Diagnosis, comorbidities, and management of restless legs syndrome

Figures & data

Table 1. Confounds in the differential diagnosis of RLS.

Confound	How many IRLSSG criteria are met?	Differentiate from RLS	Coexist with RLS
Leg cramps	4 of 4	Muscle spasm easily identified	+
Neuropathy/radiculopathy	0–4 of 4	Numbness, burning, and tingling; morning symptoms	+++
Arthritis	2–3 of 4	Discomfort in and around joints; stiffness on arising	++
Vascular	2–3 of 4	Varicosities and PVD; relief from movement slow; rub helps more; walking is worse	++
Positional discomfort	1–2 of 4	Foot or leg ‘asleep’ from compression; shift and it’s gone	−
Exacerbation of RLS	Pregnancy, blood loss, renal disease, antidepressants, dopamine blockade, Parkinson’s disease, axonal neuropathy

IRLSSG = International RLS Study Group; PVD = peripheral vascular disease; RLS = restless legs syndrome.

Table 2. Medications and substances that may exacerbate RLS symptoms.

Medication
Antidepressants (TCAs, SSRIs, and SNRIs)	Used to treat depression, anxiety, and pain disorders
Antiemetics	Used to treat nausea, including motion sickness and morning sickness
Antihistamines	Used to treat allergies Often found in over-the-counter sleep medications
Calcium channel blocking antihypertensives	Used to treat hypertension
Excessive caffeine	Found in coffee, tea, energy drinks, and other beverages Also found in chocolate
Excessive alcohol	Consumption of excessive alcohol at bedtime may exacerbate RLS

RLS = restless legs syndrome; SNRIs = serotonin–noradrenalin reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants.

Table 3. Comorbidities which may be associated with RLS based on epidemiological data.

Comorbidity	Study type	RLS assessment	Main results
ADHD
Pullen et al., 2011142	Retrospective review of medical records (374 patients with child-onset RLS)	IRLSSG criteria	Prevalence of ADHD: 25%
Picchietti et al., 2007143	Cross-sectional survey (10,523 households with children aged 8–17 years)	IRLSSG criteria for childhood RLS	Prevalence of ADD/ADHD among children with definite RLS: 8–11 year age group, 14.8%; 12–17 year age group, 17.6%
Kotagal and Silber, 2004144	Retrospective chart review (32 children with RLS)	IRLSSG criteria for childhood RLS	‘Inattentiveness’ seen in 25% of children with RLS
Wagner et al., 2004145	Cross-sectional study (62 RLS patients, 32 insomnia patients, 77 controls)	IRLSSG criteria	Prevalence of ‘highly probable’ ADHD: RLS patients, 24%; insomnia patients, 3%; controls, 4% (P < 0.01)
Chervin et al., 2002146	Cross-sectional survey (866 children aged 2–14 years)	RLS item of the Pediatric Sleep Questionnaire	Prevalence of hyperactivity: children with RLS, 18%; children without RLS, 11%
Picchietti et al., 1998147	Controlled cohort study (69 children with ADHD, 38 controls)	Modified 1995 IRLSSG criteria designed to minimize misdiagnosis in children	Prevalence of RLS: children with ADHD, 12%; controls, 3%
Chervin et al., 1997148	Cross-sectional study (70 children attending psychiatric clinic, 73 children attending general pediatrics clinic)	Pediatric Sleep Questionnaire	Prevalence of RLS symptoms: children with ADHD, 15%; children with a non-ADHD psychiatric disorder, 5%; and general pediatric patients, 10%
ED
Li et al., 2013149	Prospective cohort study (10,394 men)	IRLSSG criteria	Men with RLS had a higher risk of developing ED over 6 years of follow-up (RR = 1.38 [95% CI: 1.14–1.68]; P = 0.001) Higher frequency of RLS symptoms associated with increased risk of ED (Ptrend = 0.001)
Gao et al., 2010150	Cross-sectional study (23,119 men)	IRLSSG criteria (patients were required to have symptoms ≥5 times/month)	Prevalence of ED: RLS patients, 53%; patients without RLS, 40% (age-adjusted OR = 1.47 [95% CI: 1.3–1.7]) Higher frequency of RLS symptoms associated with increased risk of ED
Liver disease
Franco et al., 2008151	Cross-sectional study (141 patients with chronic liver disease)	IRLSSG criteria	Prevalence of RLS: 62%. Prevalence of RLS in patients without known risk factors (e.g., kidney disease, iron deficiency, and anemia): 56%
Migraine
Winter et al., 2013152	Cross-sectional study (22,926 men participating in the Physicians’ Health Study)	IRLSSG criteria	Prevalence of migraine: 12.3%; prevalence of RLS: 7.5% Migraine was associated with an increased risk of having RLS (multivariable-adjusted OR = 1.20 [95% CI: 1.04–1.38])
Schürks et al., 2012153	Cohort study (31,370 women participating in the Women’s Health Study)	IRLSSG criteria	Prevalence of migraine: 21.9% Women with migraine had an increased risk for RLS (multivariable-adjusted OR = 1.22 [95% CI: 1.13–1.32])
Seidel et al., 2012154	Case–control study in children and adolescents aged 5–18 years (111 migraine patients, 73 headache-free controls)	IRLSSG criteria	Prevalence of ‘definite’ RLS: migraine, 22%; controls, 5% (OR = 3.9 [95% CI: 1.4–10.9], P < 0.001)
Lucchesi et al., 2012155	Case–control study (277 patients with migraine [episodic: 175; chronic: 102], 200 healthy controls)	IRLSSG criteria	Prevalence of RLS: migraine patients, 22.7%; controls, 7.5% (P < 0.0001). RLS was more common with chronic than episodic migraine (34.3% vs. 16%; P = 0.0006)
Chen et al., 2010156	Cross-sectional study (1041 patients attending a headache clinic)	IRLSSG criteria	Higher prevalence of RLS in patients with migraine (11%) versus patients with tension type headache (5%) or cluster headache (2%) (P = 0.002)
d’Onofrio et al., 2008157	Case–control study (200 patients with headache, 120 controls)	IRLSSG criteria	Prevalence of RLS: headache patients, 22%; controls, 8% (P = 0.002)
Rhode et al., 2007158	Case–control study (411 patients with migraine, 411 controls)	IRLSSG criteria	Prevalence of RLS: migraine patients, 17%; controls, 6% (P < 0.001; OR = 3.5 [95% CI: 2.2–5.8])
Young et al., 2003159	Cross-sectional study (50 patients with severe headache [41 had migraine])	IRLSSG criteria	Prevalence of RLS: 34%
MS
Li, 2012160	Cross-sectional study (65,544 women [aged 41–58 years])	IRLSSG criteria (RLS symptoms ≥5 times/month)	Prevalence of RLS: women with MS, 15.5%; without MS, 6.4% (adjusted OR = 2.72 [95% CI: 1.89–3.93]) Prevalence of severe RLS: women with MS, 9.9%; without MS, 2.6% (adjusted OR = 4.12 [2.65–6.42]) Over 4 years of follow-up, women with MS had a higher risk of severe RLS compared with those without MS (adjusted RR = 3.58 [95% CI: 1.53–8.35])
Vavrova et al., 2012161	Cross-sectional study (765 patients with MS)	IRLSSG criteria	Diagnosis of RLS: 32.1%
Aydar et al., 2011162	Case–control study (98 patients with definite MS and 129 healthy volunteers)	IRLSSG criteria	Prevalence of RLS: MS patients, 27.6%; controls, 10.1% (OR = 2.55; P = 0.018)
Fragoso et al., 2011163	Case–control study (80 MS patients, 180 controls)	IRLSSG criteria	Prevalence of RLS: MS patients, 58%; controls, 18% (OR = 6.02 [95% CI: 3.36–10.78]) Average severity of RLS symptoms was higher in MS patients
Deriu et al., 2009164	Case–control study (202 MS patients, 212 controls)	IRLSSG criteria	Prevalence of RLS: MS patients, 14%; controls, 3% Risk of RLS was 5 times higher in MS patients (OR = 5.76; P = 0.00002)
Manconi et al., 2008165	Case–control study (861 MS patients, 649 controls)	IRLSSG criteria (RLS symptoms ≥2 times/month)	Prevalence of RLS: MS patients, 19%; controls, 4% Risk of RLS was 5.4 times higher in MS patients (OR = 5.4 [95% CI: 3.56–8.26])
Moreira et al., 2008166	Cross-sectional study (44 MS patients)	IRLSSG criteria	Prevalence of RLS: 27%
Manconi et al., 2007167	Cross-sectional study (156 MS patients [100 females, 56 males])	IRLSSG criteria (RLS symptoms ≥1 time/week)	Prevalence of RLS: 32.7% RLS preceded clinical MS onset in 8.5% of cases
Gómez-Choco et al., 2007168	Case–control study (135 MS patients, 118 controls)	IRLSSG criteria	Prevalence of RLS: MS patients, 13%; controls, 9% (P = not significant)
Auger et al., 2005169	Case–control study (200 MS patients, 100 controls)	IRLSSG criteria	Prevalence of RLS: MS patients, 38%; controls, 16%
Narcolepsy
Plazzi et al., 2012170	Case–control study (17 patients with narcolepsy and RLS, 68 age- and gender-matched controls [34 with narcolepsy, 17 with idiopathic RLS, and 17 healthy controls])	IRLSSG criteria (RLS symptoms recurring ≥2 times/week during preceding 6 months)	Age at onset of RLS in patients with narcolepsy: 34.2 years In the majority of cases (12/17), the onset of narcolepsy preceded RLS symptoms Structure of PLMS in narcolepsy with RLS was similar, but not identical, to that of PLMS in idiopathic RLS
Plazzi et al., 2010171	Case–control study (184 narcolepsy patients, 235 controls)	IRLSSG criteria (RLS symptoms ≥2 times/week)	Prevalence of RLS: narcolepsy patients, 15%; age-matched controls, 3% (OR = 5.6 [95% CI: 2.38–13.18])
Ferri et al., 2007172	Cross-sectional study (521 patients attending neurology clinic [9 narcolepsy patients])	Single question based on IRLSSG criteria	Prevalence of RLS in narcolepsy patients: 2 of 9 patients
Obesity
Gao et al., 2009173	Cross-sectional study (65,554 women, 23,119 men)	IRLSSG criteria (patients were required to have restless legs ≥5 times/month)	Obesity (BMI ≥30 vs. <23 kg/m^2) (OR = 1.42 [95% CI: 1.30–1.55; P trend <.0001]), higher waist circumference (OR = 1.60 [95% CI: 1.45–1.78; P trend <.0001), greater BMI in early adulthood (OR = 1.24 [95% CI: 1.01–1.52; P trend <0.004]), and weight gain (OR = 1.41 [90% CI: 1.28–1.55; P trend <0.0001]) were all associated with a higher prevalence of RLS
Kim et al., 200536	Cross-sectional study (5228 women, 4711 men)	Single question	RLS significantly associated with obesity in women (BMI ≥25 vs. <25 kg/m^2; OR = 1.19 [95% CI: 1.10–1.39; P < 0.05]) but not in men (OR = 1.1 [95% CI: 0.89–1.37; P = not significant])
Ohayon and Roth, 200263	Cross-sectional study (n = 18,980)	Minimal criteria for RLS as defined by the International Classification of Sleep Disorders	OR for RLS was 1.22 (95% CI: 1.03–1.45) for BMI of >27 versus <27 kg/m^2
Phillips et al., 2000174	Cross-sectional study (n = 1803)	Single question based on IRLSSG criteria	Higher BMI (per increased increment of 5 kg/m^2) correlated with RLS (OR = 1.31 [95% CI: 1.11–1.53])
PD
Bhalsing et al., 2013175	Case–control study (187 patients with parkinsonian disorders [134 with PD], 172 healthy controls)	IRLSSG criteria	Prevalence of RLS: all Parkinsonian patients, 9.6%; patients with PD, 11.9%; controls, 2.9%
Rajabally and Martey, 2013176	Case–control study (37 patients with PD, 37 age- and gender-matched controls)	IRLSSG criteria (patients were required to have RLS symptoms for ≥2 days/week)	Prevalence of RLS was comparable in patients with PD (16.2%) and controls (10.8%; P = 0.30)
Shin et al., 2013177	Cross-sectional study (151 drug-naive PD patients)	IRLSSG criteria	Prevalence of RLS: 16.5%
Angelini et al., 2011178	Case–control study (109 de novo PD patients, 116 controls)	IRLSSG criteria	Overall lifetime prevalence of RLS: PD patients, 6%; controls, 4% (P = not significant) No significant difference in prevalence of current/previous RLS in PD patients or controls
Gjerstad et al., 2011179	Case–control study (200 drug-naive patients with early PD, 173 age- and gender-matched controls)	IRLSSG criteria	Leg restlessness: PD patients, 40.5%; controls, 17.9% (RR = 2.26 [95% CI: 1.57–3.24], P < 0.001) Prevalence of RLS: PD patients, 15.5%; controls, 9.3% (RR = 1.68 [95% CI: 0.95–2.96], P = 0.07)
Gao et al., 2010180	Cross-sectional study (23,119 men)	IRLSSG criteria	OR for PD was 1.99 (95% CI: 1.1–3.6; P = 0.02) for men with RLS symptoms compared with men without RLS
Guerreiro et al., 2010181	Cross-sectional study (48 PD patients)	IRLSSG criteria	Prevalence of RLS: 19%
Lee et al., 2009182	Cross-sectional study (447 consecutive patients with PD attending a hospital)	IRLSSG criteria	Prevalence of RLS: 16.3% Duration of anti-Parkinson therapy (per year increase) was a contributing factor to the development of RLS (OR = 1.199 [95% CI: 1.014–1.419], P = 0.034)
Calzetti et al., 2009183	Case–control study (118 outpatients with PD attending a movement disorders clinic, 110 age- and gender- matched controls)	IRLSSG criteria	Prevalence of current/previous RLS: PD patients, 12.7%; controls, 6.3% (P = 0.16)
Gómez-Esteban et al., 2007184	Cross-sectional study (114 PD patients)	IRLSSG criteria	Prevalence of RLS: 22%
Nomura et al., 2006185	Case–control study (165 PD patients, 131 controls)	IRLSSG criteria	Prevalence of RLS: PD patients, 12%; controls, 2% (P < 0.01)
Krishnan et al., 2003186	Case–control study (126 PD patients, 128 controls)	IRLSSG criteria	Prevalence of past/current RLS: PD patients, 8%; controls, 1% (P = 0.01)
Ondo et al., 2002187	Cross-sectional study (303 PD patients)	1995 IRLSSG criteria	Prevalence of RLS: 21%

ADD = attention-deficit disorder; ADHD = attention-deficit hyperactivity disorder; BMI = body mass index; CI = confidence interval; ED = erectile dysfunction; IRLSSG = International Restless Legs Syndrome Study Group; MS = multiple sclerosis; OR = odds ratio; PD = Parkinson’s disease; RR = relative risk; RLS = restless legs syndrome.

Table 4. Presenting symptoms of RLS in children.

Symptom
Leg discomfort	Limb pain/discomfort arising during periods of inactivity and primarily occurring during the evening and at night. Unexplained limb discomfort may be attributed to ‘growing pains’
Urge to move	Difficulty sitting still particularly in the late afternoon or evening (fidgeting, running, stretching, walking, rocking, etc.)
Behavioral problems at bedtime	Reluctance to go to bed, difficulty staying in bed and falling asleep
Sleep disruption	Restless sleep, nighttime awakenings, child may get out of bed and move around during the night
Daytime sleepiness	Difficulty waking in the morning, falling asleep at school/inappropriate times, increased need for naps
Behavioral problems during the day	Reduced academic performance, irritability, moodiness, aggression, lack of concentration, and/or hyperactivity

Table 5. Pharmacological therapy for restless legs syndrome202,206–209.

Medication	Dosing	Level of evidence	Choice of therapy	Potential side effects
Intermittent RLS symptoms
Levodopa	Carbidopa/levodopa: titrate from 25 mg/100 mg to a maximum of 75/300 mg (12.5/50 mg increments every 4–7 days)	Short-term efficacy demonstrated in controlled trials	Not recommended for long-term therapy due to risk of developing augmentation	Nausea, fatigue, somnolence, augmentation
Low potency opioids or opioid agonists	Codeine (30–60 mg), tramadol (50–100 mg) or oxycodone (5–20 mg) taken as needed at bedtime, or during the day if breakthrough symptoms occur	Few controlled trials in RLS	Fast onset of action; useful for treating intermittent daytime symptoms	Constipation, nausea, respiratory depression; seizures and augmentation may occur with tramadol
Benzodiazepines/benzodiazepine agonists	Temazepam (15–30 mg), zolpidem (5–10 mg), zalepon (5–10 mg), eszopiclone (1–3 mg)	No adequate controlled trials in RLS	Useful for patients with sleep disturbances	Morning drowsiness/unsteadiness may occur with long-acting agents
Daily RLS symptoms
Non-ergot dopamine agonists	Pramipexole: 0.125–1 mg daily, taken 1–3 h before symptom onset; titrate in 0.125 mg increments every 2–3 days Ropinirole: 0.5–4 mg daily, taken 1.5 h before symptom onset; titrate in 0.25–0.5 mg increments every 2–3 days Rotigotine: 1–3 mg/24 h; titrate in 1 mg increments every 7 days	Efficacy of all three agents well established in randomized placebo-controlled trials	Recommended for very severe RLS, patients with comorbid depression or dysthymia, or obesity/metabolic syndrome; rotigotine 24 h patch may be advantageous for patients with daytime symptoms	Nausea, fatigue, somnolence, headache, augmentation, impulse control disorders, hypotension Skin reactions occur with rotigotine patch
Calcium channel α2δ ligand	Gabapentin enacarbil: 600–1200 mg taken once daily at 5 pm Gabapentin: 300–1200 mg daily, administered in once or twice daily doses; titrate in 300 mg increments every 7 days Pregabalin: 100–300 mg daily, administered in once or twice daily doses; titrate from 50 mg in 50 mg increments every 7 days	Efficacy of gabapentin enacarbil well established in randomized placebo-controlled trials; low level of evidence for pregabalin and gabapentin	May be useful for patients with comorbid pain, anxiety or insomnia, or for those who have previously experienced an impulse control disorder/addiction	Somnolence, dizziness, depression Weight gain and suicidal ideation reported with pregabalin
High potency opioids	Oxycodone, hydrocodone or methadone at low doses (∼5–20 mg)	Evidence largely based on class III and IV studies; one 12 week controlled study showed superiority of oxycodone over placebo	May be useful for patients with an unsatisfactory response to therapy with dopamine agonists or α-2-δ ligands	Constipation, nausea, dizziness, sedation and respiratory depression Potential for addiction/tolerance

Figure 1. Possible associations between RLS and comorbidities. Dotted lines indicate comorbidities for which the evidence for the association comes from epidemiologic studies. AD = use of antidepressants; ADHD = attention-deficit hyperactivity disorder; CVD = cardiovascular disease; DD = dopaminergic dysfunction; ED = erectile dysfunction; ESRD = end-stage renal disease; FM = fibromyalgia; ID = iron deficiency; MS = multiple sclerosis; PD = Parkinson’s disease; PLMs = periodic limb movements; RA = rheumatoid arthritis; RLS = restless legs syndrome; SD = sleep disruption; SFN = small fiber neuropathy; SSFL = small sensory fiber loss; VRFs = vascular risk factors.

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