Restless legs syndrome

Restless legs syndrome (RLS; also referred to as Willis-Ekbom disease) is a common sleep-related movement disorder characterized by a strong urge to move the legs that is triggered and/or worsened with rest and is usually accompanied by uncomfortable sensations (e.g., pain, pins and needles, itching, tickling, crawling sensation). The urge to move the legs increases in the evenings and at night and is typically relieved by movement. Primary RLS is idiopathic but often associated with a positive family history. Secondary RLS is less common and results from a variety of underlying conditions (e.g., iron deficiency, uremia, Parkinson disease) and drugs (e.g., H1 antihistamines, antidepressants). Diagnostic studies (e.g., iron studies, polysomnography) can help exclude causes of secondary RLS and alternative diagnoses. Treatment depends on the duration and severity of symptoms and includes medications such as alpha-2-delta calcium channel ligands and treating underlying conditions (e.g., with iron supplementation).

• RLS affects up to 15% of the general US population. ^[1]
• Sex: ♀ > ♂
• Peak incidence: 30–40 years of age (often misdiagnosed as growing pains in childhood) ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Primary RLS: (common): idiopathic, but is familial in up to 77% of cases ^[3]
• Secondary RLS: caused by an underlying condition or drug
  • Chronic conditions include:
    • Iron deficiency with or without anemia, vitamin deficiency
    • Kidney failure (uremia)
    • Peripheral neuropathy (e.g., in diabetes mellitus)
    • Inflammatory conditions: celiac disease, rheumatoid arthritis, inflammatory bowel disease ^[4][5]
    • Psychiatric: depression, anxiety disorders
    • Neurological: Parkinson disease, polyneuropathies, spinal cord diseases, multiple sclerosis
  • Associated drugs include: ^[6]
    • H1 antihistamines
    • Antidepressants (e.g., TCAs, SSRIs, SNRIs)
    • Dopamine antagonists (neuroleptics, metoclopramide)
    • Lithium
    • Beta blockers
  • Pregnancy ^[7]

• The pathophysiology of RLS remains unclear.
• Studies suggest that abnormal dopamine pathways in the brain and impaired iron homeostasis (leading to iron deficiency in the substantia nigra) are the most prominent pathophysiological mechanisms involved. ^[8]

• Main features ^[9]
  • A recurrent urge to move the legs that is:
    • Typically relieved by movement
    • Triggered and/or worsened with rest
    • Worse in the evening and at night (may occur exclusively at night)
  • The urge to move the legs is often accompanied by uncomfortable sensations (e.g., pain, pins and needles, itching, tickling, or crawling sensations).
• Other features
  • Periodic limb movements of sleep; (PLMS) or periodic limb movements of wakefulness (PLMW) are common. ^[9]
  • Other sleep disorders may be present, e.g., insomnia.
  • Patients with secondary RLS may have clinical features of the underlying disease (e.g., signs of Parkinson disease or kidney failure).

General principles ^[10]

• RLS is mainly a clinical diagnosis.
• For all patients:
  • Perform a complete neurological examination.
  • Obtain iron studies.
• Obtain further diagnostic studies to:
  • Assess for underlying conditions (i.e., causes of secondary RLS)
  • Rule out alternative diagnoses (e.g., akathisia, polyneuropathy)
• Diagnostic criteria can help confirm the diagnosis.

Diagnostic criteria ^[9]

Diagnostic studies ^[10]

Laboratory studies

• Iron studies to assess for iron deficiency, i.e. either: ^[10]
  • Ferritin ≤ 75 ng/L and transferrin saturation < 45% ^[12]
  • Transferrin saturation < 20% in patients with acute or chronic inflammation ^[12]
• CBC to assess for anemia ^[10]
• Consider further studies based on clinical suspicion, e.g.:
  • Kidney function tests to assess for uremia
  • HbA1c, folate, and vitamin B₁₂ levels if there are signs of peripheral neuropathy

Advanced testing

• Polysomnography
  • To assess for PLMS and PLMW if diagnosis is uncertain
  • To rule out other sleep disorders, e.g., obstructive sleep apnea
• Electromyography and nerve conduction studies: to rule out alternative diagnoses, e.g., polyneuropathy or radiculopathy ^[10]

30% of patients with iron deficiency have symptoms of RLS. ^[10]

Treatment is mainly symptomatic. Pharmacotherapy is based on the severity and frequency of symptoms and the presence of comorbidities.

General principles ^[10][12]

• Treat underlying and comorbid conditions.
  • Iron supplementation for patients with iron-deficiency
  • Cognitive behavioral therapy, e.g., for concomitant depression
  • Management of coexisting sleep disorders
• Consider discontinuing or adjusting medications that may cause or aggravate RLS symptoms.
• Encourage lifestyle modifications.
  • Consider a trial period of avoiding exacerbating factors, e.g., coffee and alcohol.
  • Sleep hygiene counseling
  • Regular physical activity
  • Activities to distract from symptoms, e.g., video games, crosswords
• Consider stimulation techniques, e.g., vibrating pad, acupuncture, magnetic or electrical stimulation.
• Consider pharmacotherapy in patients with inadequate response to iron supplementation and supportive care.

Iron supplementation ^[12]

• Provide oral iron supplementation; e.g., ferrous sulfate with vitamin C for patients with serum ferritin ≤ 75 ng/L and transferrin saturation < 45% ^[10][12]
• IV iron supplementation, e.g., ferric carboxymaltose , may be indicated for patients with: ^[13]
  • Moderate or severe chronic persistent RLS and either:
    • Serum ferritin levels 76–100 ng/L ^[12]
    • Need for rapid increase in iron stores
  • Intolerance or inadequate absorption of oral iron
  • Inadequate improvement after 3 months of oral iron supplementation
• Monitor serum ferritin levels every 3–6 months.
  • Safe ULN of serum ferritin: 300 ng/L
  • Consider stopping iron supplementation if ferritin levels > 100 ng/L in the absence of ongoing reasons for iron deficiency.

Pharmacotherapy ^[10][12]

Intermittent RLS

• Consider intermittent pharmacotherapy if supportive care is unsuccessful.
• Options include:
  • Carbidopa/levodopa (off-label) ^[10][12]
  • Benzodiazepines (e.g., clonazepam) or benzodiazepine receptor antagonists (e.g., temazepam)
  • Low-potency opioids, e.g., codeine, tramadol

Chronic persistent RLS ^[12]

• Alpha-2-delta ligands (e.g., gabapentin enacarbil: , pregabalin (off-label) , or gabapentin: first-line for most patients, unless contraindicated ^[12][13]
• Low-dose nonergot dopamine agonists (e.g., pramipexole , ropinirole , rotigotine ) ^[12][13]
  • Second-line for most patients
  • First-line for patients with any of the following:
    • Very severe RLS or PLMS
    • Associated moderate or severe depression, obesity, conditions that have caused respiratory failure, and history of substance use disorder
    • Compromised kidney function

Refractory RLS (or RLS associated with a severe pain disorder)

• Consider either:
  • Combination therapy with alpha-2-delta ligands and dopamine agonists
  • Low-dose opioids, e.g., codeine ^[12]
• Reassess iron studies.

For pregnant patients, nonpharmacological interventions are the mainstay of treatment because most pharmacological agents are contraindicated. ^[10][12]

Close follow-up with risk mitigation for opioid prescribing is required for patients taking opioids. ^[10]