Periodic Limb Movement Disorder

Periodic limb movement disorder (PLMD) is unique in that the movements occur during sleep. Most other movement disorders manifest during wakefulness. The condition is remarkably periodic, and the movements may cause poor sleep and subsequent daytime somnolence. PLMD may occur with other sleep disorders and is related to, but not synonymous with, restless legs syndrome (RLS), which is a movement disorder with sensory features that manifest during wakefulness. The majority of patients with RLS have PLMD, but the reverse is not true. Treatment involves either dopaminergic medication in an attempt to modify activity of the subcortical motor system or, more commonly, sedative medications to allow uninterrupted sleep. Many new agents are proving efficacious for treatment as well.

The etiology of the primary form of periodic limb movement disorder (PLMD) is uncertain. Suprasegmental disinhibition of the descending inhibitory pathways may be a factor. Vetrugno et al report that evidence supports neuronal hyperexcitability with involvement of the central pattern generator for gait as the pathophysiology of periodic limb movement.[1] This results in decreased dopamine transmission, potentially supporting the use of dopaminergic therapy to treat the condition.

Because the etiology is not clear, treatment is primarily to treat symptoms and does not modify the disease. Studies differ regarding the frequency of polyneuropathy in cases of PLMD. Martinez-Mena and Pastor found that only 1 of 9 patients had signs of neuropathy.[2]

The secondary forms of PLMD may be due to diabetes mellitus, spinal cord tumor, sleep apnea syndrome, narcolepsy, uremia, or anemia.[3] Many authors report an association between attention deficit hyperactivity disorder (ADHD) and PLMD. Family history of restless leg syndrome (RLS) may be a risk factor for PLMD, with a possible underlying genetic component mediated via single nucleotide polymorphisms in BTBD9, TOX3/BC034767 and MEIS1.[4]  Iron deficiency anemia has a well-known association with RLS, but more recently has also been found to be associated with periodic limb movement, with some studies suggesting a possible benefit to iron supplementation in patients with documented deficiency.[5]

Antidopaminergic, dopaminergic, or tricyclic drug therapy or cessation of treatment with barbiturates or benzodiazepines may initiate the syndrome as well.[6] Voderholzer et al noted an increased incidence of periodic limb movements during sleep in patients with Gilles de la Tourette syndrome.[7] However, the authors emphasized that the different responses to pharmacological treatments are evidence against a pathophysiological relationship between PLMD and Gilles de la Tourette syndrome.

Potential risk factors or etiologic factors for secondary PLMD include the following:

• Sleep apnea

• Narcolepsy

• Cataplexy

• Drug dependency

• Benzodiazepine withdrawal

• Barbiturate withdrawal

• Neuroleptic medication

• Dopaminergic medication

• Uremia

• Anemia

• Iron deficiency

• Spinal cord injury

• Diabetes mellitus

The prevalence of periodic leg movements in sleep (PLMS) is estimated to be 4–11% in adults.[8] PLMS are most frequently a symptom of restless legs syndrome (RLS). They also often occur in narcolepsy, sleep apnea syndrome, and rapid eye movement (REM) sleep behavior disorder (RBD). Some patients with otherwise unexplained insomnia or excessive daytime sleepiness exhibit an elevated number of PLMS, a condition defined as periodic limb movement disorder (PLMD).

The idiopathic form of periodic limb movement disorder (PLMD) may be chronic. Relapses and remissions may occur, but treatment does not appear to modify the disease.

The secondary form of this syndrome may cease with treatment of the underlying cause.

Picchietti et al suggested that the sleep disruption in periodic limb movement disorder (PLMD) could contribute to the inattention and hyperactivity of some children who have ADHD.[9]

Some research suggests that periodic limb movements with arousals are associated with subsequent nonsustained ventricular tachycardia (NSVT). A study of older men in their 70s and 80s found that periodic limb movements during sleep with arousal was associated with a threefold increased risk for NSVT shortly after the episode.[10]

Informing the bed partner of the condition is important so that potentially negative physical contact may be explained on a neurological (rather than an intentional) basis.

For excellent patient education resources, visit eMedicineHealth's Sleep Disorders Center. Also, see eMedicineHealth's patient education articles Periodic Limb Movement Disorder, Restless Legs Syndrome, Sleep Disorders in Women, and Sleep Disorders and Aging.

Periodic limb movement disorder (PLMD) is characterized by periodic episodes of repetitive limb movements during sleep, which most often occur in the lower extremities. These movements may cause awakening during the night resulting in excessive daytime sleepiness. Often, the presenting complaint is poor sleep or unexplained insomnia and daytime somnolence.[11] Researchers report that sleep changes induced by periodic limb movements during sleep are associated with decreased physical and psychological fitness on awakening.[12]

Leg movements associated with PLMD are stereotyped and involve one or both limbs. The movement simulates triple flexion with leg flexion, ankle dorsiflexion, and great toe extension; it lasts approximately 2 seconds and thus is not consistent with the rapid jerk that defines true myoclonus. The periodicity ranges from 20 to 40 seconds with a variable duration. The movements are said to occur mainly in non-REM sleep.

Occasionally, a bed partner may provide the history of limb movements.

Nozawa et al studied arousal index and movement index in PLMD and noted that the sleep-wake disorders associated with periodic limb movement relate to threshold of awakening.[13]

Growing evidence suggests a link between restless legs syndrome (RLS) and PLMD. Picchietti et al provide evidence supporting the concept that PLMD may be a marker for an RLS genotype.[14]

The patient history may include ADHD. Walters et al provide an association between ADHD and sleep movement disorders including PLMD.[15]  There also appears to be a high prevalence of periodic limb movements of sleep in children with Down syndrome.[16]

PLMD and epilepsy are both common at the population level, however, little research has been done to establish the prevalence of periodic limb movements during sleep in people with a history of epilepsy. A few studies regarding this association have been published, though most did not adjust for potential confounding factors. Thus, further studies are warranted to determine the prevalence of PLMD in patients with a diagnosis of epilepsy.[17]

RLS and periodic limb movements during sleep are also common in patients with a history of spinal cord injury.[18]

While some patients with increased periodic limb movements during sleep may have an underlying etiology, it is important to recognize that these movements are not always indicative of a medical condition and have been shown to occur in up to 7.7% of healthy children.[19]

Because anemia, uremia, hyperglyecemia, and iron deficiency can lead to a secondary form of periodic limb movement disorder (PLMD), laboratory screening studies should be obtained to rule out such metabolic abnormalities.

A urine drug screen may be appropriate.

Definitive diagnosis of periodic limb movement disorder (PLMD) requires polysomnography.[20] Obtaining a sleep study to evaluate for PLMD, obstructive sleep apnea (OSA), and other underlying sleep disorders may be especially useful in patients with generalized and persistent fatigue, including those with diagnosed depression and in whom antidepressant therapy has been ineffective.[21] Observation in a sleep laboratory allows documentation of the movements and rapid diagnosis.

Periodic leg movements in sleep (PLMS) are a common symptom in restless legs syndrome and are a frequent finding in polysomnography. An elevated number of PLMS are defined as PLMD.

Variability from night to night occurs in both adults and children with documented PLMD.[22]

 

The Stanford PLM automatic detector (S-PLMAD) is a robust, automated leg movement detector used to score periodic limb movement functions. According to one study, the S-PLMAD works well in controls and sleep disorder patients.[23]

Additional testing, such as cerebrospinal fluid (CSF) analysis or magnetic resonance imaging (MRI) of the brain, may be warranted if the patient history and clinical presentation are suggestive of pathologies such as sporadic Creutzfeldt-Jakob disease or fatal familial insomnia, as sleep disturbances including periodic limb movement disorder (PLMD) are common features of these conditions.[24]

A 2012 update of treatment guidelines from the American Academy of Sleep Medicine indicate that although there are no studies of dopaminergic medication effects on periodic limb movement disorder (PLMD), many of the studies of dopaminergic medication effects on restless legs syndrome looked at periodic limb movements of sleep.[25]

According to the American Academy of Sleep Medicine practice parameters, the dopaminergic agents pramipexole, ropinirole, rotigotine, and the combination of carbidopa/levodopa/entacapone, were shown in some studies to decrease periodic limb movement indices. Gabepentin and pregabalin also showed benefit in studies of subjects with restless legs syndrome (RLS).[25]

Some evidence shows that exercise therapy and cognitive-behavioral psychological intervention may provide benefit in periodic limb movement disorder (PLMD).[26]

Klassen et al report improvement with deep brain stimulation in Parkinson patients with PLMD.[27]

Although often suggested based on anecdotal evidence, magnesium supplementation has not been shown to provide significant relief of symptoms in patients with PLMD or restless legs syndrome (RLS).[28]

Therapy does not modify the disease but does relieve symptoms. The arsenal of medication options is expanding and includes dopaminergic medications,[29, 30, 31] antiepileptic agents, and even opioids, although the controlled substances may not be appropriate first-line agents. Although the benzodiazepine clonazepam has been shown to reduce the number of periodic limb movements per hour in periodic limb movement disorder (PMLD) patients, PLMD comorbid with RBD has been associated with a poor treatment response to clonazepam monotherapy.[32] Because most studies focused on restless legs syndrome (RLS), a similar and related (but separate) disorder, the best treatments for PLMD are not known. However, using RLS guidelines, dopaminergic agents are first-line treatment.

Class Summary

The efficacy of clonazepam in reducing the total number of periodic limb movements per hour has been reported.[33, 34]  However, benzodiazepines are not without risk, especially for certain patient populations, and thus their use should be carefully considered.

Clonazepam (Klonopin)

Useful in suppressing muscle contractions by facilitating action of GABA and other inhibitory neurotransmitters.

Class Summary

The levodopa/carbidopa combination has been considered an effective treatment for this condition in specific patients; on the other hand, some studies suggest that the medication may be the etiology of secondary periodic limb movement disorder in other patients. Pieta and colleagues studied pergolide in patients with secondary periodic limb movement disorder caused by uremia and found subjective improvement in sleep quality and objective reduction in limb movements during the first hour of sleep; however, no objective improvement in sleep architecture was observed.[35]

Ropinirole (Requip, Requip XL)

Second-generation, nonergoline dopamine agonist that directly stimulates dopamine receptors in the brain. Possesses high specificity for D3 receptor subtype. Indicated for moderate-to-severe restless legs syndrome.

Pramipexole (Mirapex, Mirapex ER)

D2 and D3 receptor agonist recently approved by FDA for treating Parkinson disease; also used effectively in patients with restless legs syndrome.

Carbidopa/levodopa (Sinemet)

Large neutral amino acid absorbed in proximal small intestine by saturable carrier-mediated transport system. Absorption decreased by meals, which include other large neutral amino acids. However, only patients with meaningful motor fluctuations need consider low-protein or protein-redistributed diet. Greater consistency of absorption achieved when levodopa taken > 1 h after meals. Nausea often reduced if taken immediately following meals. Some patients with nausea benefit from additional carbidopa up to 200 mg/d.

Half-life approximately 2 h.

Most common acute adverse effects are nausea, hypotension, and hallucinations. Long-term adverse effects include motor fluctuations and dyskinesia (chorea).

Pergolide (Permax)

Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to abruptly stop pergolide. Health care professionals should assess patients' need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.

Studies in patients with secondary PLM disorder caused by uremia revealed subjective improvement in sleep quality and objective reduction in limb movements during first hour of sleep; however, no objective improvement in sleep architecture was observed.

Class Summary

These agents are useful in managing severe muscle spasms.

Gabapentin (Neurontin)

Mechanism of action uncertain; although has GABA-like structure, action at GABA receptors not shown clearly. Fortunately, considered relatively safe and thus may be considered for PLM disorder.

Class Summary

These agents exert their effects by inhibiting release of excitatory neurotransmitters.

Baclofen (Lioresal)

GABA agonist at slower potassium channels in cerebellum and spinal cord. May have efficacy in PLM disorder. Because works in spinal cord and less in brain cortex, calls into question neurologic origin of PLM.

Tiagabine (Gabitril)

Antiepileptic agent FDA approved for adjunctive treatment of certain seizure types. Recent evidence supports use in PLM disorder possibly because of GABA enhancing activity or because of improved sleep quality. FDA approved for seizures at doses up to 56 mg/d. Evidence suggests that use for PLM disorder requires far lower doses, possibly 4-8 mg at bedtime.