Restless Legs Syndrome: A Comprehensive Review for the Modern Clinician

Dr Neeraj Manikath , claude.ai

Abstract

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, represents a common yet frequently underdiagnosed sensorimotor disorder affecting 5-10% of the general population. This review synthesizes current understanding of RLS pathophysiology, diagnostic approaches, and evidence-based management strategies, with emphasis on practical clinical pearls for internists managing this often-debilitating condition.

Introduction

Restless legs syndrome manifests as an irresistible urge to move the legs, typically accompanied by uncomfortable sensations that worsen during periods of rest and inactivity, particularly in the evening or nighttime hours. First described by Thomas Willis in 1685 and comprehensively characterized by Karl-Axel Ekbom in 1945, RLS has evolved from a poorly understood curiosity to a well-defined neurological disorder with significant impact on quality of life, sleep architecture, and cardiovascular health.

Despite its prevalence rivaling that of diabetes mellitus, RLS remains underrecognized in clinical practice. Studies suggest that fewer than 15% of individuals with moderate to severe symptoms receive appropriate diagnosis and treatment. This diagnostic gap reflects both limited awareness among healthcare providers and the subjective nature of symptoms that defy objective measurement.

Diagnostic Criteria and Clinical Presentation

The International Restless Legs Syndrome Study Group established five essential diagnostic criteria, updated in 2014:

1. An urge to move the legs, usually accompanied by uncomfortable sensations
2. Symptoms begin or worsen during periods of rest or inactivity
3. Symptoms are partially or totally relieved by movement
4. Symptoms are worse in the evening or at night
5. The above features are not solely accounted for by another medical or behavioral condition

Clinical Pearl: The circadian nature of RLS is diagnostically crucial. Patients may report minimal daytime symptoms yet experience severe nocturnal disturbance. Always inquire specifically about evening and bedtime symptoms rather than asking general questions about leg discomfort.

The sensory phenomenology of RLS proves remarkably difficult for patients to articulate. Descriptions range from "creeping," "crawling," and "pulling" sensations to "electric current," "itching bones," or simply an indescribable need to move. This linguistic challenge often leads to diagnostic delay.

Oyster: Approximately 80% of RLS patients experience periodic limb movements during sleep (PLMS), characterized by stereotyped leg jerks occurring every 20-40 seconds. However, PLMS occurs in many conditions and is not specific for RLS. Conversely, absence of PLMS does not exclude RLS diagnosis, which remains fundamentally clinical.

Pathophysiology: Current Understanding

The pathophysiology of RLS involves three interconnected mechanisms: iron dysregulation in the central nervous system, dopaminergic dysfunction, and genetic predisposition.

Iron Metabolism

Brain iron deficiency represents the cornerstone of RLS pathophysiology. Postmortem studies and cerebrospinal fluid analyses consistently demonstrate reduced iron concentrations in the substantia nigra of RLS patients, even when systemic iron stores appear adequate. Neuromelanin-sensitive MRI studies have confirmed decreased iron content in the substantia nigra of affected individuals.

Iron serves as a crucial cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Regional iron deficiency therefore results in inadequate dopamine production despite normal dopaminergic neuron populations. This explains why RLS responds to dopaminergic medications despite not being a dopamine-deficiency disorder in the classical sense.

Hack: Serum ferritin levels below 75 μg/L correlate with RLS symptoms, even though this threshold exceeds standard laboratory definitions of iron deficiency. Target ferritin levels of 75-100 μg/L or higher when managing RLS patients, rather than accepting "normal" values of 20-30 μg/L.

Dopaminergic Dysfunction

The dramatic response of RLS to dopaminergic agents and the circadian worsening of symptoms (corresponding to evening decreases in dopamine activity) implicate dopaminergic pathways in RLS pathogenesis. However, RLS differs fundamentally from Parkinson disease. The dopaminergic dysfunction in RLS appears hypersensitivity-related rather than degenerative, explaining paradoxical phenomena like augmentation with chronic dopaminergic therapy.

Genetic Architecture

Family history positive for RLS occurs in 40-60% of cases, with autosomal dominant inheritance patterns in many kindreds. Genome-wide association studies have identified multiple susceptibility loci, including MEIS1, BTBD9, and MAP2K5/SKOR1. These genes regulate neurodevelopment, iron homeostasis, and circadian rhythm regulation, providing biological plausibility for genetic contributions.

Secondary RLS: Recognizing Associated Conditions

While primary RLS predominates, secondary forms warrant systematic consideration, as treating underlying conditions may ameliorate or resolve RLS symptoms.

Iron deficiency represents the most common and treatable secondary cause. Pregnancy, chronic blood loss (including occult gastrointestinal bleeding and menorrhagia), and frequent blood donation all merit investigation.

End-stage renal disease associates with RLS prevalence rates of 25-50%, likely reflecting both uremic toxin accumulation and iron deficiency from repeated phlebotomy and decreased intestinal absorption. Symptoms often improve following renal transplantation.

Peripheral neuropathy of any etiology can mimic or coexist with RLS. Distinguishing features include persistent rather than circadian symptoms, sensory abnormalities on examination, and lack of urge to move. Diabetes, vitamin B12 deficiency, and alcohol use warrant evaluation.

Medications frequently exacerbate or precipitate RLS. Dopamine antagonists (metoclopramide, prochlorperazine, antipsychotics), antidepressants (particularly SSRIs, SNRIs, and mirtazapine), antihistamines, and certain anti-nausea medications top the offender list.

Pearl: When evaluating potential medication-induced RLS, remember that symptom onset may lag drug initiation by weeks to months, obscuring the temporal relationship.

Diagnostic Evaluation

RLS diagnosis remains clinical, based on history rather than testing. No laboratory test, imaging study, or electrophysiological examination definitively confirms or excludes RLS.

Essential laboratory evaluation includes:

• Complete blood count
• Serum ferritin (not iron or transferrin saturation alone)
• Serum creatinine and estimated glomerular filtration rate
• Fasting glucose or hemoglobin A1c
• Vitamin B12 level (particularly in older adults or those with suggestive symptoms)

Polysomnography rarely proves necessary for RLS diagnosis but may be indicated when comorbid sleep disorders are suspected or when treatment response is suboptimal.

Oyster: The "suggested immobilization test" can objectively assess RLS symptoms in research settings. Patients remain still in bed for 60 minutes during their typical symptom time while leg movements and subjective discomfort are monitored. This rarely proves necessary clinically but illustrates the provocation by immobility central to RLS pathophysiology.

Treatment Strategies: An Evidence-Based Approach

Non-Pharmacological Interventions

All patients benefit from initial non-pharmacological approaches, and those with mild or intermittent symptoms may require no additional therapy.

Lifestyle modifications include avoiding RLS-exacerbating substances (caffeine, alcohol, nicotine), maintaining regular sleep schedules, and engaging in moderate exercise earlier in the day. Paradoxically, both excessive exercise and complete inactivity worsen symptoms.

Mental alerting activities during symptom periods provide benefit through mechanisms that remain incompletely understood. Reading, puzzles, video games, or detailed conversation can suppress RLS symptoms, possibly through competing attentional demands.

Pneumatic compression devices and vibrating pads may provide symptomatic relief through counterstimulation mechanisms.

Iron Supplementation

Iron repletion represents the most physiologically rational intervention and should be attempted before or concurrent with initiating pharmacotherapy in patients with ferritin levels below 75 μg/L.

Oral iron: Ferrous sulfate 325 mg with vitamin C 100-200 mg, taken on an empty stomach, remains standard first-line therapy. Anticipate that achieving target ferritin levels requires three to six months. Gastrointestinal side effects limit adherence in approximately 30-40% of patients.

Hack: Alternate-day dosing of oral iron may improve absorption and reduce side effects compared to daily administration, based on recent hepcidin regulation research. Consider this approach for patients experiencing gastrointestinal intolerance.

Intravenous iron: For patients with inadequate response to oral iron, significant gastrointestinal intolerance, or urgent need for repletion, intravenous iron (ferric carboxymaltose 1000 mg or low-molecular-weight iron dextran 1000 mg) provides rapid and effective ferritin elevation. Studies demonstrate improvement in RLS symptoms within 2-4 weeks in approximately 60% of appropriately selected patients.

Dopaminergic Agents

Dopamine agonists, particularly pramipexole and ropinirole, dominated RLS pharmacotherapy for two decades based on robust efficacy data. However, recognition of augmentation as a nearly universal long-term complication has fundamentally altered prescribing patterns.

Augmentation manifests as earlier symptom onset, increased symptom intensity, shorter latency to symptoms at rest, and/or spread to previously unaffected body parts. It typically emerges after months to years of therapy and affects 60-70% of patients within 10 years of continuous dopamine agonist use.

Pearl: When dopamine agonists are necessary, use the lowest effective dose (pramipexole 0.125-0.25 mg, ropinirole 0.25-1 mg taken 1-2 hours before symptom onset). Higher doses accelerate augmentation development without providing superior efficacy.

Alpha-2-Delta Ligands

Gabapentin enacarbil, pregabalin, and gabapentin represent current preferred first-line pharmacotherapy for moderate to severe RLS based on efficacy comparable to dopamine agonists with significantly lower augmentation risk.

Gabapentin enacarbil (extended-release prodrug formulation) 600 mg taken at 5 PM demonstrates superior efficacy to immediate-release gabapentin due to enhanced absorption and more consistent blood levels during evening symptom hours.

Pregabalin 150-300 mg nightly provides an alternative with similar efficacy. Some patients prefer pregabalin for its more predictable pharmacokinetics and dosing flexibility.

Hack: When prescribing alpha-2-delta ligands, warn patients that therapeutic benefits often require 2-3 weeks to fully manifest, whereas side effects (dizziness, somnolence) appear immediately. This prevents premature discontinuation.

Opioids

Low-dose opioids (methadone 5-15 mg, oxycodone 5-15 mg, tramadol 50-100 mg nightly) demonstrate remarkable efficacy for RLS, particularly in patients with augmentation from dopamine agonists or inadequate response to alpha-2-delta ligands. Methadone proves especially effective given its long half-life and unique pharmacology.

Concerns about addiction risk must be contextualized. Appropriately selected RLS patients demonstrate low rates of abuse or dependence, though careful patient selection and monitoring remain essential.

Oyster: The efficacy of opioids in RLS provides additional evidence that RLS involves dysregulation of pain and sensory processing pathways beyond dopaminergic systems alone.

Treatment Algorithm

For mild intermittent RLS: Non-pharmacological measures, iron supplementation if ferritin <75 μg/L, as-needed therapy with carbidopa-levodopa or clonazepam.

For moderate to severe RLS: Iron supplementation if indicated, plus gabapentin enacarbil, pregabalin, or gabapentin as initial pharmacotherapy.

For refractory RLS: Low-dose opioids, or combination therapy with alpha-2-delta ligand plus low-dose dopamine agonist.

Special Populations

Pregnancy: RLS affects 25-30% of pregnant women, typically worsening in the third trimester. Check ferritin levels and supplement iron aggressively. Gabapentin and pregabalin are Category C; most clinicians reserve them for severe cases unresponsive to non-pharmacological measures and iron. Opioids and dopamine agonists carry additional concerns.

Elderly patients: Increased prevalence but also increased risk of falls and cognitive effects from pharmacotherapy. Start with lower doses and titrate cautiously. Particularly emphasize fall risk with alpha-2-delta ligands.

Conclusion

Restless legs syndrome represents a common, often debilitating disorder that responds well to appropriate diagnosis and treatment. Internists must maintain high clinical suspicion, particularly in patients presenting with sleep complaints, unexplained fatigue, or difficult-to-characterize leg discomfort. Iron repletion and alpha-2-delta ligands form the foundation of modern RLS management, with dopamine agonists relegated to adjunctive roles given augmentation concerns. As our understanding of RLS pathophysiology advances, novel therapeutic targets continue emerging, promising improved outcomes for this underserved patient population.

Key Takeaways for Clinical Practice

1. Diagnose RLS clinically using the five essential criteria—no test confirms or excludes it
2. Check ferritin in all patients and target levels ≥75 μg/L
3. Start with alpha-2-delta ligands rather than dopamine agonists for moderate-to-severe disease
4. Reserve dopamine agonists for intermittent use or lowest possible doses given augmentation risk
5. Consider low-dose opioids for refractory cases—efficacy is remarkable when appropriately prescribed
6. Review and discontinue RLS-exacerbating medications whenever possible
7. Remember the circadian pattern—always ask specifically about evening and nighttime symptoms

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Selected References

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2. Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome. Sleep Med. 2014;15(11):1288-1301.

3. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation. Sleep Med. 2016;21:1-11.

4. Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: Treatment of restless legs syndrome in adults. Neurology. 2016;87(24):2585-2593.

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6. Trenkwalder C, Allen R, Högl B, et al. Comorbidities, treatment, and pathophysiology in restless legs syndrome. Lancet Neurol. 2018;17(11):994-1005.

7. Silber MH, Becker PM, Buchfuhrer MJ, et al. The appropriate use of opioids in the treatment of refractory restless legs syndrome. Mayo Clin Proc. 2018;93(1):59-67.

8. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007;357(7):639-647.