Restless Legs Syndrome

What Causes Restless Legs Syndrome?

The cause of RLS is unknown in most cases. These cases are referred to as “idiopathic,” meaning that there is no apparent trigger for the condition. They are considered “primary” because they are not the result of another condition or disorder.

RLS is sometimes associated with other conditions and disorders. These cases are considered “secondary” RLS. Conditions associated with secondary RLS include:

• Iron deficiency
• Diabetes
• Parkinson’s disease
• Multiple sclerosis
• Rheumatoid arthritis
• Peripheral neuropathy
• Pregnancy
• Kidney disease
• Heart disease
• Fibromyalgia
• Depression
• Sleep deprivation
• Sleep apnea

The use of some medications and drugs has also been associated with RLS. These drugs include:

• Anti-nausea drugs (prochlorperazine, metoclopramide)
• Antipsychotic drugs (haloperidol, phenothiazine)
• Antidepressants (fluoxetine, sertraline)
• Cold medications (diphenhydramine)
• Alcohol
• Nicotine
• Caffeine

Is Restless Legs Syndrome Hereditary?

RLS seems to have a genetic component that may be inherited. Many people with the disorder have a first-degree relative (a parent or sibling) who also has RLS, and the disorder appears to run in some families. In addition, some studies have suggested that an early-onset form of RLS that begins before age 45 is more likely to run in families. All this evidence points to a genetic predisposition for at least some cases of RLS, but scientists have not yet identified a gene or gene mutation associated with the disorder.

Inherited cases of RLS seem to be passed from parent to child in an autosomal dominant pattern. This means that children may develop the condition if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.

How Is Restless Legs Syndrome Detected?

Most cases of RLS are diagnosed in people over the age of 40. However, about a third of people with the disorder say they first experienced symptoms before they were 20. Because a diagnosis of RLS is primarily based on the patient’s description of their symptoms, the disorder may be sometimes overlooked in children because they cannot effectively describe or communicate what they’re feeling.

Potential warning signs of RLS in children include:

• Problems at school
• Problems with social interaction
• Sleepiness or lethargy
• Behavior problems similar to those of attention-deficit/hyperactivity disorder (ADHD)

How Is Restless Legs Syndrome Diagnosed?

Doctors may take several different diagnostic steps when a patient is experiencing symptoms characteristic of RLS.

• Physical exam. A basic physical exam will screen for indications of medical conditions that could be causing the symptoms.
• Neurological exam. A basic neurological exam will test a patient’s reflexes, balance, coordination, strength, vision, and hearing.
• Blood tests. The doctor may order laboratory blood tests to rule out conditions such as iron deficiency or kidney disease.
• Sleep study. A study of the patient’s sleep patterns, which may be conducted at a sleep center, may be recommended.

For a clinical diagnosis of primary RLS, the patient’s symptoms must meet specific diagnostic criteria. The criteria include:

• The patient has a strong need to move their legs, usually associated with strong, unpleasant sensations.
• The symptoms get worse during periods of rest or inactivity.
• The symptoms are at least partially relieved by movement.
• The symptoms begin or get worse at night or in the evening.
• The symptoms are not caused by a medical or mental health-related issue.  

How Is Restless Legs Syndrome Treated?

RLS has no cure, and no single treatment consistently relieves symptoms in all cases. In cases of secondary RLS, treating the underlying condition sometimes improves RLS symptoms.

Many different medications have shown promise in treating RLS, but individual patients respond differently to various drugs. Therefore, your doctor may need to try more than one medication to find the one that works best for you.

Medications used to treat RLS include:

• Iron supplementation. This treatment may help people with low iron levels in their bloodstream.
• Dopaminergic agents. These drugs boost the action of the brain chemical dopamine. They are commonly used to treat Parkinson’s disease, and they may help RLS symptoms as well. However, long-term use of these medications may cause worsening of symptoms. Dopamine-boosting drugs include ropinirole, pramipexole, and rotigotine.
• Anti-seizure medications. Gabapentin enacarbil, gabapentin, and pregabalin are commonly prescribed to treat RLS. Gabapentin enacarbil is the only one of these drugs approved by the FDA to treat RLS, but the others may be used “off-label” to treat the disorder.
• Opioids. Drugs such as methadone, codeine, hydrocodone, or oxycodone may be used when other treatments are ineffective. However, they carry the risk of side effects and addiction.
• Benzodiazepines. The sedative drugs clonazepam and lorazepam are sometimes used to treat RLS, but only as a last line of treatment due to their side effects.

How Does Restless Legs Syndrome Progress?

RLS is a life-long disorder, and symptoms tend to worsen with age. In some cases, people with RLS will experience a period of remission in which symptoms disappear, only to recur later.

RLS itself is not life-threatening, and people with mild symptoms may not require treatment. However, severe forms of the disorder can have long-term impacts, including:

• Chronic daytime sleepiness or fatigue
• Problems at work or school
• Risk of accidents
• Depression

How Is Restless Legs Syndrome Prevented?

There is no known way to prevent restless legs syndrome, but lifestyle changes can help relieve symptoms in some cases. Potentially helpful lifestyle strategies include:

• Get regular, moderate exercise, but avoid exercising late in the day.
• Avoid stimulating activities such as watching TV close to bedtime.
• Keep to a regular sleep schedule, and try to get 7-9 hours of sleep a night.
• Avoid caffeine, nicotine, and alcohol.
• Try a heating pad, massage, or cold compresses on your legs.
• Take a warm bath.
• Try yoga, meditation, or relaxation techniques.

People with a family history of the disorder are advised to speak with a genetic counselor to assess their risks if they plan to have children.

Restless Legs Syndrome Caregiver Tips

Some people with RLS also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders that may be associated with RLS:

• RLS may be associated with an increased risk of depression.
• People with neurological disorders such as Parkinson’s disease, multiple sclerosis, and peripheral neuropathy are at increased risk of RLS.
• Children with RLS may be misdiagnosed with attention-deficit/hyperactivity disorder (ADHD).

Restless Legs Syndrome Brain Science

Research has suggested that RLS is associated with problems related to a brain chemical called dopamine. Dopamine is a neuromodulator, a chemical that helps nerve cells communicate with each other and other types of cells. It plays an essential role in many brain functions, including memory, cognition, motivation, reward response, and motor control.

Dopamine is produced by nerve cells in a brain structure called the substantia nigra. These nerve cells release dopamine as they communicate with nerve cells in another part of the brain, the basal ganglia. This chemical interaction is instrumental in controlling the movement of muscles throughout the body. In Parkinson’s disease, nerve cells in the substantia nigra deteriorate, leading to a deficiency of dopamine and the disorder’s characteristic tremors and loss of muscle control. Scientists suspect that something similar occurs in RLS, with inadequate dopamine levels contributing to that disorder’s movement-related symptoms.

Researchers are also trying to understand the role that iron plays in the biochemical process of RLS, given that many people with the disorder exhibit low levels of iron in their blood. The relationship between dopamine and iron is complex. Iron is necessary for the production of dopamine, and dopamine, in turn, may help maintain the proper amount of iron within cells. These effects may suggest why both iron supplements and dopaminergic (dopamine-boosting) medications can benefit people with RLS.

Restless Legs Syndrome Research

Title: The Effect of Magnesium Citrate Supplementation in Restless Legs Syndrome (RLS) (RLS)

Stage: Recruiting

Principal investigator: Sasikanth Gorantla, MD

OSF Healthcare Illinois Neurological Institute

Peoria, IL

The expected results of this study will have a significant impact on the treatment of RLS/WED patients. Magnesium supplementation (if proven to be beneficial) can be utilized as an inexpensive, safer, biologically plausible alternative to dopamine agonists and α2δ calcium-channel ligands.

This is an open-label, prospective, non-placebo controlled pilot study. Fifteen subjects diagnosed with restless legs syndrome (ICSD-3 diagnostic criteria) will be recruited from OSF Healthcare Saint Francis Medical Center sleep center and Illinois Neurological Institute. RLS/WED patients who meet inclusion and exclusion criteria during the initial clinic visit will be offered study participation. Standard treatment options will be discussed prior to the enrollment. Patients will be reassured that not participating in the study will not affect the future care they receive at OSF HealthCare. The potential risks and benefits of the study will be provided, and, if the patient is interested, informed consent will be obtained. If the subject withdraws consent or does not finish both pre and post-evaluation, the subject will be replaced with another recruit. The subject will come to the clinic for two visits, a pre-magnesium visit, and a post-magnesium visit. After completing the pre-magnesium visit, the subject will be given 200 mg elemental magnesium daily (will be instructed to take it with food at dinner) for eight weeks. On both Visits, the following study procedures will be performed: magnesium level, (International Restless Legs Syndrome) IRLS scale, Kohnen Restless Legs Syndrome Quality of Life Instrument (KRLS-QOL) scale, and (Multiple Suggested Immobilization (MSI) test. The post magnesium visit will be scheduled at the completion of the eight-week dose of magnesium.

Title: An Extension Study to Evaluate the Efficacy and Safety of HORIZANT in Adolescents With Moderate-to-Severe Primary RLS (RLS)

Stage: Recruiting

Study Director: Steven Caras, MD

Xenoport/Arbor Pharmaceuticals, LLC

The trial’s objectives are to evaluate the long-term efficacy and safety of HORIZANT (Gabapentin Enacarbil) 600 mg daily to treat RLS in adolescents (13 to 17 years of age) diagnosed with moderate-to-severe primary RLS.

Patients who complete the 12-week daily dosing efficacy and safety study (XP109) will be allowed to enroll in the open-label extension (OLE) study (XP110), thereby providing exposure to HORIZANT for up to 48 weeks. Enrolled patients will take open-label HORIZANT 600 mg tablets once a day at approximately 5 PM with food, beginning at Week 0 of the OLE study up to and including Week 36. After the end of the treatment period, a follow-up visit will be included 14 days (± three days) after the last dose of HORIZANT. Patients will visit the clinical site on six different occasions, including a follow-up visit 14 days (± three days) after the last dose of the study drug.

Title: Executive Dysfunction in Restless Legs Syndrome: Clinical Correlates and Outcome After Therapeutic Management

Stage: Recruiting

Principal investigator: Yves Dauvilliers, PU, PH

UH Montpellier

Montpellier, France

Restless leg syndrome (RLS) is a common neurological disorder whose diagnosis is only clinical. The efficacy of dopaminergic agents in improving sensorimotor symptoms advances the hypothesis that altered dopaminergic transmission is at the origin of this condition. RLS usually leads to sleep fragmentation, which sometimes induces severe insomnia, most often associated, in clinical practice, with a cognitive complaint (attentional). Executive functions in which dopaminergic transmission is heavily involved refer to a set of complex functions. At least three of them should be considered during their evaluation (i.e., flexibility, inhibition, and the updating of working memory). These functions are among the targets of altering the quality and quantity of sleep. Unfortunately, the few studies that have focused on studying the integrity of executive functions in RLS have discordant results. The two main reasons are the lack of control of key variables in assessing executive functioning (i.e., intellectual performance, depressive symptomatology, generalized slowing in information processing) and the lack of reference in the theoretical approach in executive functions. Moreover, the question of polysomnographic correlates and the reversibility of these cognitive abnormalities after pharmacological management of RLS remains unanswered today.

The main objective of this study is to compare the executive performance of untreated RLS patients with a group of matched controls.