eMedicine Specialties > Neurology > Sleep-Related Diseases

Periodic Limb Movement Disorder

Wayne E Anderson, DO, Assistant Professor of Internal Medicine/Neurology, Western University of Health Sciences; Assistant Professor of Family Medicine, Touro University College of Osteopathic Medicine; Consulting Staff in Pain Management, Department of Neurology, California Pacific Medical Center

Updated: Aug 26, 2009

Introduction

Background

Periodic limb movement (PLM) disorder 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. Periodic limb movement disorder may occur with other sleep disorders and is related to, but not synonymous with, restless legs syndrome (RLS), a less specific condition with sensory features that manifest during wakefulness. The majority of patients with restless legs syndrome have periodic limb movement disorder, 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.

Symonds first described periodic limb movement disorder in 1953. The original name, nocturnal myoclonus, does not describe the condition accurately, since the movements are slower than are those of myoclonus. The term nocturnal myoclonus is seldom used today.

Pathophysiology

The etiology of the primary form of periodic limb movement disorder is uncertain. Suprasegmental disinhibition of the descending inhibitory pathways may be a factor. Vetrugno and colleagues 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 periodic limb movement disorder. Martinez-Mena and Pastor found that only 1 of 9 patients had signs of neuropathy.²

The secondary forms of periodic limb movement disorder may be due to diabetes mellitus, spinal cord tumor, sleep apnea syndrome, narcolepsy, uremia, or anemia. Many authors report an association between attention deficit hyperactivity disorder (ADHD) and periodic limb movement disorder. Antidopaminergic, dopaminergic, or tricyclic drug therapy or cessation of treatment with barbiturates or benzodiazepines may initiate the syndrome as well. Voderholzer and colleagues noted an increased incidence of periodic limb movements during sleep in patients with Gilles de la Tourette syndrome.³ However, the authors emphasized that the different responses to pharmacological treatments are evidence against a pathophysiological relationship between periodic limb movement disorder and Gilles de la Tourette syndrome.

Frequency

United States

The exact frequency is not known.

International

The exact frequency is not known.

Mortality/Morbidity

Comorbid conditions may include other sleep disturbances or coexisting disorders (see Causes). The morbidity of periodic limb movement disorder itself is related to sleep disturbance.

Age

Prevalence increases with increasing age. The idiopathic form is rare before age 40 years.

Clinical

History

• Unexplained insomnia is a possible presenting symptom of periodic limb movement disorder.⁴
• The presenting symptom may be stereotyped periodic limb movements that cause awakening during the night, but often the presenting complaint is poor sleep and daytime somnolence. Haba-Rubio et al report that sleep changes induced by periodic limb movements during sleep are associated with decreased physical and psychological fitness on awakening.⁵
  • Occasionally, a bed partner may provide the history of limb movements.
  • Nozawa and colleagues studied arousal index and movement index in periodic limb movement disorder and noted that the sleep-wake disorders associated with periodic limb movement relate to threshold of awakening.⁶
• Leg movements 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 20-40 seconds with a variable duration. The movements are said to occur mainly in non–rapid eye movement (REM) sleep.
• Growing evidence suggests a link between restless legs syndrome and periodic limb movement or sleep disorder. Picchietti et al provide evidence supporting the concept that periodic limb movement disorder may be a marker for an RLS genotype.⁷
• The patient history may include ADHD. Walters et al provide an association between ADHD and sleep movement disorders including periodic limb movement disorder.⁸

Physical

Physical and neurological examinations are normal. In some cases, excessive somnolence may be noted.

Causes

Potential risk factors or etiologic factors for secondary periodic limb movement disorder 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

Differential Diagnoses

Other Problems to Be Considered

Anemia
Back pain
Benign epilepsy syndromes
Iron deficiency
Myoclonic epilepsy
Myoclonus
Paroxysmal kinesigenic choreoathetosis
Sleep apnea
Spinal injury

Workup

Laboratory Studies

• Because anemia, uremia, and the use of tricyclic antidepressant, antidopaminergic, or dopaminergic medications can lead to a secondary form of periodic limb movement disorder, laboratory screening studies should be obtained to rule out anemia or significant metabolic abnormalities.
• A urine drug screen may be appropriate.

Other Tests

Sleep laboratory

• Definitive diagnosis requires polysomnography.
• Observation in a sleep laboratory allows documentation of the movements and rapid diagnosis.
• Variability from night to night occurs in both adults and children with documented periodic limb movement disorder.⁹

Treatment

Medical Care

Patient reassurance is essential.

Consultations

Because the differential diagnosis of periodic limb movement disorder includes seizure and other forms of myoclonus, a neurology consultation is indicated to exclude other conditions.

Medication

Therapy does not modify the disease but does relieve symptoms. The arsenal of medication options is expanding and includes dopaminergic medications^10,11 , antiepileptic agents, and even opioids, although the controlled substances may not be appropriate first-line agents. Because most studies focused on restless legs syndrome, a similar and related (but separate) disorder, the best treatments for periodic limb movement are not known. However, using restless legs syndrome guidelines, dopaminergic agents are first-line treatment.

Benzodiazepines

The efficacy of clonazepam in reducing the total number of periodic limb movements per hour has been reported.^12,13

Clonazepam (Klonopin)

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

Dosing

Adult

0.5-3 mg PO qhs; in some cases, tid schedule used

Pediatric

Not established

Interactions

Clearance may be increased and effects reduced by phenytoin and barbiturates; toxicity of benzodiazepines in CNS significantly increased when used concurrently with other CNS depressants

Contraindications

Documented hypersensitivity; severe liver disease; acute narrow-angle glaucoma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Causes sedation; should not be used with alcohol; habit forming; use caution in patients with chronic respiratory disease or impaired renal function; withdrawal symptoms can result from abrupt discontinuation

Dopaminergic agents

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.¹⁴

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).

Dosing

Adult

Effective dose varies; can be as low as 10/100 mg PO qhs

Pediatric

Not established

Interactions

Effects decreased by hydantoins, pyridoxine, phenothiazine, and hypotensive agents; toxicity increased by antacids or MAOIs.

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; malignant melanoma; undiagnosed skin lesions

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Certain adverse CNS effects (eg, dyskinesias) occur at lower dosages and earlier in therapy with sustained release form; use caution in patients with history of myocardial infarction, arrhythmias, asthma, peptic ulcer disease; may worsen Parkinson disease if discontinued suddenly; patients on high-protein diets should distribute protein intake throughout day to avoid fluctuations in levodopa absorption

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.

Dosing

Adult

0.05 mg/d PO initial dose; titrate to > 1 mg/d in divided doses

Pediatric

Not established

Interactions

Use caution with dopamine antagonists such as antipsychotics and gastric motility agents; use with levodopa may cause or exacerbate preexisting states of confusion and hallucinations or dyskinesia; because >90% bound to plasma proteins, use caution if coadministered with other drugs known to affect protein binding

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adverse effects include hypotension; use caution in patients who have been treated for cardiac dysrhythmias

Anticonvulsants

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.

Dosing

Adult

300 mg/d PO initial dose; increase by 300 mg/d each week until 900 mg tid or 1200 mg tid; more rapid titration appears to increase somnolence and dizziness

Pediatric

Not established

Interactions

Bioavailability may be reduced significantly by antacids–wait > 2 h following antacid administration; may increase norethindrone levels significantly

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use caution in severe renal disease and elderly patients

Skeletal muscle relaxants

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.

Dosing

Adult

5 mg (1/2 tab) PO qhs; increase slowly to avoid sedation and other adverse effects, by 10 mg/d q5d; not to exceed 40 mg tid

Pediatric

Not established

Interactions

Effects may be increased by opiate analgesics, benzodiazepines, alcohol, tricyclic antidepressants, guanabenz, MAOIs, clindamycin, and hypertensive agents

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Use caution when spasticity utilized to obtain increased function and in patients with history of autonomic dysreflexia; withdrawal can cause autonomic dysreflexia; use caution in renal impairment

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.

Dosing

Adult

4-8 mg PO hs; titration may begin at 2 mg hs with an increase of 2-4 mg/wk

Pediatric

Not studied for the off-label use of PLM disorder

Interactions

Cleared more rapidly in patients treated with carbamazepine, phenytoin, primidone, and phenobarbital than in patients not treated with these drugs

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

For on-label use, patients receiving valproate monotherapy may require lower doses or a slower dose titration for clinical response; moderately severe to incapacitating generalized weakness has been reported following administration in up to 1% of patients with epilepsy; weakness may resolve after reduction in dose or discontinuation of drug; should be withdrawn slowly to reduce potential for increased seizure frequency; slow titration is recommended, beginning at 2 mg hs

Follow-up

Further Inpatient Care

Periodic limb movement disorder may be treated on an outpatient basis. Diagnosis may involve an overnight stay in a sleep laboratory.

Further Outpatient Care

Efficacy of treatment should be determined at the time of follow-up visits. If no information from a bed partner was available at the time of initial evaluation and diagnosis, such information, if available, can help to determine the effectiveness of treatment.

Complications

Picchietti and colleagues suggested that the sleep disruption in periodic limb movement disorder could contribute to the inattention and hyperactivity of some children who have ADHD.¹⁵

Prognosis

• The idiopathic form of this syndrome 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.

Patient Education

• 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 eMedicine's Sleep Disorders Center. Also, see eMedicine's patient education articles Periodic Limb Movement Disorder, Restless Legs Syndrome, Sleep Disorders in Women, and Sleep Disorders and Aging.

References

1. Vetrugno R, D'Angelo R, Montagna P. Periodic limb movements in sleep and periodic limb movement disorder. Neurol Sci. Jan 2007;28 Suppl 1:S9-S14. [Medline].

2. Martinez-Mena JM, Pastor J. [Polyneuropathy in patients with periodic leg movements during sleep]. Rev Neurol. Nov 1998;27(159):745-9. [Medline].

3. Voderholzer U, Müller N, Haag C, Riemann D, Straube A. Periodic limb movements during sleep are a frequent finding in patients with Gilles de la Tourette's syndrome. J Neurol. Aug 1997;244(8):521-6. [Medline].

4. Ferri R, Gschliesser V, Frauscher B, Poewe W, Högl B. Periodic leg movements during sleep and periodic limb movement disorder in patients presenting with unexplained insomnia. Clin Neurophysiol. Feb 2009;120(2):257-63. [Medline].

5. Haba-Rubio J, Staner L, Krieger J, Macher JP. What is the clinical significance of periodic limb movements during sleep?. Neurophysiol Clin. Dec 2004;34(6):293-300. [Medline].

6. Nozawa T, Ichikawa H, Takeuchi T. Periodic limb movements and sleep-wake disorder. Psychiatry Clin Neurosci. Apr 1998;52(2):192-4. [Medline].

7. Picchietti DL, Rajendran RR, Wilson MP, Picchietti MA. Pediatric restless legs syndrome and periodic limb movement disorder: Parent-child pairs. Sleep Med. Mar 20 2009;[Medline].

8. Walters AS, Silvestri R, Zucconi M, Chandrashekariah R, Konofal E. Review of the possible relationship and hypothetical links between attention deficit hyperactivity disorder (ADHD) and the simple sleep related movement disorders, parasomnias, hypersomnias, and circadian rhythm disorders. J Clin Sleep Med. Dec 15 2008;4(6):591-600. [Medline].

9. Picchietti MA, Picchietti DL, England SJ, Waiters AS, Couvadelli BV, Lewin DS, et al. Children show individual night-to-night variability of periodic limb movements in sleep. Sleep. Apr 1 2009;32(4):530-5. [Medline].

10. Littner MR, Kushida C, Anderson WM, et al. Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. May 1 2004;27(3):557-9. [Medline].

11. Hening WA, Allen RP, Earley CJ, et al. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. May 1 2004;27(3):560-83. [Medline].

12. Inami Y, Horiguchi J, Nishimatsu O, et al. A polysomnographic study on periodic limb movements in patients with restless legs syndrome and neuroleptic-induced akathisia. Hiroshima J Med Sci. Dec 1997;46(4):133-41. [Medline].

13. Horiguchi J, Inami Y, Sasaki A, et al. Periodic leg movements in sleep with restless legs syndrome: effect of clonazepam treatment. Jpn J Psychiatry Neurol. Sep 1992;46(3):727-32. [Medline].

14. Pieta J, Millar T, Zacharias J, et al. Effect of pergolide on restless legs and leg movements in sleep in uremic patients. Sleep. Sep 15 1998;21(6):617-22. [Medline].

15. Picchietti DL, England SJ, Walters AS, et al. Periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. J Child Neurol. Dec 1998;13(12):588-94. [Medline].

16. Iriarte J, Urrestarazu E, Alegre M, et al. Oscillatory cortical changes during periodic limb movements. Sleep. Dec 15 2004;27(8):1493-8. [Medline].

17. Mello MT, Silva AC, Rueda AD, et al. Correlation between K complex, periodic leg movements (PLM), and myoclonus during sleep in paraplegic adults before and after an acute physical activity. Spinal Cord. Apr 1997;35(4):248-52. [Medline].

18. Ulfberg J, Jonsson R, Lindberg E, et al. [Restless legs. A much neglected syndrome]. Lakartidningen. Mar 10 1999;96(10):1183-4, 1187-8. [Medline].

19. [Guideline] Vignatelli L, Billiard M, Clarenbach P. EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep. Eur J Neurol. Oct 2006;13(10):1049-65. [Medline].

20. Wetter TC, Pollmacher T. Restless legs and periodic leg movements in sleep syndromes. J Neurol. Apr 1997;244(4 Suppl 1):S37-45. [Medline].

Keywords

periodic limb movement disorder, PLM, restless leg syndrome, RLS, nocturnal myoclonus, sleep disorders, PLMS, periodic limb movements during sleep, ADHD, attention deficit hyperactivity disorder, PLM disorder, diabetes mellitus, spinal cord tumor, sleep apnea syndrome, narcolepsy, uremia, anemia, sleep disturbances, sleep apnea

Contributor Information and Disclosures

Author

Wayne E Anderson, DO, Assistant Professor of Internal Medicine/Neurology, Western University of Health Sciences; Assistant Professor of Family Medicine, Touro University College of Osteopathic Medicine; Consulting Staff in Pain Management, Department of Neurology, California Pacific Medical Center
Wayne E Anderson, DO is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Society of Law Medicine and Ethics, California Medical Association, and San Francisco Medical Society
Disclosure: Cephalon Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; King Honoraria Consulting

Medical Editor

Sydney Louis, MB, BCh, MD, Emeritus Professor, Department of Neurology, Brown University School of Medicine
Sydney Louis, MB, BCh, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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