Restless Legs Syndrome (RLS)

Restless Legs Syndrome (RLS) is a sensorimotor, neurological sleep disorder characterized by a desire to move the legs or arms, usually associated with uncomfortable sensations typically described as creeping, crawling, tingling, burning, or itching. The symptoms of motor restlessness are:

  • worse when the individual is at rest, and frequent movements of the legs occur in an effort to relieve the uncomfortable sensations
  • worse in the evening or night, and in some individuals they occur only in the evening or night.

The diagnosis of RLS is a clinical diagnosis, and primarily on patient self-report and history. The symptoms of RLS can delay sleep onset and awaken the individual from sleep and are associated with significant sleep fragmentation. The relief obtained from moving the legs may no longer be apparent in severe cases. RLS is associated with daytime sleepiness and is frequently accompanied by significant clinical distress or functional impairment.

The most common consequences of RLS are sleep disturbance, including reduced sleep time, sleep fragmentation, and overall disturbance; depression, generalized anxiety disorder, panic disorder, and post traumatic stress disorder; and quality-of-life impairments. RLS can result in daytime sleepiness or fatigue and is frequently accompanied by significant distress or impairment in affective, social, occupational, educational, academic, behavioural, or cognitive functioning.

Prevalence

Prevalence rates of RLS vary widely when broad criteria are utilized but range from 2% to 7% when more defined criteria are employed. When frequency of symptoms is at least three times per week with moderate or severe distress, the prevalence rate is about 2%; when frequency of symptoms is a minimum of one time per week, the prevalence rate is 4.5%. Females are up to 2 times more likely than males to have RLS. RLS also increases with age. The prevalence of RLS may be lower in Asian populations. The onset of RLS typically occurs in the second or third decade. Approximately 40% of individuals diagnosed with RLS during adulthood report having experienced symptoms before age 20 years, and 20% report having experienced symptoms before age 10 years. The prevalence of RLS during pregnancy is 2 to 3 times greater than in the general population. RLS associated with pregnancy peaks during the third trimester and improves or resolves in most cases soon after delivery.

Criterion A

An urge to move the legs, usually accompanied by or in response to uncomfortable and unpleasant sensations in the legs, characterized by all of the following:

  1. The urge to move the legs begins or worsens during periods of rest or inactivity
  2. The urge to move the legs is partially or totally relieved by movement.
  3. The urge to move the legs is worse in the evening or at night than during the day, or occurs only in the evening or at night.
Criterion B

The symptoms in Criterion A occur at least 3 times per week and have persisted for at least 3 months.

Criterion C

The symptoms in Criterion A are accompanied by significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning.

Criterion D

The symptoms in Criterion A are not attributable to another mental disorder or medical condition (e.g., arthritis, leg edema, peripheral ischemia, leg cramps) and are not better explained by a behavioural condition (e.g., positional discomfort, habitual foot tapping).

Criterion E

The symptoms are not attributable to the physiological effects of a drug of abuse or medication (e.g., akathisia).

Paediatric Diagnosis

Paediatric Diagnosis

Diagnosis of RLS in children can be difficult because of the self-report component. While Criterion A for adults assumes that the description of "urge to move" is by the patient, a paediatric diagnosis requires a description in the child's own words rather than by a parent or caretaker. Typically children age 6 years or older are able to provide detailed, adequate descriptors of RLS.

However, children rarely use or understand the word "urge," reporting instead that their legs "have to" or "got to" move. Also, potentially related to prolonged periods of sitting during class, two-thirds of children and adolescents report daytime leg sensations. Thus, for diagnostic Criterion A3, it is important to compare equal duration of sitting or lying down in the day to sitting or lying down in the evening or night. Nocturnal worsening tends to persist even in the context of paediatric RLS. As with RLS in adults, there is a significant negative impact on sleep, mood, cognition, and function. Impairment in children and adolescents is manifested more often in behavioural and educational domains.

The difference between Periodic Limb Movements (PLMD) and RLS is that PLMD is an involuntary action. The patient often sleeps through an episode of leg movements. In RLS, however, patients are awake the whole time and are jerking or kicking their legs in an effort to overcome the discomfort their brains are perceiving. In summary, RLS keeps the patient awake; PLM occurs when the patient is already asleep.

Periodic Limb Movements (PLM) is a diagnosis is based on polysomnography findings. Periodic leg movements in sleep (PLMS) can serve as evidence for RLS, with up to 90% of individuals diagnosed with RLS demonstrating PLMS when recordings are taken over multiple nights.

  • Up to 80% of RLS patients have PLMS
  • Asymptomatic PLMS does not require treatment

PLMD (Periodic Limb Movement Disorder)

PLMS plus sleep dysfunction.

  • Do you kick your legs at night?
  • Does your partner report you kick your legs at night?
  • Reduction of caudate and putamen D2 receptor binding (SPECT/PET)
  • CSF ferritin low abnormal iron transport (Brain Iron Transport)
  • Decreased thalamic blood flow during RLS symptoms (fMRI)

There are defined pathophysiological pathways subserving RLS. Genome-wide association studies have found that RLS is significantly associated with common genetic variants in intronic or intergenic regions in MEISl, BTBD9, and ΜΛΡ2Κ5 on chromosomes 2p, 6p, and 15q, respectively. The association of these three variants with RLS has been independently replicated. BTBD9 confers a very large (80%) excessive risk when even a single allele is present. Because of the high frequency of this variant in individuals of European descent, the population attributable risk (PAR) approximates 50%. At-risk alleles associated with MEISl and BTBD9 are less common in individuals of African or Asian descent, perhaps suggesting lower risk for RLS in these populations.

Pathophysiological mechanisms in RLS also include disturbances in the central dopaminergic system and disturbances in iron metabolism. The endogenous opiate system may also be involved. Treatment effects of dopaminergic drugs (primarily D2and D3 non-ergot agonists) provide further support that RLS is grounded in dysfunctional central dopaminergic pathways. While the effective treatment of RLS has also been shown to significantly reduce depressive symptoms, serotonergic antidepressants can induce or aggravate RLS in some individuals.

Polysomnography

Polysomnography demonstrates significant abnormalities in RLS, commonly increased latency to sleep, and higher arousal index. Polysomnography with a preceding immobilization test may provide an indicator of the motor sign of RLS, periodic limb movements, under standard conditions of sleep and during quiet resting, both of which can provoke RLS symptoms.

First-line treatment for RLS is through dopamine agonists.[1]

Treatment for RLS

1st line Dopamine Ergot Agonists: Ropinirole (0.25 to 3 mg
 PO daily), pramipexole (0.125 to 1.5 mg PO daily
), L-Dopa (100 to 200mg PO daily)
2nd line α2δ Subunit Gaba-ergic Agonists: Gabapentin (300-2000 mg PO daily
), pregabalin (50-200 mg PO daily)
3rd line Opioids: Codeine (15-120 mg PO daily), methadone (5-30 mg PO daily)

Benzodiazepines: Clonazepam (0.5-3 mg PO daily), temazepam (15-30mg PO daily)

Other treatments: Clonidine, baclofen, carbamazapine, B12, folate

Treating two conditions with one medication

  • If your patient has chronic pain, then you should treat with GABA-ergic agonists
  • If your patient has ADHD, then you should treat with clonidine

The most important conditions in the differential diagnosis of RLS are leg cramps, positional discomfort, arthralgias/arthritis, myalgias, positional ischemia (numbness), leg edema, peripheral neuropathy, radiculopathy, and habitual foot tapping. ''Knotting“ of the muscle (cramps), relief with a single postural shift, limitation to joints, soreness to palpation (myalgias), and other abnormalities on physical examination are not characteristic of RLS.

Unlike RLS, nocturnal leg cramps do not typically present with the desire to move the limbs nor are there frequent limb movements. Less common conditions to be differentiated from RLS include neuroleptic-induced akathisia, myelopathy, symptomatic venous insufficiency, peripheral artery disease, eczema, other orthopaedic problems, and anxiety-induced restlessness. Worsening at night and periodic limb movements are more common in RLS than in medication-induced akathisia or peripheral neuropathy.

While is it important that RLS symptoms not be solely accounted for by another medical or behavioural condition, it should also be appreciated that any of these similar conditions can occur in an individual with RLS. This necessitates a separate focus on each possible condition in the diagnostic process and when assessing impact. For cases in which the diagnosis of RLS is not certain, evaluation for the supportive features of RLS, particularly PLMS or a family history of RLS, may be helpful. Clinical features, such as response to a dopaminergic agent and positive family history for RLS, can help with the differential diagnosis.

Restless Leg vs. Akathisia
  • In RLS, you always have an urge to move
  • Pain occurs in 25% of RLS cases
  • RLS cause initial insomnia, not middle insomnia
  • Hypersomnia can result in RLS
  • Always time of onset
Secondary Causes of RLS
  • Iron deficiency, uremia, RA, peripheral neuropathy, diabetes, pregnancy, spinal cord lesion, medications (e.g. - antipsychotics)
  • SSRIs can also exacerbate RLS
Comorbidity

Depressive disorders, anxiety disorders, and attentional disorders are commonly comorbid with RLS and are discussed in the section “Functional Consequences of Restless Legs Syndrome.” The main medical disorder comorbid with RLS is cardiovascular disease. There may be an association with numerous other medical disorders, including hypertension, narcolepsy, migraine, Parkinson's disease, multiple sclerosis, peripheral neuropathy, obstructive sleep apnea, diabetes mellitus, fibromyalgia, osteoporosis, obesity, thyroid disease, and cancer. Iron deficiency, pregnancy, and chronic renal failure are also comorbid with RLS.

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