characterized by dysesthesia (eg, crawling or itching feelings) and an irresistible urge to move the legs when at rest. RLS does not cause pain, numbness, or sensory deficits. It is classified as primary (if idiopathic) or secondary (if accompanied by a predisposing condition, such as diabetes mellitus).

“uncomfortable sensations in her legs, especially at bedtime and when sitting for prolonged durations (eg, when watching a movie). The patient has no leg pain or pins and needles sensation, and the symptoms improve once she gets up and moves around. Her husband states that she frequently gets in and out of bed.”

| Manifestations | Uncomfortable urge to move legs with: • Unpleasant sensations in the legs • Onset with inactivity or at night • Relief with movement (eg, walking, stretching) partially interfere with duration and quality of sleep. | | --- | --- | | Risk factors & Associated conditions | • Iron deficiency or even low-normal ferritin levels (≤75 ng/mL) • Uremia • Pregnancy • Diabetes mellitus (especially with neuropathy) • Multiple sclerosis, Parkinson disease • Drugs: antidepressants, antipsychotics, antiemetics, antihistamines | | Diagnosis | • Clinical but serum iron studies should be obtained | | Non-pharmacologic therapy | • Limit caffeine & alcohol • Regular, moderate exercise • Warm &/or cold soaks or compresses • Improve sleep hygiene | | Medications | • Supplemental iron (if serum ferritin <75 ng/mL) • Mild intermittent symptoms: carbidopa-levodopa as needed • Frequent/daily symptoms: α2δ calcium channel ligand (eg, gabapentin, pregabalin) • Dopamine agonists (eg, pramipexole, ropinirole) not preferred |

<aside> 💡 RLS does not cause pain or symptoms of peripheral neuropathy (eg, numbness, sensory deficits).

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<aside> 💡 Reassurance of the likely temporary nature of symptoms

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<aside> 💡 women who have RLS during pregnancy are at increased risk of developing primary (idiopathic) RLS in the future.

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If additional pharmacotherapy is required, alpha-2-delta calcium channel ligands (eg, gabapentin, pregabalin) are often effective.  Dopamine agonists (eg, pramipexole, ropinirole) are not recommended for most patients due to possible augmentation (ie, paradoxical worsening with long-term therapy) of symptoms.

Although the pathophysiology is unclear, RLS seems to be related to misuse of iron in the CNS; impairment of CNS dopaminergic systems, which are located near the circadian control centers, may also play a role; peripherally, hyperalgesia is partly mediated by A-delta fiber input.

It is classified as primary (idiopathic) or secondary (if accompanied by an associated chronic disease, such as CKD.

RLS appears to be associated with central and peripheral nervous system abnormalities.  In the CNS, impaired iron use and dopaminergic systems (located close to the circadian control centers) may have a role; peripherally, hyperalgesia is partly mediated by A-delta fiber input.  Therefore, patients with iron deficiency or even low to normal ferritin levels (<75 ng/mL) should take supplemental iron.

Patients with intermittent or mild symptoms usually improve with nonpharmacologic therapy (eg, leg massage, sleep hygiene).  If pharmacotherapy is required for patients with frequent or severe symptoms, alpha-2-delta calcium channel ligands (eg, pregabalin, gabapentin) are recommended.  Dopamine agonists (eg, pramipexole, ropinirole) are no longer recommended as first-line agents for most patients due to the potential for paradoxical worsening with long-term treatment (ie, augmentation).  In addition, control of comorbid conditions (eg, MS) and iron supplementation (for patients with serum ferritin levels ≤75 ng/mL) often relieve symptoms.

(Choices A and F)  Peripheral artery disease can cause dull pain in the legs (ie, claudication); however, claudication worsens with walking and improves with rest.  Venous ultrasonography is used to characterize chronic venous insufficiency, which can present with discomfort in the legs.  Although dilated superficial leg veins may occur, patients typically have an aching or heavy feeling in the legs associated with swelling and skin changes (eg, dermatitis, ulceration).  In contrast to RLS, pain increases when walking and improves when lying down (due to gravity assisting with venous drainage).1

(Choice B)  Benzodiazepines (eg, clonazepam) are sometimes used to treat mild, intermittent RLS symptoms but are not advised for patients with frequent or severe symptoms due to the risks of adverse effects (eg, sedation) and tolerance.  They also are sometimes used to manage akathisia, which can cause restlessness and inability to sit still; however, akathisia typically is not worse at night or at rest and is an extrapyramidal symptom of antipsychotic drugs.

(Choice B)  Benzodiazepines (eg, clonazepam) bind to GABA A receptors and enhance the inhibitory effect of GABA, leading to muscle relaxation.  Although benzodiazepines can be effective for RLS, the risk for sedation, tolerance, and potential abuse makes other medications safer choices for patients with frequent symptoms.  Gabapentin, which is used in RLS, affects GABA activity but does not directly target GABA receptors.

Although compressive neuropathy can present with abnormal sensations, neuropathic pain is typically described as burning or shock-like rather than the vague discomfort seen in RLS. Unlike RLS, compressive neuropathy is typically associated with numbness and may be accompanied by motor weakness. In addition, pain due to compressive neuropathy would not immediately be relieved with movement.