Restless Legs Syndrome (RLS)

Primer

Restless Legs Syndrome (RLS), also known as Willis-Ekbom Disorder (WED) is a motor-sensory neurological sleep disorder characterized by uncomfortable sensations in the lower extremities that are accompanied by an almost irresistible urge to move the legs or arms. These uncomfortable experiences are typically described as creeping, crawling, tingling, burning, or itching sensations. Symptoms typically occur at night and are relieved by movement.

Prevalence
  • Prevalence rates of RLS but can be between 5 to 10% in the general population.
  • Females are up to 2 times more likely than males to have RLS.
  • RLS also increases with age.
  • The prevalence of RLS is much higher in Caucasians (up to 15%), and may be lower in Asian and African populations.
  • The prevalence of RLS during pregnancy is 2 to 3 times greater than in the general population.
Prognosis
  • The onset of RLS typically occurs in the second or third decade of life.

Comorbidity

  • Depressive disorders, anxiety disorders, and attentional disorders are commonly comorbid with RLS.
  • Although RLS can be idiopathic, the main medical disorders comorbid or etiologically related with RLS are cardiovascular disease, 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 (uremia) are also comorbid with RLS.

Risk Factors

Symptoms

  • The symptoms of motor restlessness are:
    • Worse 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. This is a unique feature of RLS; in the timing of the symptoms, it appears to have a circadian component, often peaking in the evening.
    • The most common consequences of RLS are sleep disturbance, including reduced sleep time, sleep fragmentation, and overall disturbance.
    • RLS can result in daytime sleepiness or fatigue and is frequently accompanied by significant distress or impairment in social or cognitive functioning.

DSM-5 Diagnostic Criteria

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.

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.

Mnemonic

The mnemonic URGE can be used to remember the core features of RLS:
  • U - Urge to move limbs
  • R - Rest worsens the sensation
  • G - Getting up to move offers temporary relief
  • E - Evening is worse for symptoms

Periodic Limb Movement Disorder (PLMD)

Periodic Limb Movements (PLMs) vs. Periodic Limb Movements Disorder (PLMD) vs. Restless Legs Syndrome (RLS)

  • Restless Legs Syndrome (RLS) refers to the symptom, while Periodic Limb Movements (PLMs) refers to the sign.
  • Periodic Limb Movements Disorder (PLMD) is a diagnosis is based on polysomnography findings (i.e. - can only be diagnosed with a sleep study).
  • Restless Leg Syndrome (RLS) is a clinical diagnosis and does not require a sleep study.
    • Up to 90% of individuals diagnosed with RLS have Periodic Limb Movements (PLMs) when sleep recordings are taken over multiple nights. Asymptomatic PLMs does not require treatment.
  • The difference between PLMD and RLS is that PLMD involves an involuntary action. The patient often sleeps through an episode of leg movements in PLMD. 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, but PLMD occurs when the patient is already asleep.

Periodic Limb Movements (PLMs)

PLMD = PLMs plus sleep dysfunction.

Screening Questions

  • Do you kick your legs at night?
  • Does your partner report you kick your legs at night?

Differential Diagnosis

Important differential diagnoses to consider include:

  • Leg cramps, muscle cramps - nocturnal leg cramps do not typically present with the desire to move the limbs, and there are rarely frequent limb movements.
  • Positional discomfort
  • Anxiety-induced restlessness
  • Arthralgias/arthritis
  • Myalgias
  • Positional ischemia (numbness)
  • Leg edema
  • Peripheral neuropathy - symptoms will be present throughout the day, and there is no night time worsening
  • Peripheral artery disease
  • Radiculopathy
  • Habitual foot tapping
  • Neuroleptic-induced or other medication-induced akathisia - symptoms will be present throughout the day, and there is no night time worsening
  • Myelopathy
  • Symptomatic venous insufficiency
  • Eczema
  • Orthopaedic problems

Multiple Diagnoses Can Occur!

Although it is important to rule out other conditions that could mimic RLS, any of these similar conditions can also co-occur in an individual with RLS.

Physical Exam Tips

Knotting of the muscle (i.e. - muscle cramps) on examination, relief with a single postural shift, limitation to joints, soreness on palpation (myalgia), and other abnormalities on physical examination are not characteristic of RLS.

Use the Your Clinical Judgment to Help You

In cases where the diagnosis is unclear, asking around PLMs or a family history of RLS can be helpful. Other clinical features, such as response to a dopaminergic agent can also help with the differential diagnosis.
Restless Leg vs. Akathisia
  • In RLS, there is always an urge to move, but there is a nocturnal worsening of symptoms
  • RLS is associated with paresthesias/dysesthesias in 25-50% of cases (described as “painful”)
  • RLS is worse or present only during rest, and
  • In both RLS and akathisia, symptoms may only be partially or temporarily relieved by activity
  • RLS can cause initial insomnia, not but middle insomnia
  • Hypersomnia can result in RLS
Secondary Causes
  • Iron deficiency, uremia, RA, peripheral neuropathy, diabetes, pregnancy, spinal cord lesion, medications (e.g. - antipsychotics)
  • SSRIs can also exacerbate RLS

Pathophysiology

  • Pathophysiological mechanisms of RLS are still being investigated. RLS is thought to be due to disturbances in the central dopaminergic system as a reduction of D2 receptor binding is seen in the caudate and putamen (on SPECT/PET).[1]
  • The positive treatment effects of dopamine agonists (D2 and D3 non-ergot) also further suggest that RLS is due to dysfunctional central dopaminergic pathways.
  • Low brain iron concentrations, disturbances in iron metabolism, and disturbances in brain iron transport are also thought to be involved.
    • In CSF samples, iron and ferritin values are also lower and transferrin levels are higher in individuals with RLS.[2] The endogenous opiate system may also be involved.[3]
  • Genome-wide association studies (GWAS) have found that RLS is significantly associated with common genetic variants in intronic or intergenic regions in MEISl, BTBD9, and MAP2K5 on chromosomes 2p, 6p, and 15q, respectively. The BTBD9 variant confers a very large risk when even a single allele is present.

Investigations

Ferritin

  • Serum ferritin levels below 75 ng/mL (75 μg/L) can exacerbate RLS symptoms. Patients diagnosed with RLS or patients with a recent exacerbation should have serum ferritin levels measured.[4]

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.

Treatment

Iron Supplementation

If there is iron deficiency, it is reasonable to start with iron supplementation as a first-choice and might be an easy “fix” if the serum ferritin level is <75.

Medications

First-line treatment for RLS is with dopamine agonists.[5]

Treatment for RLS

1st line (α2δ Subunit Gaba-ergic Agonists) • Gabapentin (300 to 2000 mg PO q evenings
)
• pregabalin (50 to 450 mg PO daily)
2nd line (Dopamine agonists) • Rotigotine (Neupro) patch (1 mg to 4 mg patch/24 hours)
• Pramipexole (0.125 to 0.5 mg PO qHS
)
L-dopa should no longer be used due to the high risk for augmentation!
3rd line Opioids:
Codeine (15 to 120 mg PO daily), Tramadol (50 mg to 100 mg PO prn), methadone (5 to 30 mg PO daily)
Benzodiazepines:
Clonazepam (0.5 to 3 mg PO daily), temazepam (15 to 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, like pregabalin
  • If your patient has ADHD, then you should treat with clonidine

Avoid Using Serotonergic Antidepressants

Although treatment of RLS will can reduce depressive symptoms, using serotonergic antidepressants (i.e. - SRRIs, SNRIs) can actually induce or aggravate RLS in some individuals.

Resources

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Articles
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References

1) Miyamoto, M., Miyamoto, T., Iwanami, M., Suzuki, K., & Hirata, K. (2009). Pathophysiology of restless legs syndrome. Brain and nerve= Shinkei kenkyu no shinpo, 61(5), 523-532.
2) Mizuno, S., Mihara, T., Miyaoka, T., Inagaki, T., & Horiguchi, J. U. N. (2005). CSF iron, ferritin and transferrin levels in restless legs syndrome. Journal of sleep research, 14(1), 43-47.
3) Walters, A. S., Ondo, W. G., Zhu, W., & Le, W. (2009). Does the endogenous opiate system play a role in the Restless Legs Syndrome?: A pilot post-mortem study. Journal of the neurological sciences, 279(1-2), 62-65.
4) Aul EA, Davis BJ, Rodnitzky RL. The importance of formal serum iron studies in the assessment of restless legs syndrome. Neurology. 1998;51(3):912.
5) Trenkwalder, C., Stiasny, K., Pollmächer, T., Wetter, T., Schwarz, J., Kohnen, R., ... & Oertel, W. H. (1995). L-dopa therapy of uremic and idiopathic restless legs syndrome: a double-blind, crossover trial. Sleep, 18(8), 681-688.