Restless Legs Syndrome

Restless legs syndrome (RLS) (also known as Willis-Ekbom disease) is characterized by an intense crawling sensation deep inside the lower legs. Most cases are familial but can be secondary to an underlying illness. Management includes treating underlying diseases, nonpharmacologic therapy, and pharmacological therapy. Severe RLS may spread to the arms and significantly reduce the quality of life. This chapter discusses etiology, pathophysiology, clinical features, diagnostic evaluation, and management of RLS.

Introduction

  • Restless legs syndrome (RLS) is also known as Willis-Ekbom disease
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Characterized by an intense unpleasant crawling sensation deep inside the lower legs
Often neglected in a clinical setting
The prevalence varies between 3.9% and 14.3% in general populations
  • Management includes treating the underlying diseases, nonpharmacologic therapy, and pharmacological therapy

Etiology

Primary (most common)

  • Idiopathic
  • Familial in ~77% of cases

Secondary

  • Iron deficiency
  • End-stage renal disease
  • Parkinson’s disease
  • Diabetes mellitus
  • Pregnancy
  • Peripheral neuropathy
  • Medication (dopamine antagonist, diphenhydramine, tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs]

Pathophysiology

  • Diminish central nervous system (CNS) iron stores
    • Studies of cerebrospinal fluid (CSF) found that RLS patients have lower ferritin and iron but higher transferrin values compared to non-RLS individuals
    • Magnetic resonance imaging (MRI) imaging with iron-sensitive sequences showed low iron content in the substantia nigra and the thalamus
  • Dopaminergic pathway
    • Despite the dramatic response of RLS symptoms to dopamine agonists, there is little evidence showing dopaminergic deficiency in patients with RLS
    • Remain not fully understood, possibly due to increased dopamine turnover
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RLS is strongly associated with family history, which has been previously reported in 40% to 60% of RLS patients. Miyamoto and colleagues have described five RLS-related loci, including RLS 1: 12q, RLS 2: 14q, RLS 3: 9p, RLS 4: 2q, and RLS 5: 20p
  • Elevating cerebral glutamate and decreasing adenosine may also play a role
  • Further investigations are needed to find the relationship between those mechanisms

Clinical features

  • Typical signs and symptoms include:
    • Unpleasant urge to move the legs
    • Begins and/or gets worse while resting, most prominent in the evening or at night
    • Temporarily relieved by movements
  • Patients with secondary RLS may have symptoms of underlying problems (e.g., end-stage renal disease, Parkinson’s disease, diabetes mellitus)

Diagnostic Evaluation

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RLS is a CLINICAL diagnosis!

Essential criteria by the International Restless Legs Syndrome Study Group (IRLSSG)*

  1. An urge to move the legs (and arms in some cases) with/without unpleasant sensations
  1. The urge begins or worsens during periods of inactivity
  1. The urge is partially or totally relieved by movement
  1. The urge only occurs or is worse in the evening or night than during the day
  1. Not associated with other disorders
* ALL criteria must be fulfilled

Clinical course

  • Intermittent RLS: bothersome symptoms required treatment, occurring on average <2 times/week for the past year
  • Chronic-persistent RLS: bothersome symptoms required treatment, occurring on average at least two times/week for the past year
  • Refractory RLS: unresponsive to monotherapy with tolerable doses of first-line treatment due to reduction in efficacy, augmentation, or adverse effects
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Determining a clinical course is very important for the next step in management!
  • Based on clinical judgment → order further diagnostic tests to RULE OUT suspected underlying causes or comorbidities
    • Laboratory tests (e.g., complete blood count [CBC], kidney functions, thyroid function tests, vitamin B9, vitamin B12)
    • Electromyography (EMG) and nerve conduction velocity (NCV) study → examine peripheral neuropathy or radiculopathy
    • Polysomnography → investigate Periodic limb movements disorder (PLMD)

Management

notion image

Iron therapy

  • Considering the pathophysiology of lower than normal iron stores in the CNS → order a full iron panel even in non-anemic individuals
    • 💡
      Full iron panel: serum iron, ferritin, total iron-binding capacity, and transferrin saturation (early morning after an overnight fast)
      💡
      Empirically iron prescription is NOT recommended due to an unknown iron overloaded status (e.g., undiagnosed hemochromatosis)

Oral iron therapy

  • Indication:
    • Serum ferritin ≤75 ug/L and transferrin saturation <45%
    • During and 6 weeks after an acute inflammatory phase, serum ferritin level could be falsely increased → transferrin saturation <20% is a more reliable measurement
  • Dosage:
    • Ferrous sulfate 325 mg (65 mg iron) with 100-200 mg vitamin C once a day or once every two days
    • 💡
      Vitamin C facilitates iron absorption in the duodenum
  • Usage:
    • In macaque monkeys, some authors observed that their brains absorbed iron more efficiently at night than in the morning → consider taking iron at night
    • Can be taken with food not high in calcium
  • Follow-up:
    • Check ferritin level after 3-4 months, then every 3-6 months. If ferritin level reaches 100 μg/L, consider stopping oral iron therapy
    • 💡
      There are very limited benefits of further taking oral iron when serum ferritin is ≥100 μg/L
  • Adverse effects:
    • Darkening of stools
    • Nausea
    • Abdominal pain

Intravenous (IV) iron therapy

  • Indication (meet any of the following):
    • Serum ferritin level 76-100 μg/L and transferrin saturation <45%
    • A need for a rapid response
    • Unable to adequately absorb oral iron (e.g, gastrointestinal disorders, bariatric surgery, or undesirable side effects)
    • Unresponsive despite an adequate 3-month trial of oral iron therapy
  • Dosage:
    • Can choose any of the FDA-approved IV iron formulations for iron deficiency anemia
    • Ferric carboxymaltose (most commonly used):
      • One single infusion (over 10 to 15 minutes) or two doses of 500 mg at 5- to 7-day intervals
      • Expect to see a clinical improvement in 4-6 weeks or longer
  • Follow-up:
    • Reevaluate in 4-6 weeks
    • If there is an adequate response but symptoms recur → consider repeat infusion at least 12-week intervals as long as serum ferritin concentration is <300 μg/L and transferrin saturation is <45%
    • If there is an ambiguous response → consider giving the 2nd infusion, especially when serum ferritin ≤100 μg/L
  • Adverse effects:
    • Hypophosphatemia
    • Nausea
    • Flushing

Nonpharmacologic therapy

  • Lifestyle changes: abstinence from coffee, nicotine, and alcohol
  • Improve sleep hygiene
  • Regular exercise
  • Avoid medication-induced RLS
  • May consider low-risk therapies such as yoga and acupuncture

Intermittent RLS

  • Nonpharmacologic therapy
  • Iron work-up → correct iron store if needed
  • Medication:
    • Oral carbidopa/levodopa as needed
      • Dosage: 25 mg/100 mg (immediate-release [IR] or controlled-release [CR])
      • Usage:
        • Before bedtime (or before any activities triggering RLS)
        • Avoid taken with protein-rich foods to maximize absorption efficiency
      • Adverse effects:
        • Exacerbate dyskinesia
        • Nausea and vomiting
        • Impulse control disorders
        • Orthostatic hypotension
        • Peripheral neuropathy
      💡
      Daily taking ≥200 mg of levodopa increases the risk of augmentation (drug-induced worsening of RLS) → only use levodopa for intermittent RLS
    • Low-potency opioids as needed
      • Dosage:
        • Codeine: 30 to 90 mg with acetaminophen
        • Tramadol: 50 to 100 mg
      • Usage:
        • Before bedtime or during the night
    • Benzodiazepine or nonbenzodiazepine receptor agonists as needed
      • It may be beneficial in patients comorbid with sleep disorders
      • Dosage:
        • Clonazepam (the best-studied benzodiazepine): 1 mg
        • Nonbenzodiazepine receptor agonists:
          • Short-acting agents: beneficial for sleep-onset insomnia complicated by RLS
            • Zolpidem/Zaleplon 5-10 mg
          • Intermediate-acting agents: beneficial in cases RLS wakes patients up during the night
            • Temazepam 15-30 mg
            • Eszopiclone 1-3 mg
      • Usage:
        • Before bedtime
      • Adverse effect
        • Falls during the night and cognitive problems, especially in the elderly
        • Zolpidem may cause sleepwalking and sleep-related eating disorder
        • Clonazepam may cause unsteadiness at night and drowsiness in the morning

Chronic-persistent RLS

  • Nonpharmacologic therapy
  • Iron work-up → correct iron store if needed
  • Monotherapy medication:
    • First-line: Alpha-2-delta calcium channel ligands
      • Table 1: Dosage of Alpha-2-delta calcium channel ligands used to treat RLS

        Gabapentin
        Pregabalin
        Gabapentin enacarbil
        Starting dose (dose in patients ≥ 65 years old)
        300 mg (100 mg)
        75 mg (50 mg)
        600 mg (300 mg)
        Maximum dose
        3600 mg
        450 mg
        600-1200 mg
        💡
        Alpha-2-delta calcium channel ligands are excreted via the kidney → adjust doses in renal impairment
      • Usage:
        • Instruct patients to increase the dose every few days from the initial dose until they meet the relief of a desirable symptom
        • Take once or twice a day, ideally 1-2 hours before the onset of symptoms
      • Follow-up:
        • The frequency is based on individual responsiveness, usually starting with at least every 3 months
      • Adverse effect:
        • Gait ataxia
        • Respiratory depression
        • Daytime drowsiness
    • Second-line: non-ergot dopamine agonists
      • Table 2: Dosage and usage of dopamine Agonists used to treat RLS

        Pramipexole
        Ropinirole
        Rotigotine patch
        Starting dose
        0.125 mg
        0.25-0.5 mg
        1 mg
        Maximum dose
        0.5 mg
        2-4 mg
        3 mg
        Usage
        - Once daily, 2 hours before bedtime - Increased by 0.125 mg every 2-3 days until symptoms relieve
        - Once daily (1.5 hours before bedtime) or twice a day (1st dose: late afternoon; 2nd dose: 1-2 hours before bedtime - Increased by 0.25-0.5 mg every 2-3 days until symptoms relieve
        - Once-daily
        💡
        Avoid Ropinirole and Rotigotine in patients with hepatic failure. All those three are excreted via the kidney → adjust doses in renal impairment
      • Follow-up:
        • Every 6-12 months to assess efficiency and complications (augmentation and impulse control disorder)
      • Adverse effects:
        • Leg edema
        • Constipation
        • Insomnia
        💡
        Two reasons dopamine agonists are less favored compared to Alpha-2-delta calcium channel ligands: - ↑ augmentation (drug-induced worsening of RLS) - ↑ the risk of impulse control disorder

Refractory RLS

  • Nonpharmacologic therapy
  • Iron work-up → correct iron store if needed
  • Medication:
    • Consider a combination of drugs used to treat intermittent and chronic-persistent RLS mentioned above
    • 💡
      Adjust a dose of a prior medication while adding a new agent into the regimen → optimizing potential adverse effects
    • Opioids as monotherapy
      • Indication (all should be considered before starting opioids)
        • Symptoms remain despite an adequate iron store
        • Rule out all possible exacerbating factors
        • Rule out dopamine agonist augmentation
        • Fail a combination therapy trial

      Table 3: Dosage of opioids

      Type
      Agent
      Lowest starting dose (mg)
      Usual effective dose range (mg)
      Low-potency opioids
      Tramadol (IR or ER)
      50 (100 with ER)
      50-100
      Codeine
      30
      60-180
      High-potency opioids
      Morphine CR
      10-15
      15-45
      Oxycodone (IR or ER)
      5-10
      10-30
      Hydrocodone (IR or ER)
      10-15
      20-45
      Methadone
      2.5-5
      5-20
    • Usage and follow-up:
      • May vary among physicians’ preferences, opioids regulation in each country, clinical scenarios, medication pricing, and patients’ tolerance
      • Important keynotes:
        • Before prescribing opioids → obtain a thorough medical, social, and family history including alcohol or drug abuse with previous/current medications, and past/present psychiatric disorders
        • Opioids could be a lifelong treatment; the goal is to reduce symptoms and improve quality of life
        • Avoid taking opioids with alcohol and benzodiazepines
        • Reevaluate every 3 to 6 months to determine efficacy, side effects, and any evidence for opioid use disorder or misuse
        • 💡
          Refractory RLS can be extremely devastating for patients’ quality of life with comorbidities including depression, suicidal ideation, and severe insomnia. After careful consideration, physicians should not be reluctant to prescribe a long-term opioids plan
    • Adverse effects:
      • Can suppress gonadotropin-releasing and luteinizing hormones → low-testosterone-related symptoms, such as excessive sweating, sexual dysfunction, and lowered mood
      • Daytime drowsiness
      • Cognitive dysfunction

Prognosis

  • The symptoms gradually become moderate to severe in ~70% of patients and may spread to the arms
  • Spontaneously resolve in some cases but recurring is common
  • If left unnoticed, RLS can significantly reduce the quality of life (e.g., depression, daytime fatigue, and insomnia)

Further Reading

Bibliography

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  • Cornelius, J. R., Tippmann-Peikert, M., Slocumb, N. L., Frerichs, C. F., & Silber, M. H. (2010). Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: A case-control study. Sleep, 33(1), 81–87.
  • Allen, R. P., Picchietti, D. L., Auerbach, M., Cho, Y. W., Connor, J. R., Earley, C. J., Garcia-Borreguero, D., Kotagal, S., Manconi, M., Ondo, W., Ulfberg, J., & Winkelman, J. W. (2018). Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: An IRLSSG task force report. Sleep Medicine, 41, 27–44. https://doi.org/10.1016/j.sleep.2017.11.1126
  • Earley, C. J., & Allen, R. P. (1996). Pergolide and Carbidopa/Levodopa Treatment of the Restless Legs Syndrome and Periodic Leg Movements in Sleep in a Consecutive Series of Patients. Sleep, 19(10), 801–810. https://doi.org/10.1093/sleep/19.10.801
  • Earley, C. J., Allen, R. P., Connor, J. R., Ferrucci, L., & Troncoso, J. (2009). The dopaminergic neurons of the A11 system in RLS autopsy brains appear normal. Sleep Medicine, 10(10), 1155–1157. https://doi.org/10.1016/j.sleep.2009.01.006
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