Restless legs syndrome: differential diagnosis and management with pramipexole

Figures & data

Table 1 NIH diagnostic criteria of RLS

Essential criteria An urge to move the legs, usually accompanied or caused by uncomfortable or unpleasant sensations in the legs. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting. The urge to move or 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 or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night.

Supportive clinical features Positive family history of RLS. Response to dopaminergic therapy. Periodic limb movements during wakefulness or sleep (PLMs)*.

Associated features Natural clinical course: Onset age is variable, in patients with earlier onset (<50 years) the symptoms are insidious, while patients with later onset have a more aggressive course. RLS is usually a chronic disease with progressive clinical course; in mildest forms of RLS the clinical course can be static or intermittent. Sleep disturbances: disturbed sleep is usually associated to RLS, this morbidity is however aspecific. Medical evaluation/Physical examination: physical and neurological examination is generally normal (except for secondary RLS). Medical evaluation should be addressed to possible causes for secondary RLS.

Abbreviations: NIH, National Institutes of Health; PLMs, periodic limb movements; PLMW, periodic limb movement during wakefulness; RLS, restless legs syndrome.

Table 2 Augmentation diagnostic criteria

A. Basic features (all need to be met) The increase in symptom severity was experienced on five out of seven days during the previous week. The increase in symptom severity is not accounted for by other factors such as a change in medical status, lifestyle or the natural progression of the disorder. It is assumed that there has been a prior positive response to treatment.

B and C. Additional features (one or both need to be met) B. Persisting (although not immediate) paradoxical response to treatment: RLS symptom severity increases some time after a dose increase and improves some time after a dose decrease.

C. Earlier onset of symptoms: An earlier onset of at least four hours or An earlier onset (between two and four hours) occurs with one of the following compared to symptoms status before treatment: Shorter latency to symptoms when at rest; E xtension of symptoms to other body parts; Greater intensity of symptoms (or increase in periodic limb movements if measured by polysomnography (PSG) or the suggested immobilization test (SIT); Shorter duration of relief from treatment.

Abbreviation: RLS, restless legs syndrome.

Table 3 Pramipexole trials in RLS

	Study design	Pramipexole administration	Outcome measure
Partinen 2006^Citation53	Multicenter, double-blind, randomized, fixed-dose, placebo-controlled trial Randomization: 1:1:1:1:1 109 patients with moderate–severe idiopathic RLS Three week period	Fixed doses: –0.125 mg –0.25 mg –0.50 mg –0.75 mg 2–3 hours before bedtime	Primary outcome: PLMI ↓ Secondary outcome: PLMSI ↓; PLMWI ↓; PLM ↓; SL ↓; time in delta sleep ↓ PLMAI →; SE →; TST → IRLS ↓; ESS →; SSQ ↑; SF-36 ↑ (improvement in social function sub-score); PGI↑; CGI ↑
Winkelman 2006^Citation50	Double-blind, randomized, fixed-dose, placebo-controlled trial Randomization: 1:1:1:1 344 patients with moderate–severe idiopathic RLS 12 week period	Fixed doses: –0.25 mg –0.50 mg –0.75 mg 2–3 hours before bedtime	Primary outcome: IRLS ↓ Secondary outcome: Improvement in PGI, CGI, VAS, ESS, RLS-QOL.
Oertel 2007^Citation51	Double-blind, randomized, flexible-dose, placebo-controlled trial. Randomization: (placebo:pramipexole = 1:2) 345 patients with moderate–severe idiopathic RLS Six week period	Starting dose = 0.125 mg, that could be increased by the physician to 0.25, 0.50 or 0.75 mg/day. 2–3 hours before bedtime	Primary outcome: IRLS ↓ Secondary outcome: Improvement in PGI, CGI, VAS
Trenkwalder 2006^Citation57	Multicenter, double-blind, randomized, flexible-dose, placebo-controlled withdrawal trial. Randomization: 1:1 150 RLS patients responding to pramipexole on a six-month period were randomly assigned to receive placebo or to continue pramipexole for three months	Individual optimized dosage (0.125, 0.25, 0.50 or 0.75 mg/die). 2–3 hours before bedtime	Primary outcome: CGI-I score of minimally, much or very much worse ↓↓ in pramipexole group (less than 50% reached the target event). An increase of IRLS to a score > 15. ↑↑ in Placebo group. Secondary outcome: CGI-I ↑↑; CGI-S ↓↓; CGI-E ↑↑; PGI ↑; RLS-QOL↑
Montplaisir 2006^Citation55	Telephone interview. 195 consecutives patients with idiopathic RLS who underwent pramipexole treatment for at least one year	Mean dose = 0.59 ± 0.31 mg (range = 0.125–2.25 mg). Mean treatment duration = 30.5 ± 10.5 months	Questionnaire on efficacy: – RLS severity ↓↓ –Difficulty in falling asleep↓↓ – Nocturnal awakenings ↓↓
Manconi 2007^Citation43	Single-blind, randomized, placebo- controlled, fixed-dose trial. Randomization: 1:1 32 patients with severe idiopathic RLS, never previously treated for RLS Comparison of clinical and neuro- physiological parameters at the base- line and after one night treatment.	Single dose of 0.25 mg Administration time = 9.00 p.m.	Primary outcome: – PLMS change index: ↓ Secondary outcome: – Sleep stage 2 ↑; time in bed, sleep (efficiency ↑) VAS (severity) = ↓↓
Partinen 2008^Citation54	Open label trial 26 week period	Initial dose = 0.125 mg (titrated up to a maximum 0.75 mg) Administration time = 8.00–9.00 p.m.	Primary outcome: IRLS ↓ Secondary outcome: Improvement in CGI-I; PGI-I; ESS; SF-36; SSQ
Ferini-Strambi 2008^Citation52	Double-blind, randomized, placebo- controlled, flexible-dose trial. Randomization: 1:1 357 patients with moderate–severe idiopathic RLS 12 week period	Initial dose = 0.125 mg (titrated up to a maximum 0.75 mg). 2–3 hours before bedtime	Primary outcome: IRLS ↓ MOS scale-sleep disturbance (initiation and maintenance) domain. ↓↓ Secondary outcome: Improvement in CGI-I; PGI-I; RLS-QOL

Abbreviations: ↑, significantly increased; ↑↑, highly significantly increased; (↑), increased but not significantly; →, unchanged; ↓, significantly decreased; ↓↓, highly significantly decreased; (↓), decreased but not significantly; PLMI, periodic limb movement during time in bed index; PLMSI, periodic limb movement during sleep index; PLMWI, periodic limb movement during wakefulness index; PLMAI, periodic limb movement during sleep with arousal index; PLM, total number of periodic limb movements; PLMS, total number of periodic limb movements during sleep; PLMA, total number of periodic limb movements during sleep with arousal; SL, sleep latency; SE, sleep efficiency; TST, total sleeping time; sREM, stage rapid eye movement sleep; RLS, restless legs syndrome; IRLS, International restless Legs Syndrome scale total score; ESS, epworth Sleepiness Scale; SSQ, subjective sleep quality scale; SF-36, Short Form 36 Health Survey Questionnaire PGI, Patient Global Impression scale; CGI, Clinical Global Impression scale; CGI-I, Glinical Global Impression – Improvement scale; CGI-S, Clinical Global Impression – Severity scale; CGI-E, Clinical Global Impression – Efficacy scale; VAS, visual analogue scale; RLS-QOL, Johns Hopkins restless Legs Syndrome Quality Of Life Questionnaire; SSQ, subjective sleep quality.

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