1. RESTLESS LEGS AND PERIODIC LIMB MOVEMENTS
ANTONIO CULEBRAS, MD, FAAN, FAHA, FAASM
Professor of Neurology
SUNY Upstate Medical University
Syracuse, N.Y. USA
SLEEP CENTER TEACHING DAY PROGRAM
May 7, 2016

2. RLS Defined
Slide ID: 20795
The definition is from an RLS Workshop conducted at the National Institutes of Health in 2002, and published the following year.1
Patients characteristically experience RLS in their legs.1 With increasing severity, RLS may also affect the hips, the trunk, the arms, and even the face.2
The urge to move occurs during efforts to sleep or rest (that is, during sitting or lying down). Actual movements often occur. Typically, these are repetitive, semirhythmic, somewhat stereotyped, involuntary leg jerks known to physicians as periodic limb movements.1
On the sensory side, the patient’s unpleasant sensations are mainly a feeling that many patients find hard to describe: a sense of ache or tension—or a “creepy-crawly” feeling—arising deep in the leg or sometimes also in other parts of the body.1
References
Allen RP, et al, for the International Restless 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:
Allen RP, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005;165:
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3. Primary & Secondary RLS
Primary RLS
No apparent cause, except perhaps genetic predisposition1-3
Severe cases appear to be a chronic condition4
Since many patients do not seek treatment, little is known about the clinical course in milder and intermittent cases4
Secondary RLS
Associated with iron deficiency,5,6 end-stage renal disease,7 and pregnancy8
May remit on resolution of the causative condition (eg, after pregnancy)9
Pramipexole is indicated for the treatment of moderate to severe primary RLS but is not indicated for the treatment of secondary RLS.
For primary (or idiopathic) RLS, no obvious cause presents itself, but intriguing evidence suggests a genetic contribution. In one study, the syndrome’s prevalence was 16.5% for persons with an RLS patient among their first-degree relatives, compared with 3.5% for persons with no such affected relative1
Other studies have linked risk of RLS to certain chromosomal regions.2,3 Nevertheless, the research has not suggested the existence of an “RLS gene”1
The characterization of severe RLS as chronic emerges from extensive clinical experience, as summarized in 2002 at an RLS Workshop held at the National Institutes of Health4
For secondary RLS, a possible cause can be discerned. Among the known possibilities, three stand out: iron deficiency,5,6 end-stage renal disease,7 and pregnancy8
In secondary RLS, the possibility of remission is illustrated by a study in which the syndrome’s prevalence increased from 0% to 23% during pregnancy, but among the seven patients, only one continued to experience RLS afterward9
Allen RP, et al. Sleep Med. 2002;3:S3-S7.
Garcia-Borreguero D, et al. Neurology. 2003;61(6 suppl 3):S49-S55.
Desautels A, et al. Am J Hum Genet. 2001;69:
Allen RP, et al, for the International Restless Legs Syndrome Study Group. Sleep Med. 2003;4:
Akyol A, et al. Clin Neurol Neurosurg. 2003;106:23-27.
O'Keeffe ST, et al. Age Ageing. 1994;23:
Winkelman JW, et al. Am J Kidney Dis. 1996;28:
Berger K, et al. Arch Intern Med. 2004;164:
Lee KA, et al. J Womens Health Gend Based Med. 2001;10:
References
1Allen RP, La Buda MC, Becker P, Earley CJ. Family history study of the restless legs syndrome. Sleep Med. 2002;3:S3-S7; 2Garcia-Borreguero D, Odin P, Serrano C. Restless legs syndrome and PD: a review of the evidence for a possible association. Neurology. 2003;61(6 suppl 3):S49-S55; 3Desautels A, Turecki G, Montplaisir J, et al. Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am J Hum Genet. 2001;69: ; 4Allen RP, Picchietti D, Hening WA, et al, for the International Restless 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: ; 5Akyol A, Kiylioglu N, Kadikoylu G, et al. Iron deficiency anemia and restless legs syndrome: Is there an electrophysiological abnormality? Clin Neurol Neurosurg. 2003;106:23-27; 6O'Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing. 1994;23: ; 7Winkelman JW, Chertow GM, Lazarus JM. Restless legs syndrome in end-stage renal disease. Am J Kidney Dis. 1996;28: ; 8Berger K, Luedemann J, Trenkwalder C, et al. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. 2004;164: ; 9Lee 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. RLS Genetics: Familial Patterns
Slide ID: 20798
In brief, a family history is likely in RLS, and familial RLS is prone to start at an earlier age.1 Both these patterns suggest that genetic factors contribute substantially to causing RLS.2
The findings1 are from a German study of 300 RLS patients, among whom 232 had idiopathic RLS. The other 68 had secondary RLS ascribable to a patient’s uremia. (End-stage renal disease is a known cause of RLS.)
In the idiopathic RLS group, 42.3%, or almost half, had a definite family history, defined by verified findings for at least one first-degree relative. A further 12.6% had a possible family history, in which family members reported to have RLS could not be contacted for verification.
In the uremic RLS group, 11.7% had a definite family history (additional to the identified non-hereditary basis for their RLS), and a further 5.8% had a possible family history.
Patients with a definite family history were significantly younger at age of onset than those with a negative family history, at 35.5 vs 47.2 years (p < 0.05). RLS symptoms, however, were similar in both groups.
References
Winkelmann J, et al. Clinical characteristics and frequency of the hereditary restless legs syndrome in a population of 300 patients. Sleep. 2000;23:
Stefansson H, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007;357:
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5. RLS Prevalence in a Primary Care Population
Slide ID: 20800
The REST researchers also surveyed a sample of patients under the care of primary care physicians.
Across four European nations and the United States, the sample totaled 23,052 adults. Of this group, almost 10% described having RLS symptoms, and more than 3% described clinically relevant RLS, defined again by symptoms at least twice weekly plus a moderate to severe QOL detriment.
For 551 of the patients with clinically relevant RLS, follow-up questionnaires were completed both by the patients and by their physicians (data not shown on the slide). About two-thirds of these persons (357 patients, or 64.8%) said they had consulted a physician about their symptoms within the preceding year, but only a small proportion (46 people, or 12.9%) had received a diagnosis of RLS. The physicians felt that 209 of the patients (37.9%) had consulted them about RLS symptoms, and that 52 patients (24.9% of the 209) had been given an RLS diagnosis.
Reference
1. Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5:
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6. RLS Prevalence by Age % of Patients With RLS 5 10 15 20 25 Age (years)5 10 15 20 25
Age (years)
18-29
30-49
50-79
≥80
Ohayon (2002)
Rothdach (2000)
Phillips (2000)
Lavigne (1994)
Berger (2004)
Ulfberg (2001)
RLS prevalence by age has been investigated in several studies, as shown in the slide above
Lavigne et al identified a connection between RLS and sleep bruxism in 2,019 Canadians as early as 19941
Rothdach et al reporting results of the MEMO study found that in women, the prevalence did not change with age, whereas men showed a nonsignificant inverse trend with increasing age2
Experiencing restless legs five or more nights per month was reported by 3% of participants aged 18 to 29 years, 10% of those aged 30 to 79 years, and 19% of those 80 years and older by Phillips et al3
In Ulfberg et al the portion of the sample reporting RLS was 1.2% for the youngest and 10.5% among the oldest responders4
Ohayon et al determined that prevalence of RLS significantly increases with age5
Berger et al support the assertion that RLS frequency increased with age6
References
1Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep. 1994;17: ; 2Rothdach AJ, Trenkwalder C, Haberstock J, et al. Prevalence and risk factors of RLS in an elderly population: the MEMO study. Memory and Morbidity in Augsburg Elderly. Neurology. 2000;54: ; 3Phillips B, Young T, Finn L, et al. Epidemiology of restless legs symptoms in adults. Arch Intern Med. 2000;160: ; 4Ulfberg J, Nystrom B, Carter N, Edling C. Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms. Mov Disord. 2001;16: ; 5Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res. 2002;53: ; 6(K. Berger, MD, unpublished data).

7. RLS is Often Undiagnosed
Slide ID: 20801
This slide depicts the disparity between the large number of persons affected by RLS and the small number who receive treatment.
The RLS Epidemiology, Symptoms, and Treatment (REST) study surveyed a total of 23,052 primary care patients in five countries: the United States, France, Germany, Spain, and the United Kingdom.
About a tenth of them (2,223 survey respondents) described having weekly RLS symptoms, and of this group, about a fourth (551 people, shown in the top tier of this slide) were considered likely to warrant treatment, on the grounds of having symptoms at least twice a week and describing a negative impact on their quality of life.
About two thirds of these sufferers (357 people, or 64.8%) had, in fact, consulted a physician within the preceding year.
Yet only a small proportion (46 people, or 12.9%) had received a diagnosis of RLS.
Reference
1. Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5:
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8. Impact on QOL: RLS Patients vs the General Population
Slide ID: 20802
The Medical Outcomes Study 36-Item Short Form Health Survey (SF-36)1 is a well-validated questionnaire exploring health-related quality of life in eight “dimensions” or “domains,” on which higher scores correspond to better health. Although it is not an RLS-specific instrument, and in fact is confined to the respondent’s daytime activities, it offers detailed information on QOL.
Here the findings for three severities of RLS are from a total of 85 adults seen at a single sleep-medicine clinic.2 For the general population, the findings are US norms from the SF-36 Health Survey Manual and Interpretation Guide.3
In all domains, RLS patients, and especially those with severe RLS, exhibited deficits. Indeed, for six of the eight domains, the deficit attached to severe RLS approached or exceeded 40 points on the hundred-point scale.
References
Ware JE Jr, et al. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30:473-83
Abetz L, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. 2004;26:
Ware JE, et al. SF-36 Health Survey Manual and Interpretation Guide. Boston, MA: Health Institute, New England Medical Center; 1993
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9. RLS Impact on QOL Resembles the Impact of Major Diseases
100
Moderate to Severe RLS Patients US (n = 158)
Patients in the General Population with:
Type 2 Diabetes Mellitus (n = 541)
Osteoarthritis (n = 175)
Depression (n = 502) 80 60
Mean Score 40 20
The burden RLS imposes on quality of life can be as severe as that imposed by other chronic medical conditions
For these comparisons, the RLS patients were from the US subset of the REST study sample of the general population in six countries. All 158 in this sample were people classified as likely to warrant treatment for having moderately or severely distressing RLS at least twice a week. In the United States, the sample was large enough to permit comparisons with other US groups
The specific comparisons are between RLS and type 2 diabetes mellitus, osteoarthritis with hypertension, and depression. On all eight domains of the Short Form 36 Health Survey (SF-36), the RLS patients generally match patients with any of the other three conditions
Physical
Role Physical
Bodily Pain
General
Energy/
Social
Role
Mental Health
Functioning
Health
Vitality
Functioning
Emotional
SF-36 Health Survey Domain
Adapted from Allen RP, et al. Arch Intern Med. 2005;165:
Reference
Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005;165:

10. Most Troublesome RLS Symptoms Rated by Patients
Slide ID: 20804
These findings are from the REST study’s survey of primary care patients, and in particular from the 551 people reporting RLS symptoms at least twice a week and substantial negative impact on their quality of life
While sleep-related symptoms head a list of problems judged to be the most troublesome facets of RLS, leg symptoms that include an “uncomfortable feeling,” inability to “stay still” or “get comfortable,” and twitching have a major impact as well
On a list of symptoms or by write-in, the respondents were free to cite more than one symptom
The category of sleep-related symptoms encompassed a range of specific complaints, including inability to fall asleep or remain asleep
The symptoms above, while associated with RLS, do not serve as diagnostic criteria. Products approved for the treatment of RLS may not improve all of these symptoms.
Reference
Hening W, Walters AS, Allen RP, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5:
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11. Some Informal Clues to the Diagnosis
Slide ID: 20808
In brief, persons with RLS may not have realized that their sleep loss and fatigue represent RLS, and may even be at a loss to describe their RLS symptoms, especially the sensory ones.
The descriptive terms cited are from a long list published by the 2002 NIH Workshop.1 Seeking to characterize the descriptions, the Workshop noted that discomfort deep in the leg, rather than at the leg surface, appears to be a common theme.
On the motor side, the patient may describe a compulsion to move to obtain relief.1 Overall, patients’ descriptions emphasize that a diagnosis of RLS emerges from a thorough exploration of the patient’s history.
For epidemiologic RLS patterns, the REST General Population Study4 is illustrative. In that survey, the prevalence of RLS was roughly twice as high among women than among men, at 9.0% versus 5.4% for any frequency of symptoms, and 3.7% versus 1.7% for RLS sufferers (those with symptoms at least twice weekly and a moderate to severe QOL impact).
In the same survey, the prevalence of RLS sufferers increased through age 79, but 36.1% of RLS sufferers were less than 50 years old.
References
Allen RP, et al, for the International Restless 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:
Hening W, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5:
Benes H, et al. Definition of restless legs syndrome, how to diagnose it, and how to differentiate it from RLS mimics. Mov Disord Jun 12; [Epub ahead of print]
Allen RP, et al. Restless legs syndrome prevalence and impact: REST general population study. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005;165:
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12. RLS Essential Diagnostic Criteria
Urge to move legs, usually accompanied by uncomfortable leg sensations
Worsening of symptoms at rest or with inactivity, such as when lying or sitting
Worsening of symptoms in the evening and at night
Relief with movement —partial or total relief from discomfort by walking or stretching
A 2002 Workshop on RLS, held by the National Institutes of Health (NIH) in collaboration with the International RLS Study Group (IRLSSG), established four essential criteria—meaning that in this system all four are required to make the diagnosis. The four are
An urge to move the legs. Although some patients have only motor symptoms, most patients who seek treatment have also had sensory symptoms. The involuntary movements of RLS must be distinguished from unconscious repetitive movements such as foot tapping
Onset or worsening during rest or inactivity. As resting begins, motor and sensory symptoms may both be absent, but the likelihood and the intensity of each side of RLS increases as resting goes on. Ordinary discomfort such as stiffness from prolonged immobility is not RLS
Relief with movement. The relief is generally described as prompt, but it may not be complete, and in severe RLS it may have been possible only at earlier stages
Worsening (or occurrence) only in the evening or at night. In severe RLS with symptoms night and day, this too may be only the patient’s memory of earlier stages
Allen RP, et al, for the International Restless Legs Syndrome Study Group. Sleep Med. 2003;4:
Reference
Allen RP, Picchietti D, Hening WA, et al, for the International Restless 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:

13. A Single Screening Question1,2
Slide ID: 20806
In several countries, various wordings of such a question have now been validated.1 In one such report,2 521 consecutive patients seen at an Italian neurology clinic were asked it. By the four essential criteria displayed in the preceding slide, 112 of the patients had RLS (including 70 idiopathic cases). For diagnosing the syndrome, the sensitivity of the single question was 100%, and the specificity was 96.8%.
In asking the question, the crucial point is to establish whether a patient’s sleep disturbance is linked to a problem in the legs. (So asking only “How’s your sleep?” is not enough.) In this way, the question can facilitate a dialogue in which all four essential criteria should be explored.
References
Benes H, et al. Definition of restless legs syndrome, how to diagnose it, and how to differentiate it from RLS mimics. Mov Disord Jun 12; [Epub ahead of print]
Ferri R, et al. A single question for the rapid screening of restless legs syndrome in the neurological clinical practice. Eur J Neurol. 2007;14:
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14. Related Clinical Features
Slide ID: 20807
The 2002 NIH Workshop1 characterized several features of RLS as supporting the diagnosis in uncertain cases, or at least as deserving consideration when a potential RLS case is assessed. This slide lists four:
Sleep disturbance. Since resting provokes RLS and motor activity relieves it, RLS is doubly disruptive of sleep, in turn contributing to daytime tiredness and fatigue. Sleep disturbance is often the reason an RLS patient seeks medical help.
Involuntary leg movements. Classically defined as combining big-toe extension, ankle dorsiflexion, and sometimes knee and hip flexion, periodic limb movements (PLMs) now appear to have varied forms. Typically, however, they occur during sleep and in rhythmic sets. In polysomnography, a count of more than five per hour (a PLM Index, or PLMI, exceeding 5) throughout an entire night is considered pathological. Although the association between PLMs and RLS is unclear, PLMs occur in 85% or more of RLS patients. Even so, PLMs are not specific for RLS. The movements occur in other disorders, including obstructive sleep apnea, and are also common in elderly persons.
Family history. As noted in a previous slide, and also at the NIH Workshop, more than half of all idiopathic RLS patients report that at least one first-degree relative shares their RLS. Indeed, the Workshop described RLS patients as being three to six times more likely to have a family history of RLS than are persons without RLS.
Response to dopaminergic therapy. In many patients, levodopa or dopamine agonists consistently improve both the sensory and motor symptoms of RLS.
Reference
Allen RP, et al, for the International Restless 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:
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16. Diagnosis of RLS History Physical examination Laboratory tests
Review essential diagnostic criteria
Physical examination
Laboratory tests
Screen for renal failure2
Screen for diabetes2
Other tests for potential secondary causes if suspected2
Polysomnography1
Serum ferritin2
Diagnosis of RLS
History
Review essential diagnostic criteria
Physical examination
A neurological examination is normal in patients with the primary or secondary form of RLS, but patients with late-onset RLS symptoms may show evidence of a peripheral neuropathy or radiculopathy
Laboratory tests
Polysomnography is not indicated in evaluation of RLS!1
Serum ferritin2
Screen for uremia2
Screening for diabetes2
Other tests for potential secondary causes if suspected2
When evaluating RLS patients, it is important for the clinical to look for factors that may exacerbate symptoms of RLS (ie, end-stage renal disease, pregnancy, and iron deficiency), since these may alter the treatment plan or make effective treatment more difficult to establish.2
Kushida CA, et al. Sleep. 2005;28:
Allen RP, et al, for the International Restless Legs Syndrome Study Group. Sleep Med. 2003;4:
References
1Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters for the indications for polysomnography and related procedures: an update for Sleep. 2005;28: ; 2 Allen RP, Picchietti D, Hening WA, et al, for the International Restless 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:

17. Differential Diagnosis
Slide ID: 20809
In obedience to the sensorimotor nature of RLS, the disorders to be distinguished from RLS can be classified as those involving motor restlessness and those involving leg discomfort or pain.4
The motor-restlessness disorders are often fairly easy to distinguish from RLS (in that akathisia and PLMD, for instance, lack a sensory component).4
Sometimes, however, the relationship between RLS and an alternative diagnosis is clouded by overlap in symptoms, as described for depression,5 and in frequent occurrence as a comorbidity, as described for ADHD.6
References
Tan EK, et al. Motor restlessness. Int J Clin Pract. 2001;55:
Allen RP, et al, for the International Restless 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:
Garcia-Borreguero D, et al. Restless legs syndrome: an overview of the current understanding and management. Acta Neurol Scand. 2004;109:
Benes H, et al. Definition of restless legs syndrome, how to diagnose it, and how to differentiate it from RLS mimics. Mov Disord Jun 12; [Epub ahead of print]
Picchietti D, et al. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep. 2005;28:
Cortese S, et al. Restless legs syndrome and attention-deficit/hyperactivity disorder: a review of the literature. Sleep. 2005;28:
Hening W, et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 2004;5:
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18. …and for RLS Management
Slide ID: 20811
The algorithm displayed here is adapted from those devised by the Medical Advisory Board of the Restless Legs Syndrome Foundation, as published in 2004 in the Mayo Clinic Proceedings.1
The nonpharmacologic management options (at the left of the flow chart) are for any patient with RLS troublesome enough to require treatment but not necessarily so frequent as to require daily therapy.
Among mental alerting activities, crossword puzzles are cited.1 The goal is for the patient to engage in engrossing evening activities—the opposite of efforts to relieve typical insomnia.
Among medications capable of contributing to RLS, several classes are cited, including antidepressants, neuroleptics, dopamine-blocking antiemetics (eg, metoclopramide), and sedating antihistamines.1
A peripheral iron deficiency, as identified by the serum ferritin level (eg, less than 20 ng/mL,1 with iron saturation <20%1), is addressable by iron replacement therapy (eg, 325 mg of ferrous sulphate tid., preferably on an empty stomach, until serum ferritin normalizes, with each dose accompanied by 100 to 200 mg of vitamin C).1
The pharmacologic options (at the right of the flow chart) are for patients requiring daily therapy. When the algorithm was published, the US Food and Drug Administration had approved no drug for RLS, so all of those mentioned would have been given “off-label.” Even so, dopamine agonists were considered the drugs of choice. Since then, two such agents, pramipexole and ropinirole, have received FDA approval for patients with moderate to severe primary RLS. The two are the only agents currently approved for RLS.
For patients requiring daily therapy, gabapentin and low-potency opioids were considered alternative choices. Gabapentin was proposed especially for patients with RLS perceived as painful or occurring in combination with a painful peripheral neuropathy or a pain syndrome.
Owing to risk of augmentation,2 as described in the following slide, levodopa was considered an option (along with dopamine agonists, low-potency opioids, and benzodiazepines) only for intermittent RLS treatment.
References
Silber MH, et al. An algorithm for the management of restless legs syndrome. Mayo Clin Proc. 2004;79:
Earley CJ, et al. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep. 1996;19:
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19. Augmentation Defined Slide ID: 20812
A risk of long-term dopaminergic RLS treatment,1 augmentation is fundamentally a worsening of RLS symptoms attributable to an RLS therapy.
In published reports, the risk has been markedly greater for levodopa than for dopamine agonists.2,3 A 2006 European Consensus Conference4 added the cautionary remark that in the continuing absence of prospective, placebo-controlled augmentation data using standardized diagnostic criteria, comparative rates across drugs are still undetermined.
In diagnostic criteria developed at the 2002 NIH Workshop,5 augmentation most often takes the form of a shift of symptoms to at least 2 hours earlier, day or night, than had been typical before the treatment started or when the treatment had kept the RLS stable. More recently, the 2006 European conference urged 4-hour advance as the optimal standard.4
Both sets of recommendations describe diagnosis from other features. In the 2002 NIH recommendations,5 for instance, augmentation may be diagnosed from any two of six features: an increase in RLS symptoms at increased dosage; a decrease in symptoms at decreased dosage; shortened duration of a dose’s benefit; a decrease in latency to symptoms while resting; extension of symptoms to previously unaffected anatomic sites; worsening or beginning of periodic limb movements while awake.
The 2002 criteria5 require that for diagnosis, augmentation must have been present for at least 1 week at a level of at least 5 days a week. They also require that there be no alternative explanation, either medical, psychiatric, behavioral, or pharmacologic.
Regarding treatment: For clinically relevant augmentation in patients on a dopamine agonist, a recent review1 notes the absence of relevant clinical trials but suggests reduced and/or split agonist dosage, or else switching the patient to an opioid or gabapentin.
References
1. Garcia-Borreguero D, et al. Augmentation as a treatment complication of restless legs syndrome: Concept and management. Mov Disord Jun 19; [Epub ahead of print]
2. Earley CJ, et al. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep. 1996;19:
3. Winkelman JW, et al. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med. 2004;5:9-14
4. Garcia-Borreguero D, et al, for the International Restless Legs Syndrome Study Group. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute. Sleep Med. 2007;8:
5. Allen RP, et al, for the International Restless 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:
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20. Prevalence by Age and Gender from the REST Population-based Survey
LEVEL 1. Epidemiological studies have consistently found that RLS is more prevalent among females.93 RLS is a common disorder seen in 5-10% of the populations from Northern European decent. Prevalence for those severe enough to warrant medical attention is estimated to be around 2.7%.92
92. Allen RP, Walters AS, Montplaisir J, et al. Restless Legs Syndrome Prevalence and Impact: REST General Population Study. Arch Intern Med 2005;165(11):
93. Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther 2004;26(6):
Allen RP, Walters AS, Montplaisir J, et al. Restless Legs Syndrome Prevalence and Impact: REST General Population Study. Arch Intern Med 2005;165(11): 25

21. Restless Legs Syndrome in Pregnancy: Prevalence
Prevalence by Month of Pregnancy
Prevalence (%)
LEVEL 1. This chart describes the prevalence by questionnaire of RLS symptoms in pregnant women in Japan. Responses included in this chart are women who responded sometimes, often, or always. Overall, the prevalence in this population was 19.9%. As well, symptoms were slightly more common in teenage pregnant women and pregnant women in their 40’s. Effects could include decreased sleep time secondary to difficulty falling and maintaining sleep as well as excessive sleepiness. Most cases that first developed during pregnancy resolves post partum.
Prevalence rates in another study were similar, but slightly higher, at 26% for symptoms occurring more than 3 times/month. When limiting it to patients who had symptoms 3 times per week or more, the prevalence dropped to 15%. Restless legs, due to the discomfort and need to move, may reduce total sleep time (TST). In one study, it was demonstrated that TST was best in the healthy group (404 minutes±129) and worst in new onset of RLS during pregnancy (345 minutes±123).95
95. Suzuki K, Ohida T, Sone T, et al. The prevalence of restless legs syndrome among pregnant women in Japan and the relationship between restless legs syndrome and sleep problems. Sleep 2003;26(6):673-7.
3-4 Mo Mo Mo > 9 Mo.
Suzuki K, Ohida T, Sone T, et al. The prevalence of restless legs syndrome among pregnant women in Japan and the relationship between restless legs syndrome and sleep problems. Sleep 2003;26(6):673-7. 26

22. Educating Patients About RLS
Slide ID: 20821
Because of its unusual symptoms, many patients with RLS may feel uneasy when seeking medical attention. The healthcare provider can alleviate several concerns. The slide specifies some points of emphasis, all of which were documented in earlier slides.
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23. THE END