Periodic Limb Movement Disorder

What Causes Periodic Limb Movement Disorder?

The cause of PLMD is unknown in most cases, but it is sometimes associated with other conditions and disorders. Conditions associated with PLMD include:

• Iron deficiency
• Diabetes
• Uremia
• Anemia
• Restless legs syndrome
• Narcolepsy or other sleep disorders
• Sleep apnea
• Attention-deficit/hyperactivity disorder (ADHD)
• Pregnancy
• Kidney or liver disease
• Parkinson’s disease
• Multiple sclerosis
• Spinal cord tumors

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

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

Is Periodic Limb Movement Disorder Hereditary?

Like RLS, PLMD seems to have a genetic component that may be inherited. Because the two disorders co-exist so often, some scientists believe that the same genes may underlie the risk for both RLS and PLMD. Many people with RLS 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 Periodic Limb Movement Disorder Detected?

PLMD is rare in children, and the risk for the disorder increases with age. The disorder’s symptoms often don’t cause the person to wake fully, so they may not know they’re experiencing limb movements in their sleep. It’s more common for the symptoms to be noticed by a partner or bedmate. However, even if the movements don’t cause full waking, they can interfere with restful sleep, resulting in effects that extend into the daytime.

Potential warning signs of PLMD include:

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

How Is Periodic Limb Movement Disorder 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.

The diagnostic process for PLMD differs from that of RLS. Doctors can diagnose RLS based solely on a patient’s description of their symptoms. PLMD diagnosis requires sleep study tests such as polysomnography or electromyography (EMG).

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Periodic Limb Movement Disorder Treated?

PLMD has no cure, and no single treatment consistently relieves symptoms in all cases. Various medications have shown promise in treating PLMD, but individual patients respond differently to different 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 PLMD 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 may also help with PLMD symptoms. However, long-term use of these medications may cause worsening of the symptoms. Dopamine-boosting drugs include ropinirole, pramipexole, and rotigotine.
• Anti-seizure medications. Gabapentin enacarbil, gabapentin, and pregabalin are commonly prescribed to treat PLMD.
• 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 PLMD, but only as a last line of treatment due to their side effects.

How Does Periodic Limb Movement Disorder Progress?

PLMD is a life-long disorder, and symptoms may worsen with age. PLMD 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 Periodic Limb Movement Disorder Prevented?

There is no known way to prevent PLMD, 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.

Periodic Limb Movement Disorder Caregiver Tips

Some people with PLMD 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 PLMD:

• PLMD 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 PLMD.
• People with PLMD or RLS may be diagnosed with attention-deficit/hyperactivity disorder (ADHD).

Periodic Limb Movement Disorder Brain Science

Research has suggested that PLMD and RLS are 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 is essential 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 PLMD, 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 PLMD and RLS, given that many people with the disorders exhibit low iron levels 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 PLMD.

Periodic Limb Movement Disorder Research

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

Stage: Recruiting

Principal investigator: Sasikanth Gorantla, MD

OSF Healthcare Illinois Neurological Institute

Peoria, IL

This study’s expected results will significantly impact 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 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 informed consent will be obtained if the patient is interested. If the subject withdraws consent or does not finish both pre and post-evaluation, the subject will be replaced with a new 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 of 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: Impact of Iron Supplementation Treatment on Brain Iron Concentrations

Stage: Recruiting

Principal Investigator: Alison E. Pritchard, PhD

Kennedy Krieger Institute

Baltimore, MD

The present study aims to provide novel data to evaluate brain iron concentration as a mediator of the association between iron supplementation treatment and improvement in symptoms of ADHD and RLS in children, including PLMS. Aim 1 is to evaluate the impact of iron supplementation treatment on peripheral iron concentrations and brain iron concentrations. The investigators hypothesize that iron supplementation treatment will result in increased peripheral and brain iron concentrations. Aim 2 is to evaluate the impact of iron supplementation treatment on symptoms of ADHD and RLS. The investigators hypothesize that iron supplementation treatment will result in decreased symptoms of ADHD and RLS. Aim 3 is to investigate the relation between brain iron concentrations and symptoms of ADHD and RLS, including PLMS. The investigators hypothesize that brain iron concentrations in the substantia nigra and the thalamus will be negatively related to symptoms at baseline. Aim 4 is to evaluate whether brain iron concentrations mediate the association between iron supplementation treatment and symptoms of ADHD and RLS. The investigators hypothesize that increased brain iron concentrations in the substantia nigra and the thalamus will fully explain any improvements in symptoms that occur with iron supplementation treatment.

Twelve participants between the ages of 5 and 18 years will be recruited via Kennedy Krieger Institute’s Sleep Disorders Clinic. Recruitment will be accomplished by posting flyers with study information at the clinic and by asking Sleep Disorders Clinic clinicians to discuss the study with their patients who may be eligible and their caregivers. To be included in the study, participants will need to have: 1) a clinical diagnosis of either RLS or ADHD, 3) PLMS > 3/hour, based on an average of 5 nights of home recording with RestEaze leg meters, and 4) fasting serum iron values with ferritin < 50 mcg/L and transferrin saturation < 45%. Exclusionary criteria will be: 1) family is not proficient in the English language, 2) child is in foster care, 3) child has a chronic medical condition or genetic/metabolic disorder that might impact iron metabolism, 4) child has another sleep disorder or neuropsychiatric condition that might influence sleep, RLS, or ADHD symptoms, and 6) child has been receiving iron supplementation or a medication that could disrupt sleep.

An uncontrolled open-label trial design is proposed for this pilot study to establish evidence to support a larger, blinded, placebo-controlled trial application. Eligible participants will be asked to complete, at baseline (pre-iron supplementation treatment) and again at follow-up (post-treatment): 1) a 7 Tesla MRI scan, 2) five consecutive nights of RestEaZe™ monitoring, 3) caregiver-reported (or patient-reported if over the age of 10 years) Cambridge-Hopkins Restless Leg Syndrome questionnaire(CH-RLSq13), and 4) caregiver-reported ADHD Rating Scale-5. The treatment interval will be three months, which has been sufficient in previous studies to allow for treatment effects to be observed. Investigators anticipate 20 to 30% attrition over the three months of treatment, leaving 8-10 participants to scan at follow-up.

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

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

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. The few studies that have focused on the study of the integrity of executive functions in RLS have discordant results. 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 to executive functions are the two main reasons. Moreover, the question of polysomnographic correlates and the reversibility of these cognitive abnormalities after pharmacological management of RLS remains unanswered.