Overview

Restless Legs Syndrome (RLS), also called Willis-Ekbom disease, is a health condition that causes an uncomfortable creeping feeling in the feet or legs, and results in an intense urge to move the legs.¹ 

RLS is a common condition of the nervous system and therefore some of its symptoms, causes and treatments overlap with those of neurological disorders.¹ This article will explore the overlapping mechanisms of RLS with other neurological disorders, similar treatments, and the link between RLS and various other conditions.

Understanding restless legs syndrome (RLS)

Symptoms 

People with RLS typically describe the sensations they experience as a feeling of creeping, crawling, aching or itching in their legs.^1,2 This unpleasant sensation is temporarily relieved when individuals move their legs or walk, therefore, RLS may be referred to as a movement disorder.² 

Symptoms of the condition worsen during periods of rest such as in the evenings or at night, and may disturb sleeping patterns by making it harder to fall asleep. Symptoms can also worsen during sedentary periods such as long travel journeys.² 

The intensity of symptoms varies between individuals. Some people may struggle with the sensations daily, while others may have the symptoms from time to time.¹ Symptoms can be ranked ‘moderate-severe’ or ‘severe’:²

• Moderate-severe RLS: experienced 1-2 times a week, causing significant difficulty when falling asleep
• Severe RLS: experience more than 2 times a week

Periodic limb movements (PLM) are often associated with the condition, although not everybody with RLS will experience them. In turn, most people with PLM don’t have RLS.² PLM refer to jerking leg movements out of your control that occur every 15-40 seconds during sleep.² PLM may also occur whilst individuals are awake.¹

The symptoms above typically affect both sides of the body and can occasionally affect the arms, chest, and face too.¹

RLS may cause resulting consequences of disturbed sleep such as:² 

• Exhaustion 
• Bad mood 
• Difficulty concentrating

Diagnosis

The criteria used in diagnosing RLS include the following:³

• Uncomfortable feeling in the legs followed by an intense urge to move them
• Symptoms worsen during rest
• Movement such as walking relieves symptoms in part or for a short period
• Symptoms worsen at night

Blood tests may also be used to test for:⁴

• Iron deficiency (anaemia) 
• Diabetes 
• Kidney disease 

These can be underlying symptoms of RLS and need to be ruled out or confirmed in order to decide on the appropriate treatment. The NHS provides more information on the diagnosis of RLS.

Pathophysiology of RLS

The exact cause of the condition is unknown in most cases of RLS and is, therefore, referred to as idiopathic or primary RLS.⁵

Genetic factors

• Sometimes RLS may be due to genetic involvement, where people with the condition may have specific gene types that make them more vulnerable to developing the condition.⁵ 
• When RLS is inherited from family members, it often presents in those younger than 40 years old.⁵  

Neurotransmitter dysregulation 

• As RLS is a movement disorder, its potential cause can be attributed to problems in the basal ganglia (a structure in the brain which controls movement)²
• The basal ganglia needs the brain chemical ‘dopamine’ to control movement.²
  • When dopamine levels are lower, perhaps because of nerve cell damage, individuals may experience these uncontrolled movements⁵ 
• Studies have shown that iron deficiency causes an excess of the chemical glutamate in the brain, which causes dysfunction⁶
  • This may lead to hyperarousal in RLS and cause the symptoms of sleep disturbance or stress

Neurological disorders associated with RLS

These underlying neurological mechanisms provide insight into the link between RLS and neurological disorders. 

Parkinson's disease 

• As another movement disorder, Parkinson’s disease is also caused by reduced dopamine due to damaged nerve cells
• If you have Parkinson’s disease it may make you more likely to develop RLS² 
• Medication used in Parkinson’s disease such as levodopa andcarbidopa can be used occasionally but are avoided for daily treatment only. This is because they may trigger symptoms of RLS and have associated complications²
  • People taking these medications for RLS may have a higher chance of developing RLS⁷

Multiple sclerosis (MS) 

• The prevalence of individuals with multiple sclerosis showing symptoms of RLS has been demonstrated in many studies; with 13.3%-65.1% of these patients showing RLS symptoms⁸ 
• However, the exact relationship between the conditions and their treatments needs further research 
• Iron deficiency and long-term inflammation may be partly responsible for the development of RLS in multiple sclerosis⁸ 

Peripheral neuropathy

• Neuropathy, or nerve damage in the hands or feet, can also be an associated underlying condition.² 
• This can be caused by diabetes (diabetic neuropathy) or alcohol use disorder.⁷ 
• The tingling associated with both conditions often overlaps.  

Spinal cord disorders

• People who have experienced damage to their spinal cord have a higher chance of developing RLS⁷  
• People who have had anaesthesia targeting their spinal cord have a higher chance of developing RLS also⁷ 

Essential tremor

• Some studies have found a co-occurrence between patients complaining of essential tremor and undiagnosed RLS.⁹ 
• Both are neurological, movement disorders where a link is likely but needs further studies. 

Attention deficit hyperactivity disorder (ADHD)

• Studies have found some strong overlap between RLS and ADHD¹⁰ 
• Although more research is required, the two conditions possibly show a similar physiological pathway involving disturbed sleep and dysfunction in the dopaminergic system¹⁰ 
• Iron deficiency anaemia can cause RLS because low iron may cause reduced levels of dopamine⁵ 

Non-neurological conditions associated with RLS

The NHS lists some non-neurological conditions related to RLS such as:^2,7

• Chronic kidney disease
  • This is due to the impact kidney failure has on the body’s iron stores
• Diabetes
• Rheumatoid arthritis 
• Hypothyroidism 
• Fibromyalgia
• Pregnancy (from week 27 until 4 weeks after birth)
• Sleep deprivation or sleep apnoea

Some medications for neurological conditions may make symptoms of RLS worse. These include:²

• Antidepressants 
• Antipsychotic drugs 
• Lithium used in bipolar disorder
• Anti-nausea medication 

Management and treatment

RLS is commonly treated with medication similar to medications used to treat neurological conditions. 

Pharmacological treatments 

Dopaminergic agents 

Medication that increases dopamine levels in the brain such as:¹¹

• Ropinirole 
• Pramipexole 
• Rotigotine skin patch

Alpha-2-delta ligands 

Anti-seizure medications such as these are usually the first medications prescribed for RLS. Gabapentin enacarbil is used to treat moderate-severe RLS.²  

Anti-seizure medications may also be used if the condition is causing pain in the legs. Furthermore, painkillers that act on the central nervous system like codeine can also be used.¹¹ 

Iron supplements

Iron supplements for individuals with anaemia may ease symptoms by helping to increase dopamine levels. 

Other medications

Benzodiazepines work to relax the central nervous system and the brain, which can be used to treat feelings of anxiousness, muscle spasms and difficulty sleeping.² 

Non-pharmacological treatments 

Less severe cases of RLS may not need medication but can treated at home. Some things that the NHS recommends you do to reduce symptoms can be:

• Avoiding caffeine, smoking and alcohol close to night hours
• Practicing good sleep hygiene
• Giving your legs a massage  
• A hot bath, or a hot compress on your legs

Stimulation to the legs may help some people with symptoms and researchers are currently testing various compact stimulation devices to treat RLS during sleep.² 

Research and future directions

Current research attempts to study the role of epigenetics in RLS and how risk factors can be controlled. This is the study of how environmental factors can influence gene expression. For example, if someone has the gene to develop RLS, research is trying to find out what environmental factors might trigger its expression so that it can be prevented. Emphasis is being put on correcting iron deficiency during pregnancy, in toddlers and children to prevent RLS in later life. The processes of how iron gets into the brain are also being researched.² 

Research is also using advanced MRI imaging to monitor and attempt to influence brain changes in people with RLS.² 

Summary

• Restless leg syndrome is a neurological movement disorder that may be associated with other neurological diseases. 
• The possible symptoms of RLS include unpleasant sensations in the legs, periodic limb movements and relief when active. 
• The suspected cause of RLS involves reduced levels of dopamine in the basal ganglia, which is similar to other movement disorders such as Parkinson’s disease. 
• Studies have found links between RLS and other neurological disorders such as multiple sclerosis, peripheral neuropathy and essential tremor. 
• Like other neurological disorders, RLS is treated with medications that act on the central nervous system such as dopaminergic agents and anti-seizure drugs.