The exact cause is unknown, but it’s strongly linked to CNS iron deficiency and subsequent dopamine dysregulation in the basal ganglia.
Can be Primary (Idiopathic), often with a positive family history (autosomal dominant), or Secondary.
Secondary Causes are high-yield and include:
Iron Deficiency Anemia: Most common and well-established secondary cause.
Uremia (ESRD): Present in up to 50% of patients on dialysis.
Pregnancy: Common, especially in the third trimester, and usually resolves post-delivery.
Peripheral neuropathy (e.g., from diabetes).
Medications: Antihistamines, antipsychotics (dopamine antagonists), and some antidepressants (SSRIs) can trigger or worsen symptoms.
Pathophysiology
The pathophysiology of RLS is incompletely understood but likely involves CNS iron deficiency (even in patients with normal serum iron levels) and abnormalities in dopaminergic transmission.
Evening/night worsening of symptoms (circadian pattern)
Leads to significant sleep disturbance and daytime fatigue.
Often associated with Periodic Limb Movements of Sleep (PLMS), which are involuntary, brief leg jerks during sleep.
Diagnostics
Clinical diagnosis: Based purely on clinical criteria (URGE criteria).
Initial / Essential Lab:
Serum Ferritin Level: Must check in all suspected pts; treat if serum ferritin ≤ 75 µg/L. c
Adjunctive Labs:
CBC (screen for anemia).
BUN/Cr (screen for uremia/renal failure).
Fasting glucose / HbA1c (screen for DM).
Polysomnography (PSG): Not required for diagnosis; indicates PLMS if performed.
EMG / Nerve Conduction Studies (NCS): Not indicated unless peripheral neuropathy or radiculopathy is suspected.
Treatment
Address and treat any underlying secondary cause first (e.g., iron supplementation, optimizing dialysis).
First-line pharmacologic agents have shifted according to recent guidelines:
Alpha-2-delta calcium channel ligands: Gabapentin or pregabalin are now strongly recommended as first-line therapy. They are particularly useful if the patient also has insomnia or neuropathic pain.
Dopamine Agonists (pramipexole, ropinirole):
Previously first-line, but their use is now discouraged for standard, long-term treatment due to the high risk of augmentation. Augmentation is a paradoxical worsening of symptoms with long-term use (earlier onset, increased intensity, spreading to arms).
Iron Supplementation:
Essential if iron stores are low (Ferritin ≤75 ng/mL).
Both oral (ferrous sulfate) and IV iron formulations (ferric carboxymaltose) are used. IV iron may be considered if oral iron is not tolerated or in more severe cases.
Refractory Cases:
Low-dose opioids may be considered for severe, refractory cases but require cautious use.