on the response, adverse effects, and patient age. Since renal metabolism is involved, the maximum dose will decrease with age and reduced renal function. In younger patients, the maximum daily dose may be 3,600 mg, if tolerated. In older patients, 1,200-1,500 mg is the maximum recommended daily dose. Side effects include sedation, dizziness, and possibly mood change and depression.

Carbamazepine (Tegretol, Tegretol XR, Carbatrol) has provided a less consistent response. The daily dose may range from 200-1,000 mg as tolerated and needed. Both short- and long-acting forms are available. Significant side effects include drowsiness, rash, hyponatremia, depression in elements of the blood count, and abnormalities of liver function. Some believe that carbamazepine may be more effective when there are more neuropathic symptoms, such as burning or aching.

Alpha2-Agonists: Clonidine (Catapres) may be helpful in relieving the symptoms of RLS. The dose may range from about 0.1 mg to as much as 0.6 mg per day, depending upon tolerability. Sedation, hypotension, and dizziness represent the major adverse effects.

Benzodiazepines: These may be beneficial when there are associated sleep problems, such as sleep-onset insomnia. Triazolam (Halcion), a shorter-acting benzodiazepine (BZD), or one of the BZD agonists will be more efficacious when RLS prevents sleep initiation. Zolpidem (Ambien) and zaleplon (Sonata) are fast-acting BZD agonists; zolpidem has a longer half-life. For the patient who may also be awakened by RLS throughout the night, a longer-acting BZD, such as temazepam (Restoril) or clonazepam (Klonopin), may be more useful. All these agents may have a role for intermittent use. With chronic use, the potential problems of dependency and daytime somnolence may become an issue.

Opiates: For refractory RLS, opiates represent a definite option, even given their side-effect profile. Low-potency opiates, such as propoxyphene compounds (Darvon) or propoxyphene napsylate 65-130 mg, or codeine 30-60 mg (with or without acetaminophen), may be useful. The potential adverse effects include dependency, constipation, daytime drowsiness, increased risk of falls, and nausea. 

When the patient fails to respond to a single agent, consider combinations chosen on the basis of responses and adverse reactions to the individual drugs already tried. 

Other treatments: Case or small studies involving one or a few patients suggest other possible treatments that can be tried after more rigorously studied approaches have failed. These include a lumbar corset that simulates abdominal pressure of walking12 and other medications, such as sodium valproate (Depakote, Depakene) 250-1,500 mg,12 methadone 5-10 mg,13 or tramadol (Ultram) 50-100 mg.

Given the wide range of effective treatments available today, you should be able to help most RLS patients achieve a significant improvement in their quality of life.

Dr. Selman is attending neurologist at Northern Westchester Hospital, Mt. Kisco, N.Y., and associate clinical professor of neurology at Columbia University College of Physicians and Surgeons in New York City, where he has a private practice.

References

1. Desautels A, Turecki G, Montplaisir J, et al. Restless legs syndrome: confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity. Arch Neurol. 2005;62:591-596.
2. Levchenko A, Montplaisir JY, Dube MP, et al. The 14q restless legs syndrome locus in the French Canadian population. Ann Neurol. 2004;55:887-891.
3. Hemmer B, Riemann D, Glocker FX, et al. Restless legs syndrome after a borrelia-induced myelitis. Mov Disord. 1995;10:521-522.
4. Krishnan PR, Bhatia M, Behari M. Restless legs syndrome in Parkinson’s disease: a case-controlled study. Mov Disord. 2003;18:181-185.
5. Iannaccone S, Quattrini A, Sferrazza B, Ferini-Strambi L. Charcot-Marie-Tooth disease type 2 with restless legs syndrome. Neurology. 2000;54:1013-1014.
6. Rotta FT, Sussman AT, Bradley WG, et al. The spectrum of chronic inflammatory demyelinating polyneuropathy. J Neurol Sci. 2000;173:129-139.
7. Tembl JI, Ferrer JM, Sevilla MT, et al. Neurologic complications associated with hepatitis C virus infection. Neurology. 1999;53: 861-864.
8. Gemignani F, Marbini A, Di Giovanni G, et al. Cryoglobulinaemic neuropathy manifesting with restless legs syndrome. J Neurol Sci. 1997;152:218-223.
9. Schols L, Haan J, Riess O, et al. Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome? Neurology. 1998;51:1603-1607.
10. Yunus MB, Aldag JC. Restless legs syndrome and leg cramps in fibromyalgia syndrome: a controlled study. BMJ. 1996;312:1339.
11. Hornyak M, Voderholzer U, Hohagen F, et al. Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study. Sleep. 1998;21:501-505.
12. Ishizu T, Ohyagi Y, Furuya H, et al. A patient with restless legs syndrome/periodic limb movement successfully treated by wearing a lumbar corset [in Japanese]. Rinsho Shinkeigaku. 2001;41:438-441.
13. Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord. 2005; 20:345-348.