Abstract | Restless legs syndrome
characterized by a distressing urge to move the legs and sometimes also therapies fail to sufficiently mitigate 2004 other parts of the body, usually RLS, treatment with dopaminergic agents or opioids frequently brings of discomfort or pain in the leg or relief. Therapy with select anticon- triggered by rest or inactivity, and patients. New research with familial relieved or suppressed by movement. It follows a circadian pattern, with disorder can be relatively mild or variety of genetic factors and other effects on a patient’s sleep and daily occurring in conjunction with other iron deficiency anemia, pregnancy, or end-stage renal disease. It has represents a primary factor in the List of Contributors
Table of Contents
Current and Former Members
of the RLS Foundation Medical
Advisory Board

Introduction . . . . . . . . . . . . . . . . . . . . . . 3
Features . . . . . . . . . . . . . . . . . . . . . . . . . 3
Charles H. Adler, MD, PhD,Mayo Graduate School of Medicine Pathophysiology . . . . . . . . . . . . . . . . . . . 7
Richard P. Allen, PhDJohns Hopkins Sleep Disorder Center Disease. . . . . . . . . . . . . . . . . . . . . . . . . . 9
Mark J. Buchfuhrer, MD, FRCP(c), FCCP Prevalence . . . . . . . . . . . . . . . . . . . . . . 10
Genetics . . . . . . . . . . . . . . . . . . . . . . . . 11
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 13
Johns Hopkins Bayview Medical Center Treatment . . . . . . . . . . . . . . . . . . . . . . . 14
Bruce Ehrenberg, MDTufts University School of Medicine Summary . . . . . . . . . . . . . . . . . . . . . . . 23
Chair, RLS Foundation MedicalAdvisory Board References . . . . . . . . . . . . . . . . . . . . . . 23
Research Grants . . . . . . . . . . . . . . . . . . 29
Wayne A. Hening, MD, PhDUMDNJ - RW Johnson Medical School William Ondo, MDBaylor College of Medicine Daniel Picchietti, MDCarle Clinic Association David B. Rye, MD, PhDEmory University School of Medicine Michael H. Silber, MB, ChBMayo Medical School Max-Planck Institute of Psychiatry Arthur S. Walters, MDNew Jersey Neuroscience Institute John W. Winkelman, MD, PhDHarvard Medical School Marco Zucconi, MDH San Raffaele Scientific Institute andHospital 819 Second Street SW | Rochester MN 55902-2985 USA Introduction and History of Restless
Features of Restless Legs Syndrome
Legs Syndrome
reported to be helpful in controllingthe symptoms of RLS.(8;9) Diagnostic Criteria
This urge to move the legs is usually fortable and unpleasant sensations tions. Sometimes the arms or other body parts are involved in addition terms as uncomfortable and inside the leg, or compare the sensations to 507-287-6465 | Email [email protected] | www.rls.org Table 1 | Features of RLS
A. Essential criteria: These primary
features must be present for a
diagnosis of RLS.
1. An urge to move the legs, usually during periods of rest or inactivity, in the legs (Sometimes the urge to move is present without the uncom- involved in addition to the legs.) periods of rest or inactivity such as sensations are partially or totally walking or stretching, at least as sensations are worse in the evening only occur in the evening or night. severe, the worsening at night may B. Supportive clinical features of RLS:
Presence of these features may help
resolve any diagnostic uncertainty.
1. Periodic limb movements (during deficit is likely to be worst,(22) nor is 3. Response to dopaminergic therapy C. Associated clinical features: These
activity leading to reduced alertness.
features may provide additional
information about the patient’s
1. Natural clinical course following 819 Second Street SW | Rochester MN 55902-2985 USA lasts, the more likely it is to give rise to be made; in severely affected patients, sensations are worse in the evening sensations of RLS are partially or totally relieved by movement, such only occur in the evening or night. as walking or stretching, at least as long as the activity continues. Supportive Clinical Features of RLS
Parkinson’s disease.(27-35) This initial 507-287-6465 | Email [email protected] | www.rls.org Table 2 | Representative patient
descriptions of RLS sensations in
• Like Coca Cola bubbling through my veins Associated Features of RLS
• Like maggots crawling through my limbs 1. Natural clinical course following certain bance may be a less significant issue.
819 Second Street SW | Rochester MN 55902-2985 USA RLS Pathophysiology
into three areas: 1) localization of anatomic substrate; 2) neurotransmit- ter systems; and 3) iron metabolism. Anatomic Localization of Dysfunction
for the different periodicities some-times noted in different limbs of the Associated with RLS
3. Medical evaluation/physical examination nology of the PLM observed with RLS.
dopamine agonists to reduce theperipheral adverse effects without 507-287-6465 | Email [email protected] | www.rls.org Neurotransmitter Systems Involved
Brain Dopaminergic Function in RLS
night when subjects are symptomatic.
819 Second Street SW | Rochester MN 55902-2985 USA Opioid vs Dopaminergic System
Involvement in RLS
Opiates provide good treatment with RLS severity.(56;57) In one study, interesting pattern of decreased ferritin or a high transferrin or both.
Iron Metabolism and RLS
— regional brain iron insufficiency.
Disease Course
lase, the rate-limiting enzymatic stepin the production of dopamine.
507-287-6465 | Email [email protected] | www.rls.org from getting a good night’s sleep.
It is now clear that symptoms of presence of RLS symptoms; 5.9% of associations to body mass index, Sweden,(101;102) Chile,(103) and Europe(104) reported “leg restlessness at bedtime”; 819 Second Street SW | Rochester MN 55902-2985 USA Table 3 | Criteria for the diagno-
sis of definite RLS in children
and Iceland). A major susceptibilitylocus for RLS has been reported on a 1. The child meets all four essential Genetics of RLS
2. The child relates a description in his or her own words that is consis-tent with leg discomfort. (The child Astrong familial component in Quebec.(115) The significance of this may use terms such as oowies, tick- le, spiders, boo-boos, want to run, describe symptoms. Age-appropriate “familial,” 25% to 40% of first-degree 1. The child meets all four essential 2. Two of three following supportive Supportive criteria for the diagnosis of definite b) A biologic parent or sibling has individual’s first-degree relatives (i.e., c) The child has a polysomnographi- RLS — best characterized as “spo-radic” — typically appear in later RLS in Children
507-287-6465 | Email [email protected] | www.rls.org to as low as zero have been suggested.
cases.(118;120;122;123;127-134) Some of these pains.”(117-119) In others, the leg-jerk- Pregnancy
common in these children.(118;119;121-126) individual responses to strict limit-set- Diagnosis
819 Second Street SW | Rochester MN 55902-2985 USA Table 4 | Differential diagnosis
• Leg pains from arthritis or other disorder percent ferritin saturation, and totaliron-binding capacity. With findings End-stage Renal Disease
62%,(132;144-153) though due to the vari- 507-287-6465 | Email [email protected] | www.rls.org Treatment
The goal of any medical therapy, patient (e.g., video games, computer agents, and most antipsychotics.
Nonpharmacologic Therapies
For patients with mild RLS, non- most lower-limb symptoms (includ- strated.) Bupropion, a dopamine- sclerotherapy or “vein stripping”) is exacerbate RLS, often rather severely.
Substances to Avoid
819 Second Street SW | Rochester MN 55902-2985 USA Table 5 | Primary pharmacologic
agents for treatment of RLS
de novo leg and sleep symptoms that as long as there is careful monitoring.
Pharmacologic Treatments
erbate restlessness.(164;165) This interac- Primary Treatments
507-287-6465 | Email [email protected] | www.rls.org Dopaminergic Agents
Dopamine Precursors
Dopamine-receptor Agonists
819 Second Street SW | Rochester MN 55902-2985 USA Ergotamine Dopamine Agonists
trolled trials(30-32) have shown efficacy Non-ergotamine Dopamine Agonists
quality of life, and severity of RLS.
relief of restlessness” and the remain- golide and 6 patients discontinued it.
507-287-6465 | Email [email protected] | www.rls.org their use of other pharmacotherapies.
patients with Parkinson’s disease.
819 Second Street SW | Rochester MN 55902-2985 USA tific confirmation in controlled trials.
tions to treat a long-term condition.
Benzodiazepines and Other Sleeping Pills
507-287-6465 | Email [email protected] | www.rls.org the greatest benefit from gabapentin.
patients treated over a 5-week period.
819 Second Street SW | Rochester MN 55902-2985 USA Secondary Treatment
used with only the greatest caution.
Treatment in Special Populations
End-stage Renal Disease
in alfa(85) and the use of clonidine(218) side or resolve following childbirth.
Deficiency States
507-287-6465 | Email [email protected] | www.rls.org of ferritin were seen after treatment.
stores is that the gastrointestinal tract (ferritin <5 mcg/L), the gastrointesti- ferritin level is in the normal range.
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507-287-6465 | Email [email protected] | www.rls.org Restless Legs Syndrome Foundation
The Restless Legs Syndrome Foundation is a nonprofit 501(c)3 organization that provides information about RLS; develops support groups; funds research to find better treatments and, eventually, a definitive cure; and publishes aquarterly newsletter known as NightWalkers. Annual updates to this medical bulletin are available free of charge from the RLS Foundation. In addition, the RLS Foundation provides complimentary copies of our patient-education brochure,Living with Restless Legs. Your support of the RLS Foundation helps to underwrite the cost of these publications, entitles you to receive quarterlycopies of our newsletter, and funds the RLS Foundation’s research and education programs.
If you would like to receive brochures for your office, to receive publications, or for more information, please contact theRLS Foundation.
RLS Foundation, Inc. | 819 Second Street SW | Rochester MN 55902-2985Telephone (507) 287-6465 | Fax (507) 287-6312 | E-mail [email protected] | Website www.rls.org Restless legs syndrome can be a serious disorder. Persons suspecting that they may have RLS should contact a qualified healthcare provider. Literature concerning RLS that isdistributed by the Restless Legs Syndrome Foundation, Inc., is offered for information purposes only and should not be considered a substitute for the advice of a healthcareprovider. 2004 Restless Legs Syndrome Foundation, Inc. RLS Foundation, Inc.
819 Second Street SWRochester MN 55902-2985

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