TOC  | Neurology

Restless Leg Syndrome (RLS)          RX   
Restless legs syndrome (RLS)
is a common neurologic condition characterized by bilateral or unilateral unpleasant  ("creeping, crawling, tingling, cramping, pulling, pain, electric, tension, itching, stinging, nervousness, growing pains, and burning") , but not painful,sensations deep inside the legs that occur at rest and are worse at bedtime. These paresthesias are accompanied by an irresistible urge to move the legs, which results in a temporary relief of the symptoms.  

The symptoms are described as affecting the depth of the extremity rather than the surface of the skin. The majority of patients describe these symptoms occurring predominantly between the ankle and knee, although the entire leg, as well as the arms, could be involved.  Volitional movements, such as walking, stretching, or shaking the legs, attenuate the sensory symptoms for most patients.

RLS can occur in either

  1. the idiopathic - most individuals with RLS suffer from the idiopathic form  or
  2. the secondary form:  as seen more commonly in association with uremia, iron deficiency, polyneuropathy, pregnancy, fibromyalgia, rheumatoid arthritis, Sjögren's syndrome, radiculopathy, cobalamin deficiency, folate deficiency, and ADHD.

    
International Restless Legs Syndrome Study Group (IRLSSG) Diagnostic Criteria for RLS
  1. An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs.
    Sometimes the urge to move is present without the uncomfortable sensations.
    Sometimes the arms or other body parts are involved in addition to the legs.
  2. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying down or sitting.
  3. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.
  4. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night.
    When symptoms are very severe, the worsening at night may not be noticeable but must have been previously present.

    
Periodic limb movements of sleep (PLMS) are observed in virtually all patients with RLS.
PLMS are stereotyped, periodic, jerking movements typically consisting of flexion of the ankle, knee, and hip. These are sometimes accompanied by awakenings resulting in sleep fragmentation and subsequent excessive daytime sleepiness, although this latter sequela is controversial among sleep specialists.

Periodic Limb Movement Disorder (PLMD)  

PLMD is a condition characterized by limb movements during sleep that may result in a complaint of insomnia and excessive daytime sleepiness. Up to 80% of those with RLS also experience PLMS, and there is some controversy concerning whether PLMD is a distinct disorder separate from RLS. Periodic limb movements affecting the lower extremities are described as intermittent extension of the big toe and dorsiflexion of the ankle with occasional flexion of the knee and hip.[17] These movements are often bilateral but may predominate in one leg or alternate between legs, and may also occur during wakefulness. Periodic limb movements may affect the upper extremity and manifest as intermittent flexion at the elbow. PLMS predominantly occur during the first half of the night, with a typical pattern of progressive decline through the rest of the night.

Although RLS is a clinical diagnosis made on the basis of the characteristic symptoms of the disorder, the diagnosis of PLMD is made by polysomnography using electromyography (EMG) recordings from the tibialis anterior muscles. Movements are diagnostic if they last 0.5-5 seconds and occur in a series of 4 or more at intervals of 5-90 seconds. The EMG amplitude of the nocturnal limb movements must reach 25% or more above the baseline EMG amplitude of the limbs while awake.

The severity of PLMD is determined by the periodic limb movement of sleep index, which equals the number of periodic limb movements per hour of sleep. The periodic limb movement arousal index is the number of PLMS associated with electroencephalographic arousals per hour of sleep. Mild PLMD is defined as 5-25 PLMS per hour of sleep; moderate as 25-50 PLMS per hour of sleep; and severe as more than 50 PLMS per hour of sleep, or more than 25 PLMS associated with arousals per hour of sleep.

When symptoms of insomnia and excessive daytime sleepiness exist in addition to PLMS, the diagnosis of idiopathic PLMD can be made if no other medical, psychiatric, or sleep disorders can be found to account for these symptoms. PLMD may also occur in association with medications or a variety of other conditions, such as narcolepsy and obstructive sleep apnea.

    
Treatment of Restless Leg Syndrome

[Four groups of drugs are available to treat restless legs syndrome (RLS) and periodic limb movement in sleep:

  1. dopaminergic drugs (e.g., carbidopa-levodopa and dopamine agonists such as pergolide, pramipexole, ropinirole, and cabergoline);
  2. benzodiazepines (e.g., clonazepam);
  3. opioids (e.g., codeine, propoxyphene, oxycodone, and hydrocodone); and
  4. anticonvulsants (e.g., gabapentin).

The best drug for initial therapy in most cases is a dopamine agonist. The only drug currently approved by the Food and Drug Administration for use in RLS is ropinirole, but several clinical trials have proved that other agents can be used for this disorder.   REF:   ACP Medicine 2006  

Requip (Ropinirole) 0.25-4 mg
It has been shown to significantly reduce the sensory discomfort of RLS as measured by the IRLS scale. Furthermore, ropinirole at bedtime dramatically reduced the number of PLMS as well as the arousals caused by periodic limb movements.  The optimal dosage range of this medication is 0.25-4 mg. The benefits of ropinirole appear to remain intact 12 months after initial treatment.]

Mirapex (Pramipexole) 0.125, 0.25, 0.5, 0.75, 1, and 1.5 mg tablet

    
Epidemiology

RLS is a common neurologic disorder with a prevalence of approximately 1% to 10% in different ethnic populations.  One large study comprising 2099 primary care patients found that 24% experienced RLS symptoms and 15.3% reported noting these symptoms at least weekly. Symptoms of RLS were reported significantly more often by women than men.  The prevalence of RLS significantly increases with age.

The mean age of onset of RLS is 27.2 years; in 38.3% of patients, the onset is before age 20 years.  A majority of patients with RLS will demonstrate PLMS on polysomnographic studies, and approximately one third of those with PLMS will have RLS.

Hereditary Characteristics

RLS can occur with an autosomal dominant mode of inheritance; 92% of individuals with the idiopathic form have a family history of RLS, whereas only 13% of individuals with secondary RLS have a family history of RLS. In a study of monozygotic twins, 10 of 12 twin pairs were concordant for RLS symptoms. Despite the high concordance rate, however, the disease severity, age at onset, and symptom descriptions often varied between twins.

Pathophysiology

The pathophysiology of both RLS and PLMD is unknown. Pharmacologic evidence that RLS is highly responsive to dopaminergic agents suggests an underlying defect in dopaminergic function.

    
Differential Diagnosis of RLS

Several significant psychiatric, medical, and sleep disorders may be mistaken for RLS.

Anxiety disorders
often involve motor activity but evidence of sympathetic activity, such as sweating and palpitations, are present as well.

Akathisia
is an inner sense of restlessness accompanied by a desire to move but this is usually found in association with use of neuroleptics.

"Vesper's curse" is a transient lumbar stenosis
caused by venous plexus engorgement from increased right atrial filling pressure while lying down; the stenosis results in lower-extremity paresthesias and lumbosacral pain, which arouse the patient from sleep.

Children with ADHD
experience high levels of nocturnal activity.
Furthermore, the sleep disruption of PLMD and motor activity of RLS while awake could contribute to the inattention and hyperactivity seen in children with ADHD.[50]

PLMS also must be clearly distinguished from upper airway resistance syndrome (Obstructive Sleep Apnea).  With technologic advancements in polysomnographic and respiratory monitoring, it is now recognized that PLMS may be triggered by subclinical hypopneas or respiratory effort-related arousals and improve after nasal continuous positive airway pressure is administered.

Nocturnal epilepsy
can manifest as localized or generalized tonic-clonic activity.  Enuresis and postictal confusion may accompany seizures but not PLMD.

Nocturnal leg cramps
are painful spasms of the calf or foot that may occur with greater frequency during pregnancy; in women and the elderly; after intense exercise; and as a result of diabetes, fluid and electrolyte imbalances, and musculoskeletal disorders. Nocturnal paroxysmal dystonia is characterized by stereotypic dystonic movements that can follow sudden awakenings from non-rapid eye movement (NREM) sleep.

Rapid eye movement (REM) sleep behavior disorder
occurs when REM sleep-related muscle atonia is lost. Body movements ranging from simple motions to highly elaborate enactment of dreams may occur, and typically begin 60-90 minutes following sleep onset.

Rhythmic movement disorder typically affects young children and is characterized by repetitive, stereotypic, rhythmic movements (eg, head banging, head rolling, body rolling, body rocking) that precede sleep onset and continue transiently into early light sleep. Sleep starts are brief asymmetric contractions of the extremities at sleep onset that can be accompanied by a feeling of "falling."

    
Management

Investigation and Treatment of Secondary Causes

Serology for iron, ferritin, folate, cobalamin, urea, and creatinine levels should be obtained. Patients with a history of iron deficiency should undergo a thorough evaluation to find an etiology. Serum transferrin saturation and ferritin levels should be measured before initiating iron therapy. Furthermore, patients who have histories suggestive of hemochromatosis, iron overload, elevated pretreatment transferrin saturation, or serum ferritin levels should be evaluated to determine the cause of these abnormalities before they are treated with iron. For all persons with RLS treated with oral iron supplementation, serum iron parameters should be remeasured once or twice yearly during therapy.[53]

Additional serology examinations for serum protein electrophoresis, antinuclear antibody, rheumatoid factor, thyroid stimulating hormone, liver function, and hemoglobin A1C should be considered if a peripheral neuropathy is suspected. Electrodiagnostic testing with nerve conduction studies and electromyography are useful to detect subtle peripheral neuropathies. A complete connective tissue disorder work-up should be conducted if clinically indicated.[54] A polysomnogram with esophageal pressure monitoring is warranted if other sleep disorders, such as upper airway resistance syndrome, are suspected.

Lifestyle Modification

Sleep hygiene. Conservative treatment begins with instituting proper sleep hygiene.[55] Well-established principles, such as adhering to fixed bedtimes and wake times, obtaining adequate amounts of sleep, and establishing proper nutritional intake, are important.[56]

Avoid exacerbating factors. Alcohol intake may aggravate both RLS symptoms and PLMS and should be avoided.[57] Caffeine increases nervous system arousal and heightens the toxic sensory experience of RLS.[58] Antidepressant medications such as fluoxetine, paroxetine, sertraline, mirtazapine, and mianserin have been reported to worsen RLS and/or PLMD.[59-64] Neuroleptics such as olanzapine and risperidone can also induce RLS.[65,66] Other medications, such as beta-blockers, phenytoin, zonisamide, methsuximide, and lithium, have been reported to worsen RLS symptoms.[67-70] Stress, shift work, and engaging in strenuous physical activity close to bedtime may also exacerbate RLS and/or PLMD.[71] There are conflicting results regarding the effect of tobacco smoking on symptoms of RLS and PLMS.[72,73]

Pharmacologic Agents

Using a pharmacologic agent to treat RLS is symptomatic and not curative. When initiating treatment with a pharmacologic agent, a number of factors should be considered, including the age of the individual, severity of symptoms, and frequency of symptoms. It is typically prudent to begin with the lowest medication dose and increase it gradually to the lowest effective dose. Medications should also be started at bedtime and adjusted to the patient's needs based on clinical results. Augmentation and rebound (Table 3) need to be considered. In augmentation, the symptoms of RLS develop earlier in the day (eg, morning or afternoon vs evening) and become more severe than the symptoms reported before treatment was started. Combination therapy with multiple pharmacologic agents may be necessary for some individuals.

Table 3. Characteristics and Treatment Strategies for Augmentation and Rebound

Augmentation  =Increase in symptom severity and involvement of other limbs.
Symptoms undergo time shift from bedtime to early evening to daytime.
Treatment:  

  1. Adding a middle-of-the-night dose.
  2. Switching to a dopamine agonist with a longer half-life or controlled-release levodopa.
  3. Using a combination of regular-release and controlled-release levodopa.

Rebound =  Wearing off of drug effect, typically in the morning.
Treatment:

  1. Reducing the dose of the provocative medication.
  2. Switching to an alternate dopaminergic medication with a longer half-life or to a different class of medication (opioid or anticonvulsant).
  3. Using a drug combination with a lower dopaminergic dose.

    
Dopamine Agonists

The dopamine agonists are considered by many to be the first-line treatment for RLS.

Nonergotamine Dopamine Agonists

The nonergotamine dopamine agonists are very effective for RLS and patients report infrequent and minimal side effects, such as nausea, dizziness, orthostasis, insomnia, and sleepiness.

  1. Pramipexole (Mirapex) has been shown to dramatically reduce the sensory discomfort of RLS and the frequency of PLMS.[76] The optimal dose range is 0.25-0.75 mg at bedtime. A single dose at bedtime seems to have lasting effects throughout the night and the following day. Furthermore, one study found the therapeutic effect to be intact 7.8 months after the initiation of treatment.[77]
  2. Ropinirole (Requip) is among the best-studied pharmacologic treatments for RLS,[78-84] with several double-blind, placebo-controlled studies and 1 open-label trial. In these studies, ropinirole has been shown to significantly reduce the sensory discomfort of RLS as measured by the IRLS scale. Furthermore, ropinirole at bedtime dramatically reduced the number of PLMS as well as the arousals caused by periodic limb movements.[83,84] The optimal dosage range of this medication is 0.25-4 mg. The benefits of ropinirole appear to remain intact 12 months after initial treatment.[85]

Ergotamine Dopamine Agonists

  1. Pergolide, when given at a mean dose of 0.51 mg 2 hours before bedtime, resulted in a reduction in PLMS and symptoms of RLS as well as an increase in total sleep time.[86] Pergolide has also been demonstrated to be superior to levodopa, with long-term follow-up demonstrating that efficacy persists after an average of 517 days.[87,88] These results suggest that augmentation may not be as significant a problem with pergolide as it is with levodopa.[89] The starting dose of pergolide is 0.05 mg at bedtime.
  2. Bromocriptine 7.5 mg at bedtime has been demonstrated to produce a subjective improvement in restlessness and paresthesias, reduce the number of PLMS, and improve sleep efficiency.[90] The usual starting dose is 1.25 mg at bedtime.
  3. Cabergoline at a mean dose of 2.1 mg and a range from 1-4 mg was found to be effective and well tolerated for patients with RLS, especially those with severe RLS and those who developed augmentation with levodopa therapy.[91]

Levodopa

Levodopa is administered with a peripheral decarboxylase inhibitor, usually in the form of carbidopa. One to 2 tablets of carbidopa/levodopa 25/100 mg can be taken 1-2 hours before bedtime to effectively reduce symptoms of RLS and PLMS.[92] However, once-a-night bedtime treatment with carbidopa/levodopa has been reported to result in morning end-of-dose, rebound worsening of periodic limb movements in about 25% of patients.[93] A controlled-release formulation of carbidopa/levodopa 50/200 mg can be given if this problem develops or if the patient's symptoms occur later in the night. A combination of regular-release levodopa and sustained-release levodopa may be ideal to reduce RLS symptoms and PLMS and to improve sleep quality.[94,95]

Levodopa has been demonstrated to be effective for RLS and PLMS. However, chronic treatment with levodopa, especially at doses above 200 mg, usually results in augmentation of RLS symptoms and periodic limb movements. The temptation to increase the dose of levodopa to overcome augmentation should be avoided because increasing the dosage only further exacerbates the problem. A medication change is required for 13% to 70% of patients and the best option is to switch to dopamine-agonist therapy.[96,97] Characteristics and treatment strategies for augmentation and rebound are summarized in Table 3.[98-100]

Benzodiazepines

Clonazepam has shown conflicting results in the treatment of RLS and PLMS. One small clinical trial found clonazepam to be ineffective for treating RLS.[101] Another small clinical trial found that clonazepam did not significantly reduce the number of PLMS but did improve the sleep of those individuals with insomnia.[102] However, other trials, including 2 small, double-blind studies, have demonstrated that clonazepam effectively reduces the sensory discomfort of RLS and number of PLMS.[103-105] The dose of clonazepam ranges from 0.5 to 2 mg at bedtime.

A study of temazepam at a dose of 30 mg at bedtime effectively treated the insomnia associated with PLMS but did not reduce the number of nocturnal myoclonic events.[106] Triazolam at a dose of 0.25-0.50 mg has been found to be effective in diminishing daytime sleepiness and improving sleep continuity and duration in patients with PLMS. Of note, although the frequency of periodic limb movements was unchanged, the frequency of associated arousals declined after treatment.[107] Alprazolam has also been suggested to possibly control the symptoms of RLS.[108]

Adrenergic Agonists

Clonidine at a mean dose of 0.05 mg per day has been shown to reduce the sensory symptoms of RLS but not the number of PLMS. Therefore, clonidine may be an effective treatment for patients with RLS who do not experience a large number of PLMS.[109]

Antiepileptic Drugs

Gabapentin improves the sensory and motor symptoms of patients with RLS and also improves sleep architecture and reduces the number of PLMS.  In a head-to-head comparison study of gabapentin vs ropinirole, both drugs were similarly effective in the treatment of RLS and PLMS.   The starting dose of gabapentin was 300 mg at bedtime, with a mean dose of 800 mg and range of 300-1200 mg.

Carbamazepine has been shown to be effective in treatment of the sensory discomfort of RLS.  However, treatment with carbamazepine does not modify the pattern of nocturnal myoclonus and its relationship to arousals during sleep.

Opioids

Oxycodone at an average dose of 15.9 mg subjectively reduces leg sensations and motor restlessness and improves daytime alertness. Furthermore, oxycodone significantly reduces the number of periodic limb movements and arousals during sleep.  When naloxone is given parenterally to patients treated with opioids for RLS and PLMS, their signs and symptoms of RLS and periodic limb movements have reappeared.  Long-term effectiveness ranging from 1 to 23 years has been documented in patients taking opioids for the treatment of RLS and PLMS.

N-Methyl-D-Aspartate (NMDA) Antagonists

Amantadine started at 100 mg daily and increased to a maximum of 300 mg daily has resulted in subjective improvement of RLS in 52% of patients. The mean effective dose was 227 mg daily. Oral ketamine has also been used to treat RLS.

Other Medications

Bupropion has not been associated with antidepressant-induced PLMD. On the contrary, treatment with bupropion has been found to reduce the objective measures of PLMD.  Consequently, bupropion may be appropriate for patients with depression and PLMD. Folate may ameliorate the symptoms of RLS in patients with acquired folate deficiency and those with familial symptomatology. Tramadol is a centrally acting analgesic that has fewer side effects and a lower abuse potential than opioids. Tramadol given at a dose ranging from 50 to 150 mg per day for 15-24 months resulted in clear amelioration of symptoms in 10 of 12 patients. No major tolerance to the treatment effect emerged among those who needed only a single evening dose.

Selegiline has been shown to reduce the number of PLMS. The alerting effect associated with the medication did not have a significant effect on sleep efficiency or sleep-onset latency. Entacapone is a catechol-O-methyltransferase inhibitor that increases the duration of action of carbidopa/levodopa. When given in conjunction with carbidopa/levodopa, it has resulted in longer periods of symptomatic relief in a patient with RLS.

    
Conclusions

RLS and periodic limb movement disorder are common neurologic disorders that may be associated with insomnia and excessive daytime sleepiness. They are prevalent conditions and easily diagnosed but often underrecognized. RLS should be suspected in any individual with leg discomfort in the evening or in bed. RLS is often idiopathic, but secondary causes, such as iron deficiency, should be investigated. Dopamine agonists are generally considered the first-line therapies; secondary therapies include anticonvulsants and opioids. Considerable research has been directed towards elucidating the basic mechanisms and optimizing the management of RLS and PLMD, but further research in this area is necessary.

    

     

2008

REF: Medscape 3-2004    http://www.medscape.com/viewarticle/468433_2