Restless Legs Syndrome

Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. The syndrome can be idiopathic, or due to secondary causes such as iron deficiency, pregnancy, diabetes mellitus, uremia, and Parkinson’s disease. Some drugs, most notably antidepressants and metoclopramide, can also trigger the syndrome. Management involves treatment of the underlying condition, supportive measures, and dopamine agonists.

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Epidemiology and Pathology

Epidemiology

  • Prevalence:
    • Approximately 2% of the population are affected by a severe form of restless legs syndrome (RLS).
    • Approximately 20% experience a milder form of RLS at some point in their lives.
    • Highest prevalence: Northern Europe and North America
    • Lowest prevalence: Africa
  • More common in women than men (attributed to pregnancy as risk factor)
  • Positive family history in 40%–60% of cases
  • Age of onset:
    • RLS has been described in all age groups.
    • Most common and most severe in the middle-aged and elderly populations

Pathophysiology

The exact pathophysiology of RLS is still under investigation. Although more frequent in advanced age, neurodegenerative processes are not shown to play a role in RLS. Studies have shown some factors causative for or associated with the condition:

  • Central nervous system:
    • Reduced central iron stores
    • Abnormalities in dopaminergic systems 
    • Thalamic dysfunction 
    • Impaired neurotransmitter metabolism (glutamate, glutamine, GABA, endogenous opioids) 
  • Peripheral nervous system:
    • A-delta fiber sensitization (transmits signals of hyperalgesic, neuropathic pain)
    • Altered, intramuscular blood flow of the leg
    • Peripheral hypoxia 
    • Altered endothelial function
  • Other:
    • Family history and genetics
    • Iron deficiency anemia and low iron stores
    • Pregnancy (especially in the 3rd trimester) 
    • Chronic kidney disease (uremia)
    • Parkinson’s disease
    • Multiple sclerosis
    • Diabetes mellitus
    • Thyroid disorders
    • Drugs:
      • Antidepressants
      • Antihistamines
      • Dopamine receptor antagonists 
      • Caffeine

Clinical Presentation and Diagnosis

Clinical presentation

  • Patients complain of a constant, intense urge to move their legs or arms (rarely other body parts):
    • Worsened with inactivity
    • Relieved with movement
    • Worse at night than during the day
  • The sensations triggering the urge to move may be described as:
    • Unpleasant, but not necessarily painful 
    • Deep
    • Tingling
    • Burning
    • Itching
    • Creeping
    • Cramping
    • Tension 
  • Symptoms are unexplained by other medical or behavioral disorders.
  • Symptoms in arms: described mostly in severe, persistent RLS 
  • Secondary symptoms: insomnia, depression, anxiety

Diagnosis

The diagnosis is made clinically using the criteria above.

  • Laboratory studies to exclude secondary causes:
    • Iron studies
    • BUN
    • Creatinine
    • Fasting blood glucose
    • Thyroid-stimulating hormone (TSH)
    • Vitamin B12
    • Folate
    • Magnesium
  • Needle electromyography (EMG) and nerve conduction studies should be considered if polyneuropathy or radiculopathy is suspected.

Management and Prognosis

Nonpharmacologic management

  • Recommended for mild to moderate RLS
  • Avoid aggravating medications or substances (caffeine).
  • Supportive measures (exercise, leg massages, heating pads, education)
  • Treat the underlying cause:
    • Iron replacement if ferritin is ≤ 75 μg/L
    • Hemodialysis in the case of renal failure

Pharmacologic management

  • Recommended for chronic to severe RLS
  • Levodopa: used for intermittent RLS (not daily symptoms)
  • Alpha-2-delta calcium channel ligands:
    • 1st-line treatment
    • Best for patients with comorbid pain, anxiety, insomnia, or addiction to dopamine agonists
    • Examples: gabapentin, pregabalin 
  • Dopamine agonists: 
    • 1st-line treatment
    • Best for patients with comorbid depression or obesity/metabolic syndrome
    • Examples: pramipexole, ropinirole, rotigotine
  • Anticonvulsants:
    • Consider in severe cases (daily symptoms).
    • Examples: carbamazepine, valproate
  • Benzodiazepines and opioids can relieve symptoms, but are best avoided due to potential for misuse and dependency. 
  • Consider augmentation therapy (combination of 2 medications) in cases where monotherapy fails.

Prognosis

  • Spontaneous remission rates: 30%–60%
  • Risk factors for chronicity: positive family history, higher age of onset

Differential Diagnosis

  • Periodic limb movement disorder: a sleep disorder defined by an excessive number of periodic limb movements during sleep. The disorder can cause sleep disturbance, daytime fatigue, and polysomnography changes. Management is similar to RLS. Periodic limb movement disorder is a diagnosis of exclusion and should always be considered as a differential diagnosis to RLS. 
  • Akathisia: a movement disorder marked by an inner feeling of generalized restlessness and inability to sit down, and an intense urge to move. Akathisia is usually associated with the use of antipsychotic medications (especially dopamine antagonists). Unlike RLS, symptoms are not only present at night, are not accompanied by unpleasant sensations in the legs or other body parts, and do not improve with movement. 
  • Parasomnias: a pattern of sleep disorder marked by unusual actions, activities, or physiological events occurring during sleep or sleep-wake transitions. Symptoms may include abnormal movements, emotions, dreams, and autonomic activity. Unlike RLS, symptoms manifest during sleep and do not cause continued disturbance.

References

  1. Latha Ganti, Matthew Kaufman, and Sean Blitzstein. (2016). First Aid for the Psychiatry Clerkship, 4th edition. Chapter 15, sleep-wake disorders, page 169.
  2. Matthew Sochat, Tao Le, and Vikas Bhushan. (2019). First Aid for the USMLE Step 1, (29th ed.), page 507.
  3. Sadock, B. J., Sadock, V. A., & Ruiz, P. (2014). Kaplan and Sadock’s synopsis of psychiatry: Behavioral sciences/clinical psychiatry (11th ed.). Chapter 16, Sleep-wake disorders, pages 533–563. Philadelphia, PA: Lippincott Williams and Wilkins.
  4. Ondo, W. (2021). Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults Retrieved March 28, 2021, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-restless-legs-syndrome-and-periodic-limb-movement-disorder-in-adults 
  5. Mansur A, Castillo PR, Rocha Cabrero F, et al. Restless Leg Syndrome. [Updated 2020 Oct 23]. In: StatPearls [Internet]. Treasure Island (FL). https://www.ncbi.nlm.nih.gov/books/NBK430878/
  6. Lee, C. S., Kim, T., Lee, S., Jeon, H. J., Bang, Y. R., & Yoon, I. Y. (2016). Symptom Severity of Restless Legs Syndrome Predicts Its Clinical Course. The American journal of medicine, 129(4), 438–445. https://doi.org/10.1016/j.amjmed.2015.12.020

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