Restless Leg Syndrome

Article Author:
Abeera Mansur
Article Author (Archived):
Pablo Castillo
Article Editor:
Syed Rizwan Bokhari
7/28/2019 3:35:19 PM
PubMed Link:
Restless Leg Syndrome


Restless legs syndrome, or Willis-Ekbom Disease, is a common, chronic, multifactorial, movement disorder of the limbs in which patients have an irresistible urge to move the legs. This is often associated with abnormal, non-painful sensations that start at rest and are improved by activity. There is a diurnal pattern of worsened symptoms at night. There is sleep disturbance as well as an association with involuntary jerking movements of the legs during sleep known as periodic leg movements of sleep. In the United States, there are more than three million cases per year. 


There are two type of Restless Legs Syndrome. Primary Restless Legs Syndrome and Secondary Restless Legs Syndrome.  [1]

Secondary Restless Legs Syndrome can occur secondary to some disorders including:

  • Iron deficiency
  • End Stage Renal Disease
  • Pregnancy
  • Diabetes Mellitus
  • Rheumatic disease
  • Venous insufficiency
  • Peripheral neuropathy
  • Folate or magnesium deficiency
  • Amyloidosis
  • Lumbosacral radiculopathy
  • Fibromyalgia
  • Celiac disease
  • Medications have been known to cause or exacerbate the symptoms of Restless Legs Syndrome. They include antidopaminergic medications (e.g., neuroleptics), Diphenhydramine, Tricyclic antidepressants (TCAs), Selective serotonin reuptake inhibitors (SSRIs).


Between 5% to 15% of the population may have Restless Legs Syndrome. Familial Restless Legs Syndrome tends to occur at ages younger than 45 years. Age can be from childhood to older than 90 years.  Women are affected more than men. African Americans are less frequently affected as compared to whites. Eleven percent to 29% of pregnant women are affected. It is threefold more common in pregnant women than in the nonpregnant women and has a higher prevalence in the third trimester. [2] [3] As many as 25% to 50% of patients with end-stage renal disease have Restless Legs Syndrome with symptoms, particularly during hemodialysis. [4][5] 


In idiopathic Restless Legs Syndrome, a dysfunction of the dopaminergic system and iron stores in specific regions in the brain diminish. There may be an autosomal dominant inheritance; there have been reports of several large kindreds with different susceptibility loci with Restless Legs Syndrome. This suggests a genetic basis for the disease. 

Calcium/phosphate imbalance, anemia, functional iron deficiency, and subclinical peripheral nerve abnormalities may be involved in the pathophysiology of uremic Restless Legs Syndrome.

Vitamin D deficiency and calcium metabolism, pre-eclampsia, a strong family history, low serum iron and ferritin level, high estrogen level may also play a role in pregnancy. 

Polymorphisms in genes including BTBD9 and MEIS1 are associated with Restless Legs Syndrome.

Human neuropathologic and imaging studies have shown decreased iron in different brain regions including substantia nigra and thalamus. These areas also demonstrate a state of relative dopamine excess.[3] [6] [1]

Restless leg syndrome is extremely common during pregnancy, especially during the third trimester.

History and Physical

Terms that patients use to describe the symptoms include crawling, creeping, pulling, itching, drawing, or stretching, all localized to deep structures rather than the skin. Pain and tingling paresthesia of the type that occurs in painful peripheral neuropathy are usually absent, and there is no sensitivity to touching of the skin. Symptoms can range from some patients experiencing very mild problems to others having major disruption of sleep and impairments in quality of life. 

Symptoms typically worsen towards the end of the day and are maximal at night, when they appear within 15 to 30 minutes of reclining in bed. In severe cases symptoms may occur earlier in the day while the patient is seated, thereby interfering with attending meetings, sitting in a movie theater, and similar activities. In milder cases, patients will fidget, move in bed, and kick or massage their legs for relief. Occasionally, the arms may be affected. Patients with more severe symptoms feel forced to get out of bed and pace the floor to relieve symptoms. 

Periodic leg movements of sleep are characterized by involuntary, forceful dorsiflexion of the foot lasting 0.5 to five seconds and occurring every 20 to 40 seconds throughout sleep. There may be limb twitching during sleep. These occur in 80% of patients with Restless Legs Syndrome.

The physical examination is usually normal in patients with Restless Legs Syndrome. It is performed to identify secondary causes. 


There are no specific tests except the ones to rule out a secondary cause.

Essential diagnostic criteria (all must be met):[7]

  • An urge to move the legs usually but not always accompanied by, or felt to be caused by, uncomfortable and unpleasant sensations in the legs.
  • The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting.
  • The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.
  • The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day.
  • The occurrence of the above features is not solely accounted for as symptoms primary to another medical or a behavioral condition (e.g. myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping).

Treatment / Management

Avoid caffeine, antidepressants, antipsychotics, dopamine-blocking anti-emetics, and centrally acting antihistamines. Short daily dialysis in renal failure patients, iron replacement, exercise, massage, and heat can all alleviate the symptoms.

Dopamine agonists including pramipexole, ropinirole, rotigotine, and cabergoline have reduced symptoms, improved sleep quality, and quality of life. Pramipexole and ropinirole have adverse effects including gambling addiction and extreme weight gain.

The rotigotine transdermal patch can also be used. It is well tolerated and has a relatively low risk of clinically significant augmentation of restless legs syndrome.

In a large meta-analysis involving 3286 participants, pramipexole was shown to improve the symptoms of patients with primary moderate-to-severe Restless Leg Syndrome and may be better than ropinirole. In a small study, rotigotine improved periodic limb movements and Restless Leg Syndrome symptoms in the short term among end-stage renal disease (ESRD) patients. 

The use of alpha2-delta calcium-channel ligand (Gabapentin or Pregabalin) should be considered for initial treatment of those patients who have severe sleep disturbance, comorbid insomnia, anxiety, pain, or a previous history of an impulse control disorder (ICD). [8][9][10]

Restless leg syndrome in pregnancy usually resolves after delivery.

Pearls and Other Issues

With prolonged dopamine agonists use, there may symptoms may increase in severity despite appropriate treatment. There may be a requirement for an increase in the dose, with earlier onset of symptoms, spreading to unaffected parts, and shorter duration of action of the medication. This is known as Augmentation.

Restless Leg Syndrome may gradually worsen with age. The progression is slower in patients with the idiopathic form of the disease than for those who have an associated medical condition.

Enhancing Healthcare Team Outcomes

The diagnosis and management of restless leg syndrome is complex. The condition can be disabling and is best managed by an interprofessional team that includes a nurse practitioner, neurologist, internist and the primary care provider. While there are many drugs used to treat ths disorder, none has been shown to be superior to other classes. Plus, these drugs are not reliable or consistent in their efficacy. Relapses are common. More important, many patients develop adverse reactions to the drug and non-compliance is a major problem in the long run. Overall, the quality of life of patients with RLS is poor.[11]


[1] Restless Legs Syndrome/Willis-Ekbom Disease and Periodic Limb Movements: A Comprehensive Review of Epidemiology, Pathophysiology, Diagnosis and Treatment Considerations., Pratt DP,, Current cardiology reviews, 2016 Feb 23     [PubMed PMID: 26902775]
[2] Restless Legs Syndrome/Willis-Ekbom Disease and Pregnancy., Prosperetti C,Manconi M,, Sleep medicine clinics, 2015 Sep     [PubMed PMID: 26329442]
[3] Restless legs syndrome and pregnancy: prevalence, possible pathophysiological mechanisms and treatment., Gupta R,Dhyani M,Kendzerska T,Pandi-Perumal SR,BaHammam AS,Srivanitchapoom P,Pandey S,Hallett M,, Acta neurologica Scandinavica, 2015 Oct 19     [PubMed PMID: 26482928]
[4] Epidemiology, impact, and treatment options of restless legs syndrome in end-stage renal disease patients: an evidence-based review., Giannaki CD,Hadjigeorgiou GM,Karatzaferi C,Pantzaris MC,Stefanidis I,Sakkas GK,, Kidney international, 2014 Jun     [PubMed PMID: 24107848]
[5] Restless legs syndrome in patients on dialysis., Kavanagh D,Siddiqui S,Geddes CC,, American journal of kidney diseases : the official journal of the National Kidney Foundation, 2004 May     [PubMed PMID: 15112166]
[6] Restless Leg Syndrome in Neurologic and Medical Disorders., Askenasy N,Askenasy JJ,, Sleep medicine clinics, 2015 Sep     [PubMed PMID: 26329444]
[7] Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria--history, rationale, description, and significance., Allen RP,Picchietti DL,Garcia-Borreguero D,Ondo WG,Walters AS,Winkelman JW,Zucconi M,Ferri R,Trenkwalder C,Lee HB,, Sleep medicine, 2014 Aug     [PubMed PMID: 25023924]
[8] Rotigotine in Hemodialysis-Associated Restless Legs Syndrome: A Randomized Controlled Trial., Dauvilliers Y,Benes H,Partinen M,Rauta V,Rifkin D,Dohin E,Goldammer N,Schollmayer E,Schröder H,Winkelman JW,, American journal of kidney diseases : the official journal of the National Kidney Foundation, 2016 Feb 2     [PubMed PMID: 26851201]
[9] Efficacy of Pramipexole for the Treatment of Primary Restless Leg Syndrome: A Systematic Review and Meta-analysis of Randomized Clinical Trials., Liu GJ,Wu L,Lin Wang S,Xu LL,Ying Chang L,Fu Wang Y,, Clinical therapeutics, 2016 Jan 1     [PubMed PMID: 26572941]
[10] Randomized trials of dopamine agonists in restless legs syndrome: a systematic review, quality assessment, and meta-analysis., Zintzaras E,Kitsios GD,Papathanasiou AA,Konitsiotis S,Miligkos M,Rodopoulou P,Hadjigeorgiou GM,, Clinical therapeutics, 2010 Feb     [PubMed PMID: 20206780]
[11] McCullagh MC, Restless Legs Syndrome Negatively Impacts Worker Health and Safety. Workplace health     [PubMed PMID: 29897020]