Periodic Limb Movement Disorder
and Restless Leg Syndrome

C. David Sudduth, M.D., FCCP Diplomat American Board of Sleep Medicine, Associate Director, Sleep Management Center, Southeast Georgia Regional Medical Center, Brunswick, GA

 
Introduction

Periodic Limb Movement Disorder and Restless Leg Syndrome, often concurrent, are under diagnosed disorders of sleep. They can affect patients of all age groups1, although the prevalence increases with increasing age2,3,4, and collectively they represent one of the most commonly encountered sleep disorders in a primary care setting.5 6 In the case of RLS the diagnosis can be made clinically, and a variety of treatment7 options are available. The disorders may cause significant symptoms for the patient and bed partner8, especially with respect to daytime somnolence9 ,10, difficulty falling asleep, and in severe cases, pain.11 With proper diagnosis and effective treatment patients improve their ability to fall asleep, maintain sleep, and increase their sense of well being.12

Background

Restless Leg Syndrome (RLS) has been reported in 5% of patients in the primary care setting, although estimates from a recent study put the number closer to 15%.13 For some perspective, the estimated incidence of obstructive sleep apnea is 5% of men older than 50. Often the symptoms are ignored as a `normal' part of aging by the patient, or dismissed as a familial and inevitable condition. In fact, there is evidence that RLS is more common with increasing age14, and that the disorder shows familial clustering.15,16 RLS may be easily overlooked in the standard system review and because of dismissal by the patient, rarely is it a presenting complaint. Patients may present with complaints of excessive sleepiness, interrupted sleep, or fatigue. On close questioning, patients often report excess movement, or discomfort in the lower extremities. The symptoms may be compared to a crawling sensation in the legs and some relief is possible by massage or walking. Often the description includes cramping, however the disorder is nosologically different from nocturnal leg cramps. The symptoms appear maximally later in the day and often peak at bedtime.17 As a result, some may initially complain of difficulty falling asleep or insomnia. 18,19,20 Symptoms tend to wax and wane over time, but in severe cases may be present nightly or begin earlier in the day.

In a significant portion of patients with RLS (up to 80%), the excess motor movements may persist past sleep onset, and result in Periodic Limb Movements of Sleep (PLMS). 18 PLMS is defined based on criteria present on a polysomnogram (figure 1). The hallmark is regularly occurring muscle twitches of 0.5-4.0 second duration in either upper or lower extremities, which may be associated with EEG arousals.21 In order to be scored as PLMS on polysomnography, the time period between movements must be between 4 and 90 seconds. Patients with PLMS may have enough movement to disrupt a bed partner's sleep and this can result in separate sleeping. If associated with arousals frequent enough to disrupt normal sleep architecture, complaints of excessive daytime sleepiness or nonrestorative sleep may ensue. The movements typically include extension of the great toe, dorsiflexion of the ankle and occasionally flexion of the knee or hip. 22 Anterior tibialis recording is usually adequate to detect the episodes on polysomnography, although exclusive involvement of the upper extremities may occur 23,24.

Although the etiology of the motor movements is not completely known, evidence suggests a centrally located origin rostral to the pons acting as central pacemaker.21 This is based on evidence including the gross similarity to the Babinski response, as well as human and animal studies of normal sleep and of coma. Periodicity similar to that of PLMS is seen with cycling of heart rate , blood pressure, intraventricular pressure and EEG arousal which suggests disinhibition of a central pacemaker. 25 There is mounting evidence that dopaminergic pathways are involved in production of the movements. 26 Dopamine agonsists including L-Dopa and bromocriptine are effective treatment and dopamine antagonists block the therapeutic effect of opioids in one study. 27

Approach to the Patient with RLS/PLMS

RLS/PLMS may be isolated or seen in conjunction with a variety of other disorders (Figure 2). In most cases this is easily distinguished by clinical history and physical examination. There are several clinical pearls to remember, however. One key to evaluation is exclusion of iron deficiency with determination of hemoglobin level. 28 Symptoms can improve with resolution of the anemia. 29
RLS may be associated with peripheral neuropathy from amyloidosis30 or diabetes31,32. RLS is frequently associated with uremia and may occur prior to initiation of hemodialysis or after. 33 34,35 Drug withdrawal of benzodiazepines and barbiturates is also a reported cause, as well as administration of alcohol 36 lithium carbonate37,38 venlafaxine 39 or tricyclic antidepressants. 40,41 On polysomnography, PLMS may be mimicked by the arousal response of sleep apnea or occur independently of apnea in the same patient. 42

History should include questions about leg movements or feelings of restlessness at bedtime and family history of similar complaints. If available, history from the bed partner may lead to a diagnosis when most of the movements are present after sleep onset. Neurological examination can detect confounding disorders such as Parkinson's disease, or akithesia related to neuroleptic use. 43 A thorough medication history can exclude movements related to barbiturate, tricyclic antidepressant or benzodiazepine withdrawal. If symptoms are only those of restless legs and no or only mild symptoms of daytime hypersomnolence or nocturnal awakening are present, then treatment may be initiated based on a clinical diagnosis and no polysomnograghy is needed. 44 If there is significant hypersomnolence, or if a concurrent sleep disorder is suspected (such as sleep apnea or narcolepsy), then polysomnography is indicated.

The endpoint of treatment is twofold; maximum reduction of symptoms with minimum side effects and restoration of sleep quality through the elimination of movement related EEG arousals.

Treatment

Although behavioral strategies have been reported, pharmacotherapy is the mainstay of treatment. Several agents have been tried for both RLS and PLMS, including carbamazepine, 45 ,46 baclofen, 47 and clonidine, 48,49 however study results are not uniformly conclusive. Dopaminergic agents, specifically L Dopa /carbidopa are most effective. In patients with recurring symptoms, therapy should begin with 25 mg at bedtime, and if needed titrated to 50 mg. Symptom control occurs at a lower dose than that typically required for Parkinsons Disease. With respect to L dopa administration, there are two potential problems. First, rebound of symptoms may occur as the drug level drops. 50 Given the fact that Non Rapid Eye Movement sleep, which is most likely to contain limb movements, dominates the sleep cycle until late in the sleep period; repeat dosing in the middle of the night may be necessary, and sustained release preparations (Sinemet CR) may provide longer relief. Secondly, if sustained release formulations are administered, they may `chase' the peak period of movements from 4:00 PM- 4:00 AM later into the waking hours, a phenomenon known as augmentation. 51 If daytime symptoms occur, either daytime doses must be administered or an alternate drug chosen. Despite these caveats, L Dopa/ carbidopa remains a reasonable initial choice for therapy. 52,53 Other dopaminergic agents reported as useful for RLS/PLMS include bromocriptine (2.5-10 mg/day), 54 pergolide (0.1-0.75 mg/d), 55,56 pramipexole (0.25-1.5 mg/d) 57 and ropinirole (0.5-3.0 mg/d). 58,59

Benzodiazepines have also been used effectively for PLMS/RLS. Within this class, most clinical experience is with clonazepam. 60,61 In trials with clonazepam, polysomnography may show persistence of the movements, 62 however EEG arousals are suppressed. The improved sleep continuity is thought to decrease daytime sleepiness and result in subjective improvement for the patient. The problems with prolonged use of clonazepam are those of possible dependence as well as daytime sedation. 63 Additionally, caution must be exercised if the patient has concurrent sleep apnea. If sleep apnea is untreated, benzodiazepine administration may worsen the severity of apneas by blunting the arousal response. If used for PLMS/RLS a dose of 0.5-1.0 mg of clonazepam is usually effective.

Opioids are the oldest treatment for these disorders. They work by an uncertain means to improve RLS/PLMS. 64 Although evidence does suggest that the mechanism does not directly involve opiate receptors in the dopaminergic pathways, when used, drugs with less potential for dependence (codeine, propoxyphene, or hydrocodone) or tolerance (levorphanol 1-6 mg) are preferable. 65 Undesirable side effects including prolonged sedation, constipation or confusion may make this class less well suited for the geriatric patient. 53

Anticonvulsants (carbamazepine, gabapentin) have been reported as beneficial in RLS/PLMS, resulting in decreased restlessness and pain reduction. 66 67 There is less certainty as to their efficacy in patients with severe symptoms and they are not generally regarded as first line agents or as adequate monotherapy. The patient with concurrent peripheral neuropathy may be an exception, however.

Various nutritional supplements have been used, including magnesium 68 and calcium, as well as vitamin B12, vitamin C and vitamin E. Results although inconsistent, do show benefit of administration in cases of deficiency. As mentioned previously, correction of iron deficiency can give significant relief. Current recommendations include supplementation with iron sulfate or gluconate to the point where serum ferritin is greater than 50 mg/dL. 69

Conclusion

Restless Leg Syndrome and Periodic Limb Movement Disorder are commonly encountered parasomnias in the primary care practice. Although the patient may dismiss the condition as a normal part of aging, the conditions are very discomforting to the patient and quite responsive to treatment. With an increasing incidence with age, the geriatric patient is disproportionately affected. Evaluation of the patient should include medication history, neurological examination and assessment of iron stores. If anemia is present, appropriate diagnostic evaluation and correction with iron supplementation can provide significant relief. Polysomnography is not generally required prior to initiation of therapy unless an additional problem is suspected. For patients with only occasional symptoms, nonpharmacologic therapy including heat or massage is preferable. Although the exact pathophysiology is not yet known, several drugs have proven useful in patients with more severe or persistent symptoms. Dopamine agonists should be tried first, recognizing that rebound or augmentation may need to be addressed by using sustained release preparations, or by changing to an alternate drug. Rarely, a patient may require treatment beginning early in the day and drug dosing should begin shortly before the time of typical symptom onset. In patients with severe symptoms narcotic analgesics have been used, and although drug dependence and tolerance are potential problems, there is little reported evidence to confirm this. Adequate treatment can improve sleep quality, reduce daytime hypersomnolence, and improve the patients sense of well being.

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Jacksonville Medicine / March, 2001

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