What conditions, besides low serum iron and ferritin concentrations, can contribute to restless leg syndrome (RLS) and poor sleep in adults, particularly those with chronic diseases or during pregnancy?

Conditions Contributing to Restless Leg Syndrome and Poor Sleep Beyond Iron Deficiency

Beyond low iron and ferritin, the most important contributors to RLS and poor sleep include end-stage renal disease, pregnancy, peripheral neuropathy, and medication-induced exacerbation—particularly from dopamine antagonists (antipsychotics), SSRIs, tricyclic antidepressants, and lithium. 1, 2

Secondary Medical Conditions

Renal Disease

• End-stage renal disease (ESRD) is a major secondary cause of RLS, with increasing prevalence as kidney function declines 1, 3
• Uremia-related RLS requires different treatment algorithms, including consideration of IV iron sucrose when ferritin <200 ng/mL and transferrin saturation <20% 2
• Gabapentin dosing must be adjusted in ESRD patients, starting at 100 mg post-dialysis with maximum doses of 200-300 mg daily 2

Pregnancy

• Pregnancy is associated with RLS in 25-30% of affected individuals, making it one of the most common secondary causes 4
• Iron supplementation is particularly important during pregnancy, with oral formulations favored throughout gestation for safety 2, 3
• Medication safety profiles require special consideration in pregnant patients with RLS 2

Peripheral Neuropathy and Radiculopathy

• Peripheral neuropathy can present with RLS-like symptoms and requires thorough neurologic examination to distinguish from primary RLS 1, 5
• Diabetic neuropathy (screened via HbA1c) may mimic or coexist with RLS 5
• Radiculopathy must be excluded through careful history and physical examination 1, 5

Medication-Induced Exacerbation

Dopamine Antagonists

• Antipsychotic medications (dopamine antagonists) are well-established triggers for worsening RLS through their blockade of dopamine receptors 1, 2
• Lurasidone and other antipsychotics can significantly worsen RLS symptoms and should be avoided or switched to alternatives with less dopamine antagonism 2

Antidepressants and Mood Stabilizers

• SSRIs, tricyclic antidepressants, and lithium have been reported to exacerbate RLS 1, 2
• These medications should be reviewed and potentially adjusted in patients with worsening RLS symptoms 2

Other Exacerbating Medications

• Antihistaminergic medications can worsen RLS symptoms 2
• Bupropion is specifically recommended against for RLS treatment 2

Lifestyle and Environmental Factors

Substance Use

• Increased caffeine intake, particularly in the evening, significantly worsens RLS symptoms due to the circadian pattern of the disorder 1, 2
• Alcohol consumption should be eliminated or reduced, especially within 3 hours of bedtime 2
• Tobacco use contributes to RLS symptom severity 1

Body Composition and Activity

• Increased body mass index (BMI) is associated with worse RLS symptoms 1
• Sedentary lifestyle contributes to symptom severity 1
• Lower socioeconomic status has been correlated with increased RLS prevalence 1

Sleep-Related Comorbidities

Obstructive Sleep Apnea

• Untreated obstructive sleep apnea (OSA) is an important exacerbating factor that must be addressed before optimizing RLS treatment 2
• OSA treatment is particularly critical before considering opioid therapy for refractory RLS due to respiratory depression risk 2

Critical Diagnostic Considerations

Conditions That Mimic RLS

• Vascular disease (intermittent claudication) can present with leg discomfort but lacks the circadian pattern and relief with movement characteristic of RLS 1, 5
• Neuroleptic-induced akathisia must be distinguished from RLS through careful medication history 1, 5
• Arthritides and collagen vascular diseases can mimic RLS but typically show joint-localized pain without circadian pattern 5
• Venous varicosities may cause leg discomfort but lack the compelling urge to move 1
• Nocturnal leg cramps differ from RLS in their presentation and response to movement 2

Laboratory Screening Beyond Iron Studies

• Renal function (electrolytes, creatinine) identifies chronic kidney disease as a secondary cause 5
• Thyroid function (TSH) screening is part of standard endocrine assessment 5
• HbA1c screens for diabetes mellitus, which has been associated with RLS 5
• Complete blood count (CBC) assesses for iron-deficiency anemia requiring more aggressive repletion 5
• Calcium levels are included in baseline metabolic assessment 5

Common Pitfalls to Avoid

• Do not assume RLS is primary without excluding secondary causes, particularly ESRD, pregnancy, and peripheral neuropathy 1, 5, 3
• Do not overlook medication review—16% of patients may be misclassified as having RLS if mimics are not excluded 5
• Do not ignore untreated OSA before initiating pharmacologic therapy, especially opioids or alpha-2-delta ligands 2
• Do not dismiss lifestyle factors—caffeine, alcohol, and tobacco cessation are critical first-line interventions 1, 2