What investigations and management are recommended for patients presenting with restless legs syndrome (RLS)?

Investigations and Management of Restless Legs Syndrome (RLS)

Alpha-2-delta ligands (pregabalin and gabapentin) are strongly recommended as first-line pharmacologic therapy for RLS due to their strong efficacy and favorable long-term safety profile compared to dopaminergic agents, which should only be used short-term due to risk of augmentation. 1

Diagnostic Criteria and Initial Evaluation

The diagnosis of RLS is primarily clinical, based on the following essential criteria:

1. Urge to move the legs, usually with uncomfortable sensations
2. Symptoms worsen during periods of rest or inactivity
3. Symptoms improve with movement
4. Symptoms worsen in the evening or at night 2

Key Investigations

• Blood tests:

  • Serum ferritin, transferrin saturation, iron studies
  • Renal function, electrolytes
  • Thyroid function
  • HbA1c, calcium 2, 1
  • Consider initiating iron therapy if ferritin ≤75 ng/mL or transferrin saturation <20% 1

• Urine tests:

  • Albumin:creatinine ratio
  • Dipstick for blood/protein 2

• Other assessments:

  • 72-hour bladder diary (if nocturia is present)
  • Blood pressure assessment 2
  • Pregnancy test where applicable 2

Screening for Comorbid Conditions

Assess for conditions that commonly coexist with RLS (SCREeN conditions):

• Sleep disorders: OSA, insomnia, periodic limb movements of sleep
• Cardiovascular: hypertension, CHF
• Renal: CKD
• Endocrine: diabetes, thyroid disorders
• Neurological conditions 2

Management Algorithm

First-Line Treatment

1. Non-pharmacological approaches:

   • Regular aerobic and resistance exercise
   • Good sleep hygiene
   • Avoidance of substances that worsen RLS (caffeine, alcohol, antihistamines, most antidepressants) 1

2. Iron therapy:

   • Initiate if ferritin ≤75 ng/mL or transferrin saturation <20%
   • Oral ferrous sulfate for most patients
   • IV ferric carboxymaltose for inadequate response to oral iron
   • IV iron sucrose for ESRD patients with ferritin <200 ng/mL and transferrin saturation <20% 1

3. Pharmacological therapy:

   • Alpha-2-delta ligands (first-line): pregabalin or gabapentin 1
     • Preferred over dopaminergic agents due to lower risk of augmentation
     • Particularly recommended for patients with CKD or ESRD (with dose adjustment)

Second-Line Treatment

• Dopamine agonists (short-term use only):
  • Ropinirole, pramipexole, or rotigotine patch 1, 3
  • Initiate at low doses (e.g., ropinirole 0.25 mg once daily) 3
  • Titrate based on clinical response and tolerability
  • Monitor closely for augmentation (paradoxical worsening of symptoms)
  • Mean effective dose of ropinirole is approximately 2 mg/day 3

Refractory RLS

• Opioids:

  • Extended-release oxycodone for moderate to severe RLS that has failed other therapies 1
  • Requires monitoring for respiratory depression and central sleep apnea

• Combination therapy:

  • Consider combining medications from different classes
  • Alpha-2-delta ligands plus low-dose dopamine agonists
  • Alpha-2-delta ligands plus opioids 1

Special Populations

Patients with End-Stage Renal Disease

• First-line: Gabapentin (with dose adjustment)
• Consider cool dialysate for patients on hemodialysis
• IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 1

Pregnant Patients

• Prioritize non-pharmacological approaches
• Careful risk-benefit assessment for any medication use 1

Children

• Iron therapy as first-line for those with low iron stores
• Limited evidence for medications; no FDA-approved options 1

Management of Augmentation

Augmentation is a serious iatrogenic complication of dopaminergic therapy characterized by:

• Earlier onset of symptoms during the day
• Increased symptom intensity
• Spread of symptoms to other body parts
• Shorter duration of relief from medication

If augmentation occurs:

1. Gradually taper and discontinue the dopamine agonist
2. Transition to alpha-2-delta ligands or opioids
3. Consider IV iron therapy 1

Monitoring and Follow-up

• Regular assessment of symptom severity using validated tools (International RLS Rating Scale)
• Monitor for medication side effects, particularly augmentation with dopaminergic agents
• Periodic reassessment of iron status
• Evaluate for development or worsening of comorbid conditions

By following this structured approach to the investigation and management of RLS, clinicians can effectively diagnose and treat this common condition while minimizing the risk of treatment complications.