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Common Comorbidities and Differential Diagnosis of Restless Legs Syndrome

William G. Ondo, MD

Department of Neurology, University of Texas Health Science Center, Houston

Restless legs syndrome (RLS) is a common sensory motor disorder characterized by an urge to move a leg, which may or may not encompass some sort of paresthesias; a worsening of symptoms with physical and cognitive inactivity; transient improvement with motor and cognitive activity; and a worsening of symptoms in the evening and at night.1 Between 63% and 92% of patients report a family history of RLS, so a family history in first-degree relatives supports the diagnosis.2 Because no biomarkers or tests are available to aid in diagnosing RLS, clinicians should be aware of other conditions that mimic RLS or that are associated with secondary RLS.

Differential Diagnosis

Classic RLS is fairly easy to diagnose, but a number of conditions can mimic RLS. (For more information on diagnosing RLS, see “Screening for Sleep Disorders: Recognizing the Features and Presentations of Restless Legs Syndrome.”)

AV 1. Differential Diagnostic Criteria for RLS Vs Akathisia (1:25)

AV 1. Differential Diagnostic Criteria for RLS Vs Akathisia

Akathisia. Akathisia has a constellation of symptoms that resemble RLS more than any other condition (AV 1).2 Feelings of restlessness and an urge to move are central to both akathisia and RLS, but in akathisia, these feelings typically occur throughout the whole body. In RLS, the urge to move is confined to the limbs, primarily the legs. Akathisia may worsen at night, but it does not have the dramatic circadian pattern that RLS has nor is it as genetically robust.

Painful legs and moving toes (PLMT) and leg cramps. While PLMT is associated with a writhing movement of the toes, this syndrome generally does not coincide with an urge to move, which is essential for a diagnosis of RLS, nor does it improve with movement.3 Nocturnal leg cramps are extremely common and easy to distinguish from RLS. Unlike RLS, leg cramps have an acute onset and a true muscle contraction that can be touched.

Symptoms in children. Growing pains in children and adolescents can be easily confused with RLS.2 Growing pains are defined by pain but not the urge to move, which distinguishes them from RLS. On the other hand, while ADHD is not commonly confused with restless legs, children and adolescents who are diagnosed with ADHD have a higher incidence of RLS.4 Inattention and fidgetiness are symptoms of both RLS and ADHD in youth.5

Rare conditions. Vesper's curse is a rare condition related to congestive heart failure that causes nocturnal pain in the lower extremities.3 Like RLS, Vesper’s curse worsens when the patient is lying down and improves with movement. However, Vesper’s curse is associated with pain, specifically vascular claudication, rather than with symptoms more closely associated with RLS.

Orthostatic tremor, a rare condition in which patients are unsteady when standing, is characterized by a need to walk, rather than stand, in order to alleviate a feeling of poor balance, so they cannot stand still, which can be misdiagnosed as RLS.6 While these patients may also have RLS, the 2 remain distinct diagnoses.

Periodic limb movements in sleep (PLMS). PLMS is commonly associated with RLS but is not part of the clinical definition of RLS. The diagnosis of PLMS is made from a polysomnogram, and collaborative reports can also be obtained from a bed partner. While PMLS and RLS are different entities,3 studies1 have found that more than 80% of patients with RLS have PLMS. Therefore, PLMS is a supportive clinical feature of RLS.2

Psychogenic RLS. Psychogenic or malingering RLS is uncommon. However, because RLS has become part of the layperson’s lexicon, patients can complain of RLS criteria. There is little way to definitively differentiate this from true RLS.

Disorders Associated With RLS

Some diseases are associated with secondary RLS, and idiopathic RLS can be exacerbated by a variety of diagnoses and medications.

Iron deficiency. Reduced brain iron appears in patients with both idiopathic7 and secondary RLS, which can be caused by a systemic iron deficiency (AV 2).2 In older patients, RLS onset is more associated with low serum ferritin levels relative to having a family history of the condition, which is more common in younger onset RLS.8,9 Although reduced serum ferritin is the main indicator of low iron status, high serum ferritin levels do not rule out iron deficiency because they also indicate inflammation and normally increase with age.

AV 2. Iron Deficiency in RLS (1:15)

AV 2. Iron Deficiency in RLS

Renal failure. The next most common and robust association with secondary RLS is that of renal failure. RLS in these patients does not improve with dialysis, but it does improve with a successful transplant.10 Importantly, RLS increases the risk of mortality in patients with long-term dialysis.11

Neuropathy. Sensory symptoms of polyneuropathy are similar to those of RLS but are more likely to be located in the feet rather than the legs and are not alleviated with movement.2 The association between neuropathy and RLS is unclear. For example, Gemignani and colleagues12 found that, in 99 patients with neuropathy, one-third had RLS, and these patients were more likely to have small fiber sensory neuropathy than those without RLS. In another study,13 patients with neuropathy were not overall more likely than controls to have RLS, although an increase of RLS was found in patients with hereditary neuropathy compared with controls and patients with acquired neuropathy.

Multiple sclerosis (MS). The rate of RLS is higher among patients with MS than among controls.14 Manconi et al14 found that 19% of patients with MS had RLS symptoms 2 or more times per week for the past 6 months, compared with 4% of controls. Primary progressive MS tends to be the form most robustly associated with RLS. Older age, longer duration of illness, and global disability are also risk factors for RLS in the MS population.14

AV 3. Frequency of RLS According to Stage of Pregnancy (0:58)

AV 3. Frequency of RLS According to Stage of Pregnancy

Pregnancy. Approximately 11% to 27% of pregnant women meet criteria for RLS.15 The prevalence of RLS peaks in the last trimester, and RLS almost always resolves with delivery (AV 3).16 Multiple pregnancies seem to be a risk factor for transient RLS,17 and transient pregnancy-related RLS may be a risk factor for later development of idiopathic RLS.18 Low folate, low iron, and hormonal changes have been considered to be risk factors for RLS in pregnancy.15 However, most pregnant women take folate supplements now, and iron deficiency is difficult to assess during pregnancy because ferritin increases. A correlation probably exists between higher levels of estradiol and RLS.18

Parkinson’s disease. Symptoms of RLS are common in patients with Parkinson’s disease and, again, may be related to low serum ferritin levels.19 The presence of RLS in Parkinson's disease does not seem to be a major contributor to morbidity, and it does not seem to be associated with other sleep parameters in Parkinson's disease, which has a number of sleep abnormalities.20 In most cases, Parkinson's disease is the primary diagnosis.19 No evidence has shown that having RLS predicts the subsequent development or is a forme fruste of Parkinson's disease.2

Essential tremor. Essential tremor is also associated with higher rates of RLS. In one study,21 one-third of patients with essential tremor met criteria for RLS, many of whom had family histories of both RLS and essential tremor, suggesting a genetic association between the 2 conditions. Typically, RLS in patients with essential tremor is less severe than in those with only RLS and present with tremor rather than RLS.

Drug-induced RLS. A number of medications can markedly exacerbate RLS or precipitate latent RLS. Antihistamines, especially sedating antihistamines, frequently exacerbate RLS (almost immediately upon taking the drug) and cause jitteriness, anxiety, and insomnia.2 Additionally, because the most common treatments for RLS are dopamine agonists, dopamine blocking agents may worsen RLS.2 Antidepressants, particularly TCAs and SSRIs with anticholinergic/antihistaminergic properties, can also exacerbate RLS symptoms, but the presence of RLS is not an absolute contraindication to the use of antidepressant medications.


A number of diseases have symptoms that are often confused with those of RLS, and other conditions are associated with higher rates of RLS. What is not yet clear is whether or not secondary RLS is identical to idiopathic RLS or if RLS is a feature of the disease. However, it is clear in these associations that the pathology is different between RLS and the associated diseases. When treating an RLS patient, assess for associated disorders like tremor, renal failure, and iron deficiency. Other associated diagnoses, such as pregnancy and Parkinson's disease, are often self-evident but influence the treatment of the patient.

Clinical Points
  • Understand the diagnostic criteria for RLS
  • Differentiate between symptoms of RLS and those of disorders that are often confused with RLS
  • Recognize symptoms and disorders that often co-occur with RLS
  • Know which medications may induce or exacerbate RLS
  • ADHD = attention-deficit hyperactivity disorder
  • MS = multiple sclerosis
  • PLMS = periodic limb movements in sleep
  • PLMT = painful legs and moving toes
  • RLS = restless leg syndrome
  • SSRI = selective serotonin reuptake inhibitor
  • TCA = tricyclic antidepressants
Take the CME posttest.
  1. Allen RP, Picchietti D, Hening WA, et al, for the International Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology: a report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4(2):101–119. PubMed
  2. Satija P, Ondo WG. Restless legs syndrome: pathophysiology, diagnosis and treatment. CNS Drugs. 2008;22(6):497–518. PubMed
  3. Chaudhuri KR, Appiah-Kubi LS, Trenkwalder C. Restless legs syndrome. J Neurol Neurosurg Psychiatry. 2001;71(2):143–146. PubMed
  4. Picchietti DL, Stevens HE. Early manifestations of restless legs syndrome in childhood and adolescence. Sleep Med. 2008;9(7):770–781. PubMed
  5. Maheswaran M, Kushida CA. Restless legs syndrome in children. Med Gen Med. 2006;8(2):79. PubMed
  6. Gerschlager W, Münchau A, Katzenschlager R, et al. Natural history and syndromic associations of orthostatic tremor: a review of 41 patients. Mov Disord. 2004;19(7):788–795. PubMed
  7. Rizzo G, Manners D, Testa C, et al. Low brain iron content in idiopathic restless legs syndrome patients detected by phase imaging [published online ahead of print June 18, 2013]. Mov Disord. doi:10.1002/mds.25576. PubMed
  8. O'Keeffe ST. Secondary causes of restless legs syndrome in older people. Age Ageing. 2005;34(4):349–352. PubMed
  9. Allen RP, Earley CJ. Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset. Sleep Med. 2000;1(1):11–19. PubMed
  10. Azar SA, Hatefi R, Talebi M. Evaluation of effect of renal transplantation in treatment of restless legs syndrome. Transplant Proc. 2007;39(4):1132–1133. PubMed
  11. La Manna G, Pizza F, Persici E, et al. Restless legs syndrome enhances cardiovascular risk and mortality in patients with end-stage kidney disease undergoing long-term haemodialysis treatment. Nephrol Dial Transplant. 2011;26(6):1976–1983. PubMed
  12. Gemignani F, Brindani F, Vitetta F, et al. Restless legs syndrome in diabetic neuropathy: a frequent manifestation of small fiber neuropathy. J Peripher Nerv Syst. 2007;12(1):50–53. PubMed
  13. Hattan E, Chalk C, Postuma RB. Is there a higher risk of restless legs syndrome in peripheral neuropathy? Neurology. 2009;72(11):955–960. PubMed
  14. Italian REMS Study Group, Manconi M, Ferini-Strambi L, et al. Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study. Sleep. 2008;31(7):944–952. PubMed
  15. Manconi M, Govoni V, De Vito A, et al. Pregnancy as a risk factor for restless legs syndrome. Sleep Med. 2004;5(3):305–308. PubMed
  16. Lee KA, Zaffke ME, Baratte-Beebe K. Restless legs syndrome and sleep disturbance during pregnancy: the role of folate and iron. J Womens Health Gend Based Med. 2001;10(4):335–341. PubMed
  17. Neau JP, Marion P, Mathis S, et al. Restless legs syndrome and pregnancy: follow-up of pregnant women before and after delivery. Eur Neurol. 2010;64(6):361–366. PubMed
  18. Cesnik E, Casetta I, Turri M, et al. Transient RLS during pregnancy is a risk factor for the chronic idiopathic form. Neurology. 2010;75(23):2117–2120. PubMed
  19. Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson disease and restless legs syndrome. Arch Neurol. 2002;59(3):421–424. PubMed
  20. Swick TJ. Parkinson's disease and sleep/wake disturbances. Parkinsons Dis. 2012;2012(205471):doi:10.1155/2012/205471. PubMed
  21. Ondo WG, Lai D. Association between restless legs syndrome and essential tremor. Mov Disord. 2006;21(4):515–518. PubMed
From the Series:
Restless Legs Syndrome: Recognition, Diagnosis, and Treatment of a Common Sleep Disorder

Supported by an educational grant from UCB, Inc.

CME Background Information

Supported by an educational grant from UCB, Inc.


After completing this educational activity, you should be able to:

  • Complete a differential diagnosis to confirm RLS

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Ondo has received grant/research support from Ward Media, Dystonia Coalition, and Tremor Research Group and is a member of the speakers/advisory boards for Teva, UCB, Ipsen, Merz, and Lundbeck.

The Chair for this activity, Richard P. Allen, PhD, is a consultant for Xenoport, UCB, Pfizer, and Impax; has received grant/research support from Pharmacosmos, GlaxoSmithKline, and NIH; and has received honoraria from UCB.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.

Release, Review, and Expiration Dates

This Neurology Report was published in December 2013 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2016. The latest review of this material was October 2013.

Statement of Need and Purpose

Restless legs syndrome (RLS) is a common neurologic disorder of unknown etiology that causes significant distress. The symptoms of RLS—uncomfortable sensations that create an urge to move the legs that worsen during periods of rest and are relieved temporarily by movement—can severely disrupt sleep, leading to a reduced quality of life, daytime tiredness, a lack of energy, a disturbance of daily activities, and a tendency to become depressed. The prevalence and severity of RLS increase with age, and, due to the aging of the population, the personal and societal burden of RLS will become ever greater in coming years, increasing the need for prompt and effective treatment. Due to the nature of RLS symptoms, patients may seek treatment from a variety of health care providers, including primary care physicians, psychiatrists, and neurologists. However, even though diagnostic criteria for RLS have been established, patients are often misdiagnosed. In many cases, patients should be screened for RLS even though they do not directly report RLS symptoms. Health care providers should also be aware that the majority of people with insomnia never discuss sleep problems with their physicians and patients should, therefore, be routinely screened for sleep disturbances. Once RLS has been diagnosed, treatment is generally pharmacologic because sleep hygiene behaviors that promote relaxation or comfort may worsen or trigger RLS symptoms. However, mild exercise may relieve the symptoms long enough to let the patient get to sleep. Unfortunately, many patients are currently prescribed therapies not known to be effective in RLS, including analgesics, anti-inflammatories, and medications for gout and cramps. Clinicians need education on recognizing and assessing RLS symptoms in clinical practice and then treating RLS effectively to improve patients’ outcomes and quality of life. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on RLS.

Disclosure of Off-Label Usage

Dr Ondo has determined that, to the best of his knowledge, no information that is outside of US Food and Drug Administration–approved labeling has been presented in this activity.

Review Process

The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.


This Neurology Report is derived from the planning teleconference series “Restless Legs Syndrome: Recognition, Diagnosis, and Treatment of a Common Sleep Disorder,” which was held in June and July 2013 and supported by an educational grant from UCB, Inc. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.