Restless Legs Syndrome: Symptoms, Types, Causes and Treatment

Restless Legs Syndrome (RLS), also known as Willis-Ekbom disease, is a neurological disorder that often disrupts sleep and daily life for millions of people worldwide. Characterized by an irresistible urge to move the legs—especially during periods of rest or inactivity—RLS can present in diverse ways and has complex underlying causes. In this comprehensive guide, we'll explore its symptoms, types, underlying mechanisms, and the latest evidence-based approaches to treatment.

Symptoms of Restless Legs Syndrome

Restless Legs Syndrome symptoms can be subtle or severe, often making it challenging to recognize and diagnose. These sensations typically worsen at night and are relieved by movement, but their impact can extend well beyond bedtime.

Symptom	Description	Occurrence/Pattern	Source
Urge to Move	Uncontrollable need to move legs	Worse at rest, evening/night	3 4 9
Discomfort	Unpleasant/tingling/painful leg sensations	Relieved by movement	3 4 10
Daytime Symptoms	Sudden crises, especially with inactivity	Common in moderate-severe RLS	1 4
Sleep Disruption	Difficulty falling or staying asleep	Leads to poor quality of life	4 5

Table 1: Key Symptoms

The Core Features of RLS

The hallmark of RLS is an overwhelming urge to move the legs, often accompanied by uncomfortable sensations like tingling, crawling, or pain. These feelings are typically worse during periods of rest—such as when sitting or lying down—and are most pronounced in the evening or at night, disrupting sleep and rest routines 3 4 9.

Daytime Manifestations

Contrary to popular belief, RLS is not confined to nighttime hours. Over half of people with moderate-to-severe RLS experience “breakthrough” symptoms during the day, often triggered by inactivity (like sitting in meetings or during travel). These episodes have a substantial effect on daily functioning and quality of life 1.

Impact on Sleep and Mental Health

RLS frequently causes difficulties in falling or staying asleep, leading to chronic sleep deprivation. This sleep loss can trigger or worsen anxiety, depression, and cognitive difficulties. In certain populations, such as people with multiple sclerosis, RLS symptoms are linked to higher levels of anxiety, poorer sleep quality, and overall worse mental health-related quality of life 5.

Types of Restless Legs Syndrome

RLS is not a one-size-fits-all disorder. It can be classified into distinct types based on its origin, age of onset, and anatomical presentation. Understanding these distinctions is crucial for effective management.

Type	Description	Key Factors/Features	Source
Primary (Idiopathic)	No identifiable cause; genetic component	Early onset, family history	3 4 7 9
Secondary	Linked to other conditions (e.g., iron deficiency, kidney disease, pregnancy)	Later onset, treat underlying issue	2 7 9
Variants	Symptoms in non-leg areas (arms, torso)	Less common, distinct entity	6

Table 2: RLS Types

Primary (Idiopathic) RLS

This form of RLS has no identifiable underlying cause and often runs in families, suggesting a strong genetic predisposition. It typically begins earlier in life and may gradually worsen over time 3 4 7 9.

Secondary (Symptomatic) RLS

Secondary RLS is associated with other medical conditions or triggers. Common causes include:

• Iron deficiency (with or without anemia)
• Chronic kidney disease (especially in dialysis patients)
• Pregnancy, particularly in the third trimester

Managing the underlying condition can sometimes lead to significant improvement or even resolution of RLS symptoms 2 7 9.

RLS Variants

While RLS is classically a disorder of the legs, some individuals experience similar symptoms in the arms, torso, or other body regions. These "RLS variants" are less common and may require a tailored approach to diagnosis and management 6.

Causes of Restless Legs Syndrome

The exact cause of RLS remains a subject of ongoing research. However, several interconnected biological and environmental factors have been identified.

Cause	Description	Contribution to RLS	Source
Iron Deficiency	Low brain iron, even with normal blood iron	Key pathophysiological role	8 9 10 11 13
Dopaminergic Dysfunction	Abnormal dopamine signaling in brain	Drives symptoms, target for treatment	8 9 10 11
Genetics	Multiple genes implicated	Family history common	4 9 10 11
Comorbid Diseases	CKD, pregnancy, iron deficiency, MS, others	Trigger or worsen RLS	2 5 7 9

Table 3: RLS Causes

Iron Deficiency in the Brain

Brain iron deficiency is now recognized as a central factor in RLS. Strikingly, iron levels in the brain can be low even when blood iron is within normal range. This deficiency disrupts normal dopamine production and signaling, which is crucial for controlling movement and sensory processing 8 9 10 11 13.

Dopamine Imbalance

Dopaminergic dysfunction—often due to impaired iron-dependent dopamine production—plays a pivotal role in RLS. The disorder is associated with both an initial excess of dopamine activity and subsequent downregulation with chronic treatment, which can worsen symptoms over time 8 9 10 11.

Genetic and Environmental Factors

Genetic studies have identified several risk genes, such as BTBD9 and MEIS1, associated with RLS. These genes may influence brain iron handling, dopamine signaling, or neurodevelopment, further predisposing individuals to the condition 4 9 10 11. Environmental triggers or comorbid illnesses can interact with these genetic factors to provoke symptoms.

Secondary Causes and Comorbidities

RLS is commonly seen in association with:

• Chronic kidney disease: up to 25% of dialysis patients have RLS, with symptoms linked to iron and dopamine metabolism 2
• Pregnancy: likely due to hormonal and iron changes
• Multiple sclerosis: higher prevalence, possibly due to neurological changes 5
• Other conditions: diabetes, certain medications, and neurological diseases may also contribute, though evidence varies 7 9

Treatment of Restless Legs Syndrome

Management of RLS is tailored to the severity and frequency of symptoms and whether an underlying cause is identified. Both non-pharmacological and pharmacological options exist, with new treatments and guidelines continuing to emerge.

Treatment Approach	Examples/Options	When Used/Notes	Source
Non-Pharmacological	Lifestyle changes, sleep hygiene, activity	Mild/intermittent cases, adjunct	3 4 12 14
Iron Supplementation	Oral or IV iron (if ferritin low)	First-line for low iron stores	13 14 15
Dopaminergic Agents	Pramipexole, ropinirole, rotigotine	Moderate-severe, risk of augmentation	3 12 14 15 16
Alpha-2-delta Ligands	Gabapentin, pregabalin	Alternative first-line, low augmentation risk	3 12 14 15
Opioids	Oxycodone/naloxone, methadone (severe cases)	For refractory or severe cases only	12 14 15

Table 4: RLS Treatment Approaches

Non-Pharmacological Strategies

• Lifestyle adjustments: Regular exercise, good sleep hygiene, and avoiding caffeine or alcohol can reduce symptoms for some 3 4.
• Pneumatic compression devices: Shown to be likely effective in reducing RLS symptoms in certain individuals 14.

Iron Supplementation

• First-line for low iron: In people with low ferritin (<75–300 μg/l, depending on guidelines), oral or intravenous iron can be highly effective.
  • IV ferric carboxymaltose is particularly effective in moderate-severe RLS 13 14.
  • Oral iron is less effective, especially in people with normal iron stores 13 14.
• Algorithmic approach: Regular re-evaluation and repeated iron supplementation may be necessary 13.

Dopaminergic Medications

• Pramipexole, ropinirole, rotigotine: Effective for many, but long-term use can lead to "augmentation" (worsening or earlier onset of symptoms), especially at higher doses 12 14 15.
• Guideline recommendations: Use the lowest effective dose, and monitor for augmentation. Avoid older agents like pergolide and cabergoline unless necessary due to potential safety concerns 12 14 15.

Alpha-2-delta Calcium Channel Ligands

• Gabapentin, pregabalin: Effective as first-line agents, especially for those at risk for augmentation or with comorbid sleep disturbance or pain 12 14 15.
• Lower risk of augmentation compared to dopaminergic drugs 14 15.

Opioids and Other Agents

• Oxycodone/naloxone, methadone: Reserved for refractory, severe cases or when other treatments fail 12 14 15.
• Other options: Benzodiazepines, anticonvulsants, and non-traditional therapies may be considered in selected situations 3 16.

Managing Long-Term Complications

• Augmentation: A major challenge in long-term RLS therapy. Prevention includes using non-dopaminergic agents first, keeping dopaminergic drug doses low, and supplementing iron when needed. Switching to gabapentin, pregabalin, or rotigotine, or adding opioids in severe cases, are recommended strategies 12 14 15.
• Addressing comorbidities: Treating underlying conditions (e.g., iron deficiency, kidney disease) remains key to reducing RLS symptoms 7 15.

Conclusion

Restless Legs Syndrome is a complex, often underrecognized neurological disorder with a wide spectrum of symptoms, causes, and treatment options. Understanding its multifaceted nature is essential for effective management and improved quality of life.

Key Takeaways:

• RLS symptoms include an irresistible urge to move the legs, discomfort, and significant sleep disruption, often worsening at night but sometimes occurring during the day 1 3 4.
• There are primary (idiopathic) and secondary (symptomatic) forms, with variants affecting non-leg body parts in some cases 2 3 6 7.
• Brain iron deficiency and dopaminergic dysfunction, influenced by genetic and environmental factors, are central causes; comorbid diseases like chronic kidney disease and pregnancy can trigger or worsen symptoms 2 4 8 9 10 11.
• Evidence-based treatment involves lifestyle changes, iron supplementation (when indicated), dopaminergic agents, alpha-2-delta ligands, and, in severe cases, opioids. Avoiding and managing augmentation is crucial for long-term success 12 13 14 15.
• Tailored management, regular reassessment, and addressing underlying medical conditions can greatly enhance outcomes.

By staying informed and working with healthcare providers, those affected by RLS can find relief and regain control over their sleep and daily well-being.