The Six Ds of RLS diagnosis and treatment.

By Philip M. Becker, MD, and Muhammad Sattar, MD

Diagnosing and treating difficult cases of restless legs syndrome (RLS) can be a complicated task, but identifying and managing the disorder can be less daunting when putting the “six Ds” into practice:

  1. diagnosis incorrect (consider primary versus secondary etiology);
  2. drug side effects;
  3. drug is ineffective;
  4. dosage is too low;
  5. dyssomnia from other sources
    1. depression
    2. anxiety;
  6. dopaminergic augmentation.

Cases of RLS can take unexpected twists, potentially leading patients to a knotted state of mismanagement. Proper use of the six Ds can help practitioners untangle difficult RLS cases and facilitate proper care. Mr D, the subject of this case report, required shifts in strategic management for his RLS and became a testimony to the positive outcomes when the six Ds are put into practice.


RLS is a neurosensorimotor disorder. Refractory RLS causes significant discomfort/pain, insomnia, and impairment in social function. The US incidence of RLS was reported in 2005 as 9.7% (11% of women and 8% of men).1 A Canadian survey estimated the prevalence of RLS symptoms at 17% for women and 13% for men,2 while in Singapore a study yielded much lower prevalence, 0.6% in an older and 0.1% in a younger cohort.3

Although etiology for RLS remains unknown, hypotheses include dysfunctional iron regulation4 or dopamine deficit in the central nervous system.5 In studies of potential candidate genes, links to familial RLS have been found on chromosome 12q6 and periodic limb movements of sleep (PMLS) with and without restless legs syndrome on chromosome 6p21.2.7

Ropinirole and pramipexole are approved treatments of RLS, although off-label therapies are common—clonazepam, gabapentin, pregabalin, levodopa, and opiates. Initial response to drug therapy is seen in about 70% to 80% of patients, but successful long-term management of moderate to severe RLS frequently requires pharmacologic adjustment and combination therapy.8 The Medical Advisory Board of the Restless Legs Syndrome Foundation (RLSF) has proposed the RLSF algorithm based on frequency of symptoms to assist clinicians in the management of patients with RLS.9


Mr D, age 64, presented with a 24-year history of severe sleep onset insomnia. He denied daytime sleepiness. The insomnia coincided with the development of bilateral discomfort deep in each of his calves beginning with watching evening TV. The leg discomfort was “kind of painful.” He was in and out of bed three or four times to walk. He was in good health with mild snoring, hypertension controlled by beta blocker, and a stable weight with BMI of 27. Neurologic examination was normal. Chemistries, including serum ferritin at 68 ng/ml, were normal. A clinical diagnosis of moderate-severe restless leg syndrome was made. He was started on pramipexole at 0.125 mg at 17:00 and 0.25 mg at 21:00 for a 23:30 bedtime.

For 3 years, he reported sleeping well for 7 or more hours. RLS symptoms then presented earlier at 13:00. Over 1 year, pramipexole was adjusted, eventually reaching 0.25 mg at 12:00, 0.25 mg at 17:00, and 0.5 mg at 21:00. RLS symptoms then presented as early as 11:00 with infrequent involvement of the arms. Recheck of ferritin was 62 ng/ml. Mr D met criteria for augmentation of RLS. A taper and discontinuation of pramipexole occurred over 2 weeks. Concurrently, the high-potency, longer-acting opiate levorphanol tartrate was increased to 2 mg one half tablet at 17:00 and one tablet at 22:00, and he reported excellent relief of RLS and normal sleep.

Four years into levorphanol therapy, he developed daytime sleepiness. Snoring had worsened. Polysomnography demonstrated 19 obstructive apnea/hypopneas per hour and minimal central events. Nasal CPAP to 8 CWP was titrated, but adherence was poor. A change to an oral appliance was accepted, but sleepiness did not improve (Epworth sleepiness score of 14). Modafinil, taken as needed, improved sleepiness with no change in RLS symptoms while continuing levorphanol.


The RLSF algorithm defines refractory patients as having nearly daily RLS symptoms with ineffective therapeutic response, intolerable side effects, and/or augmentation. We propose assessment of these difficult RLS patients using the six Ds to enhance case management.


Ask whether the diagnosis is correct. Early in their course, refractory patients should have met the four essential clinical criteria to diagnose RLS. The first author has proposed the acronym “URGE” to assist assessment:

  1. Urge to move is the core symptom of RLS that is uniquely described by the patient. More than 25% of patients use the term “painful.”
  2. Rest, eg, sitting or lying still, increases symptom presentation. RLS symptoms manifest when the individual is in a resting position. They are not positional discomfort from the temporary compression of a nerve or vessel (“leg is asleep”).
  3. Gyration or Going relieves or reduces the symptoms. However, if the person stops moving, the symptoms may return.
  4. Evening/night worsening represents circadian influences on RLS presentation.

Primary or idiopathic RLS is common. Secondary RLS can arise from iron dysregulation and neurologic disorders. Secondary causes of RLS include pregnancy (>30% presentation in the last trimester), end stage renal disease (30%-70%), anemia,10,11 Charcot-Marie-Tooth disease (35%),12 Parkinson’s disease (20%),13 and ADHD (26%).14 Neuropathy can also increase RLS presentation.

RLS mimics should be excluded and include leg cramps, noted in up to 50% of seniors15 from muscle fatigue, vascular disease, or metabolic disturbance; primary akathisia; and secondary akathisia from treatment with neuroleptics and metoclopramide (Reglan).

Do not confuse RLS with PLMS. Approximately 80% of patients with RLS have PLMS, and 30% of patients with PLMS have RLS symptoms. To lessen confusion, consider the following:

RLS PLMS Comparisons

 PSG = polysomnography, EDS = Excessive daytime sleepiness

Neurological examination is usually normal in idiopathic cases. Iron deficiency has been defined as a ferritin level <18 ng/ml or a transferrin saturation <16%. Ferritin levels <50 ng/ml in RLS patients should result in treatment with oral iron supplementation (ferrous sulfate 325 mg with vitamin C 100 mg up to tid on an empty stomach for better iron absorption).

Polysomnography is not needed for the diagnosis of RLS, unless other sleep disorders are suspected.


Side effects to therapy may limit dosing or complicate therapy. The FDA-approved dopaminergic agents for RLS cause nausea, vomiting, dizziness, excessive sedation, worsening of insomnia, and peripheral edema. Although less frequent in RLS patients than in patients with Parkinson’s disease, any use of dopaminergic medications should be closely observed for pathological sleepiness, compulsive gambling, and hypersexuality.


Responsiveness to therapies may be reduced in iron-deficient patients. Supplemental iron should be considered in these patients. Approximately 25% of patients receiving ropinirole16 or pramipexole17 responded inadequately in large clinical trials. Addition or change to another therapeutic agent is needed.

RLS Medication and Dosage


In cases of insufficient response, dose increase should be considered. Unless limited by side effects, treatment should be adjusted until reaching “trigger” dosage, highest dose, or intolerable side effects.


Literature review by Picchietti and Winkelman18 indicated that symptoms of depression are common in adults with RLS. The relationship appears complex with overlap between RLS and depressive symptoms. In another study, Saletu et al reported RLS patients have more symptoms of depression and anxiety (on the Zung Self-Rating Depression and Anxiety Scales) and lower quality of life than healthy controls.19

In refractory RLS patients, clinicians should review all medications that are taken by the patient. Most antidepressants and lithium have been reported to exacerbate RLS. Most SSRI reduce CNS dopamine transmission (exception high dose venlafaxine) and may worsen RLS and PLMS.20 Bupropion21 and trazodone may reduce PLMS and are considered to be the preferred agents for depression in RLS.

Another confound is the similarity of clinical symptoms or consequences of RLS and mood disorders.


Augmentation is defined as RLS symptoms that develop 4 hours earlier than pretreatment symptoms. Additionally, augmentation can be diagnosed if symptom onset presents 2 hours earlier plus at least two of the following:

  • spread to other body areas;
  • rapid increases in severity;
  • worsening with increased dose;
  • improvement with decreasing dose;
  • shorter periods of relief from a dose.22

Augmentation occurs in 70% of patients treated with levodopa,23 as compared to 20% to 35% of patients who are on dopamine agonists like pramipexole.24,25 The risk of augmentation is apparently reduced when levodopa is used less than three times per week.

The RLSF algorithm outlines four options of pharmacologic management of augmentation.9

  1. Change timing of dosing or to a different dopamine agonist;
  2. Change to gabapentin;
  3. Add a second agent such as benzodiazepine or a low-potency opioid to reduce dose of dopamine agonist;
  4. Change to high-potency opioid.

In summary, treatment strategies should be based on symptom frequency and severity. All patients should limit caffeine consumption past noon, obtain exercise in midday, and avoid use of decongestants and antihistamines. For intermittent RLS, the risk of augmentation from treatment is lower with prn dosing, so ropinirole, levodopa-carbidopa 25/100, or sedative-hypnotics can be offered as needed up to three times per week. For near daily RLS, the dopamine agonists, particularly pramipexole or ropinirole, would be the drugs of choice. Alternative therapies include gabapentin, pregabalin, codeine, propoxyphene, and tramadol, particularly if the patient’s RLS includes other painful conditions. The most severe patients benefit from high-potency, long-acting opiates such as methadone, levorphanol, and fentanyl patch. Treatment of RLS should be individualized with consideration of age, concomitant medications, other diseases, and history of augmentation or rebound. Future medication options will likely include the Neupro patch (rotigotine) and gabapentin enacarbil.

Philip M. Becker, MD, is clinical professor, and Muhammad Sattar, MD, is a sleep medicine fellow at the Sleep Medicine Fellowship Program, Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas.


  1. Phillips B. Prevalence and correlates of restless leg syndromes from the 2005 National Sleep Foundation Poll. Chest. 2006;129:76-80.
  2. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep. 1994;17:739-43.
  3. Tan EK, Seah A, See SJ, et al. Restless leg syndrome in an Asian population; a study in Singapore. Mov Disord. 2001; 16:577-9.
  4. Allen RP, Earley CJ. Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol. 2001;18:128-147.
  5. Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function in restless leg syndrome. Neurology. 1999;52:932-37.
  6. Desautels A, Turecki G, Montplaisir J, et al. Dopaminergic neurotransmission and restless legs syndrome: a genetic association analysis. Neurology. 2001;57:1304–6.
  7. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007;357:639-647.
  8. Earley CJ. Clinical practice. Restless legs syndrome. N Engl J Med. 2003;348:2103-9.
  9. Silber M, Ehrenberg B, Allen R, et al. An algorithm for the management of restless leg syndrome. Mayo Clin Proc. 2004;79: 916-922.
  10. Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep. 1998;21:371-710.
  11. Aul EA, Davis BJ, Rodnitzky RL. The importance of formal serum iron studies in the assessment of restless leg syndrome. Neurology. 1998;51:912.
  12. Gemignani F, Marbibi A, Di Giovanni G, Salih S, Terazano MG. Charcot Marie-Tooth disease type 2 with restless legs syndrome. Neurology. 1999;52:1064-1066.
  13. Ondo WG, Vuong KV, Khan H, Atassi F, Kwak C, Jankovic J. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology. 2001;57:1392-1396.
  14. Wagner ML, Walters AS, Fisher BC. Symptoms of attention-deficit hyperactivity disorder in adults with restless legs syndrome. Sleep. 2004;27:1499-1504.
  15. Abdullah AJ, Jones PW, Pearce VR. Leg cramps in the elderly: prevalence, drug and disease association. Int Clin Pract. 1999;53:494-6.
  16. Bogan R, Fry J, Schmidt MH. Treat RLS US Study Group. Mayo Clin Proc. 2006;8(1):17-27.
  17. Winkelman JW, Sethi KD, Kushida CA, Becker PM. Efficacy and safety of pramipexole in restless legs syndrome. Neurology. 2006;67:1034-1039.
  18. Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep and depression. Sleep. 2005;28:891-8.
  19. Saletu B, Anderer P, Saletu M, Hauer C, Lindeck-Pozza L, Saletu-Zyhlarz G. EEG mapping, psychometric, and polysomnographic studies in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) patients as compared with normal controls. Sleep Med. 2002;3(suppl):S35–42.
  20. Rottach KG, Schaner BM, Kirch MH, et al. Restless legs syndrome as side effect of second generation antidepressants. J Psychiatr Res. 2008;43(1):70-5.
  21. Kim SW, Shin IS, Kim JM, Yang SJ, Shin HY, Yoon JS. Bupropion may improve restless legs syndrome: a report of three cases. Clin Neuropharmacol. 2005;28:298–301.
  22. Garcia D, Allen RP, Kohnen R, Hogl B. Diagnostic standards for dopaminergic augmentation of restless legs syndrome. Sleep Med. 2007;8:520-530.
  23. Earley CJ, Allen RP. Pergolide and carbidopa/levodopa treatment of the restless leg syndrome and periodic limb movements in sleep in a consecutive series of patients. Sleep. 1996;19;801-810.
  24. Silber M, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome: an extended study. Sleep. 2003;26:819-821.
  25. Hening WA, Allen RP, Earley CJ, et al. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27:560-583.