Overview

Restless limbs syndrome, also known as Willis-Ekbom disease, is a common neurological sensorimotor disorder that disrupts sleep and daily life. It is characterised by an irresistible urge to move the limbs to relieve sensations of dysesthesia or hyperesthesia.¹ It can be idiopathic or linked to an underlying condition. Symptoms typically occur during periods of rest and sleep at night time.

They are temporarily relieved by movement. Furthermore, it varies widely in symptoms and severity. Often misdiagnosed or underdiagnosed, it needs more attention to help those struggling with this condition. 

It varies significantly in terms of age at onset, frequency, and severity. Severe forms can significantly impact sleep, quality of life, and mood. It is ranked as the fourth leading cause of insomnia. The disorder is considered to be complex. It involves genetic predisposition, environmental factors, and associated comorbidities. 

Restless limbs syndrome primarily affects the legs. However, it has also been reported in other body regions such as: 

• The mouth 
• The neck 
• The arms (restless arm syndrome) 
• The face 
• The abdomen 
• The genitals²

People assigned female at birth (AFAB) are twice as likely to develop restless limbs syndrome as people assigned male at birth (AMAB). It affects nearly one-third of pregnant people AFAB. The symptoms typically subside within a few weeks after delivery. However, people AFAB who experience this condition during pregnancy have a four-fold increased risk of developing chronic restless limbs syndrome.³

Origin of restless limbs syndrome

The origin of restless limbs syndrome can be understood through its two types: primary and secondary.³

Primary restless limbs syndrome

It is a central nervous system disorder of unknown cause (idiopathic). It is often familial, with a genetic component observed in 25-75% of patients. It may follow autosomal dominant or recessive inheritance patterns. Patients with familial restless limbs syndrome typically present at a younger age (often younger than 45 years) and may experience slower disease progression. Psychiatric factors, stress, and fatigue can make the symptoms of primary restless limbs syndrome worse.

Secondary restless limbs syndrome

It can occur as a result of various underlying disorders, including:^3,4

• Iron deficiency
• End-stage renal disease
• Diabetes mellitus
• Rheumatic diseases
• Venous insufficiency
• Peripheral neuropathy
• Folate deficiency 
• Magnesium deficiency
• Amyloidosis
• Lumbosacral radiculopathy
• Fibromyalgia
• Celiac disease
• Thyroid disease

Many substances and medications are known to make restless limbs syndrome worse. These include: 

• Antidopaminergic medications 
• Diphenhydramine 
• Tricyclic antidepressants (TCAs) 
• Selective serotonin reuptake inhibitors (SSRIs) 
• Serotonin-norepinephrine reuptake inhibitors (SNRIs) 
• Alcohol 
• Caffeine 
• Lithium 
• Beta-blockers 

Restless limbs syndrome is influenced by iron deficiency in the brain. Iron deficiency causes hypoxia and demyelination (damage to the protective cover around the nerves). This disrupts normal brain function and worsens symptoms.

 Dopaminergic dysfunction is another central factor in the occurrence of restless limbs syndrome. Dopaminergic dysfunction is responsible for worsening symptoms at night. It also affects sleep quality due to its circadian rhythm.⁵ 

The pathophysiology of restless limbs syndrome is not fully understood. However, understanding the primary and secondary conditions is crucial for accurate diagnosis and appropriate management. 

Signs and symptoms of restless limbs syndrome

Restless limbs syndrome manifests with an irresistible urge to move the limbs to relieve uncomfortable sensations. These sensations are described as "creeping, crawling, tingling, pulling, itching, drawing, or stretching." It is localised deep within the legs rather than on the skin. It does not typically involve pain or tingling paresthesia and there is no sensitivity to touch on the skin.

Both legs are affected, though not necessarily at the same time or to the same extent. The middle parts of the calves and thighs are the most commonly affected areas. Unilateral (only on one side) symptoms require careful differentiation from other neurological conditions. 

Symptoms typically worsen towards the end of the day. They peak at night, usually within 15 to 30 minutes after lying in bed. Difficulty initiating sleep is a frequent complaint of this condition.⁵ In severe cases, symptoms may start earlier in the day while sitting. Mild cases may involve: 

• Fidgeting 
• Leg movement in bed 
• Kicking
• Massaging legs for relief 

Patients with severe symptoms may feel compelled to get out of bed and walk around to ease discomfort.

Periodic leg movements of sleep are a hallmark of restless limbs syndrome. It is characterised by involuntary, forceful dorsiflexion of the foot (movement at the ankle joint that brings the toes closer to the shin). These dorsiflexions last 0.5 to 5 seconds, occurring every 20 to 40 seconds throughout sleep. Limb twitching during sleep is also common. It is observed in approximately 80% of patients.⁴

Severe cases may progress to affect not only the legs but also the arms. Apart from extreme discomfort, there is sleep disruption and interference with daily activities. Restless limbs syndrome exhibits a significant circadian rhythm of symptoms. They peak at night.⁴

The signs and symptoms of restless limbs syndrome (RLS) vary significantly. These variations affect management strategies due to differences in symptom frequency, severity, disease progression, and treatment response. An expert consensus statement has categorised RLS into distinct diagnostic groups based on these clinical features:²

• Intermittent restless limbs syndrome: Symptoms occur less than twice a week. However, they are bothersome enough to require treatment
• Chronic persistent restless limbs syndrome: Symptoms occur at least twice a week. They are moderately to severely distressing, requiring daily treatment
• Refractory restless limbs syndrome: Symptoms do not respond to first-line medications. This can be due to reduced efficacy, intolerable side effects, or augmentation (worsening of symptoms with earlier onset and increased intensity)

There have also been reported cases of “phantom” restless limbs syndrome. This type of RLS causes patients with an amputated limb to experience sensations in the location of the absent limb.

The presence of most symptoms or features of RLS is sometimes misunderstood for another medical or behavioural condition. Examples of such conditions are: 

• Myalgia 
• Venous stasis (blood pools in legs as a result of poor circulation) 
• Leg oedema 
• Arthritis 
• Leg cramps 
• Positional discomfort 
• Habitual foot tapping

Diagnosis of restless limbs syndrome

The diagnostic tests to diagnose restless limbs syndrome and to rule out secondary causes include:^2,3

1. Iron studies, measuring
   • Serum iron
   • Transferrin saturation
   • Ferritin
   • Total Iron-Binding Capacity (TIBC)

These tests help assess iron deficiency. Iron deficiency can worsen the symptoms of restless limbs syndrome.

2. Complete blood count (CBC): It helps rule out anaemia and other blood-related disorders

3. Metabolic panel:
   • Blood urea nitrogen (BUN)
   • Fasting blood glucose
   • Creatinine
   • Electrolytes (including magnesium)

These tests evaluate kidney function, glucose metabolism, and electrolyte balance. Any abnormalities can contribute to the symptoms of restless limbs syndrome.

4. Vitamin and mineral levels:
   • Vitamin B12 and folate levels
   • Magnesium

These tests can help identify vitamin and magnesium deficiencies. Vitamin deficiencies can mimic or worsen the symptoms of restless limbs syndrome. Low levels of magnesium may contribute to muscle cramps and discomfort.

5. Thyroid function tests: 

This test evaluates the levels of thyroid-stimulating hormone (TSH). Unusual changes could potentially worsen restless limbs syndrome.

6. Neurological Tests:
   • Nerve conduction studies: Assess peripheral nerve function and help diagnose polyneuropathy
   • Needle electromyography (EMG): Detects abnormalities in muscle function and can aid in diagnosing radiculopathy or neuropathy

Treatment of restless limbs syndrome

While many people with RLS have mild symptoms, only a small percentage seek medical consultation. Furthermore, an even smaller percentage require drug treatment. The management of restless limbs syndrome involves a spectrum of approaches. These range from non-pharmacological methods to various pharmacotherapies based on symptom severity and patient response.^2,3,5

Non-pharmacological approaches

These include: 

1. Massage 
2. Stretching 
3. Walking 
4. Cognitive distraction by playing games or puzzles 
5. Warm or cool baths 
6. Pneumatic foot compression
7. Acupuncture 
8. Transcranial magnetic stimulation 
9. Transcranial direct current stimulation 
10. Near-infrared light spectroscopy (NIRS) 
11. Exercise 
12. Yoga 

These interventions have limited evidence and are usually recommended as complementary therapies. A regular sleep-wake cycle is advised. Triggering substances like alcohol, caffeine and certain medications should be avoided.

Pharmacological approaches

1. Iron-replacement therapy with oral iron is the first-line approach if iron stores (ferritin, transferrin saturation) are low. Intravenous iron is considered if oral iron is ineffective or not tolerated. Intravenous iron is typically ferric carboxymaltose or iron dextran
2. Gabapentinoid/alpha-2-delta ligand drugs such as gabapentin, gabapentin enacarbil and pregabalin. They are started at low doses and gradually increased as tolerated to control symptoms. They are considered the first-line agents in severe cases. This is especially true if those severe cases include sleep disturbances or anxiety
3. Dopaminergic therapies like pramipexole, ropinirole, and rotigotine are highly effective. Unfortunately, they carry risks such as augmentation (worsening of symptoms with earlier onset and increased intensity) and impulse-control disorders 
4. Opioid therapies including tramadol, oxycodone, and methadone are reserved for severe cases or when other therapies fail. Sedation, nausea, constipation, and potential for abuse or dependency are the possible adverse effects of opioids
5. Benzodiazepines like clonazepam are used to improve sleep quality in patients with associated insomnia. There is a risk of sedation and falls in the elderly

Summary

Restless limbs syndrome is characterised by uncomfortable sensations in the legs and an irresistible urge to move them. These sensations typically occur during periods of rest or inactivity, often worsening at night. The exact cause is not fully understood.

However, both genetic and environmental factors are believed to play a role. Iron deficiency, dopamine dysfunction, and abnormalities in brain circuits involved in movement control are thought to contribute to its development. Management begins with non-pharmacological approaches including lifestyle changes. If symptoms persist or worsen, pharmacotherapy may be considered, seek a doctor's advice. 

Emerging therapies and investigational approaches hold promise for expanding treatment options in the future. These new treatment options have the potential to offer relief to those whose symptoms are not adequately controlled with current methods.