Restless legs syndrome

Restless legs syndrome (RLS), also referred to as Willis-Ekbom disease (WED), is a relatively common, neurological sleep disorder characterized by unpleasant sensations in the legs and a strong urge to move them. The urge increases during periods of rest, especially in the evenings, and may diminish with movement. Primary RLS is idiopathic and is often associated with a positive family history. Secondary RLS is less common and can result from a variety of underlying conditions, including iron deficiency, attention deficit hyperactivity disorder (ADHD), uremia, and Parkinson disease. Diagnostic tests are used to exclude secondary causes of RLS. Tests include ferritin levels, vitamin levels, autoantibody assays, thyroid profile, etc. Treatment for severe primary RLS includes alpha-2-delta calcium channel ligands, while secondary RLS is managed by treating the underlying cause. If left untreated, RLS can cause significant social and functional impairment.

• 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: (common): idiopathic, but is familial in up to 77% of cases ^[3]
• Secondary
  • Chronic conditions
    • Iron deficiency with or without anemia, vitamin deficiency
    • Peripheral neuropathy (e.g., in diabetes mellitus)
    • End-stage renal disease (uremia)
    • Inflammatory conditions: celiac disease, rheumatoid arthritis, inflammatory bowel diseases ^[4][5]
    • Psychiatric: depression, anxiety disorders
    • Neurological: Parkinson disease, polyneuropathies, spinal cord diseases, multiple sclerosis
  • Drugs ^[6]
    • H1 antihistamines
    • Antidepressants (e.g., TCAs, SSRIs, SNRIs)
    • Dopamine antagonists (neuroleptics, metoclopramide, MDMA)
    • 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 clinical features ^[9]
  • A recurrent, uncomfortable urge to move the legs that is:
    • Typically relieved by movement
    • Begins and/or worsened with rest
  • Symptoms are worse in the evening and at night (may occur exclusively at night)
  • Can be accompanied by dysesthesias (e.g., pain, pins and needles, itching, tickling, or crawling sensations).
• Other features
  • In secondary RLS: clinical features of the underlying disease (e.g., signs of chronic kidney disease, signs of Parkinson disease)
  • Can be associated with periodic leg movements of sleep (PLMS): frequent, involuntary flexions and extensions of the toes and ankles (and sometimes the knee and hip) during sleep ^[10]
    • Most commonly associated with restless legs syndrome, but can also occur in other sleep disturbances (e.g., narcolepsy)
    • Rarely, it can occur in isolation, in which case it is known as periodic limb movement disorder (PLMD)

RLS is mainly a clinical diagnosis but additional testing may be indicated to rule out an underlying disease, including conducting laboratory tests, nerve conduction studies, polysomnogram, and needle electromyogram.

• Clinical diagnosis (according to DSM V) ^[11]
  • See “Clinical features” above
  • Symptoms occur at least 3 times per week and persist for at least 3 months
  • Symptoms cause significant distress or impairment in social, occupational, educational, academic, behavioral, or other areas of functioning
  • Symptoms cannot be attributed to another medical condition (e.g., leg edema, arthritis, leg cramps) or behavioral condition (e.g. positional discomfort, habitual foot tapping)
  • Symptoms cannot be explained by drug/medication abuse
• Laboratory tests
  • Iron studies (best initial test)
  • Other: CBC, kidney function tests, TSH, vitamin B12, folic acid, Mg²⁺
• Polysomnogram: quantification of periodic limb movements of sleep (PLMS)
• Needle electromyogram and nerve conduction studies: if a polyneuropathy or radiculopathy is suspected ^[12]

Treatment for primary RLS is largely symptomatic. Treatment of secondary RLS depends on the underlying cause. Intermittent treatment may be necessary for recurrent cases with spontaneous remission.

• General
  • Lifestyle changes: abstinence from coffee, nicotine, and alcohol
  • Discontinue offending agent (e.g., dopamine antagonists).
  • Supplemental iron only if serum ferritin < 75 ng/mL. ^[13]
  • Treatment of underlying conditions
• Medical therapy: indicated in patients with significant functional and sleep impairment ^[14]
  • For intermittent symptoms: levodopa with carbidopa
  • In chronic persistent symptoms
    • First-line: alpha-2-delta calcium channel ligands (gabapentin, gabapentin enacarbil, or pregabalin)
    • Second-line: dopamine agonists (e.g., pramipexole, ropinirole; , rotigotine, cabergoline)
  • If not responsive to any other therapy: benzodiazepines (e.g., clonazepam) or opioids (e.g., codeine)
• Vibrating pad: provides counterstimulation to the patient's legs while lying in bed (improves sleep quality)