Dr. Jonathan Marcus, MD – Associate Professor of Clinical Neurology, Sleep Medicine Specialist

What is restless legs syndrome (RLS)?

Restless Legs Syndrome (RLS), sometimes known as Willis-Ekbom Disease, is a neurological condition.

It is a sleep disorder. It is known for its primary symptom: uncontrollable movement in your legs.

RLS can be uncomfortable, causing sleep disturbances and affecting the quality of life.

One study demonstrated that RLS occurs in roughly 7 percent of individuals in the general population, but significant cases occur in 2.7 percent of the population.

Restless legs syndrome is more common in women, and its prevalence increases with age.

RLS can have early-onset (before 45 years of age) or late-onset (after 45). Early-onset RLS, or Primary RLS, is frequently hereditary and progresses slowly.

Late-onset RLS or Secondary RLS is also likely hereditary and progresses quickly.

Late-onset RLS can also have other associated disorders, such as iron deficiency.

Differences between both types of RLS are briefly discussed below.

What is primary versus secondary Restless legs syndrome?

Experts categorize RLS into two groups: primary RLS and secondary RLS.

These two groups differ in what is the underlying cause of symptoms.

Most cases are categorized as primary RLS. Primary, or “idiopathic,” means that there is no known cause of the condition.

Secondary Restless legs syndrome is when another underlying condition causes RLS.

We will discuss the possible causes of RLS later in the article.

What are the symptoms of RLS?

Symptoms of RLS usually occur in the legs and on both sides of the body.

However, the condition can sometimes affect the arms and alternate between sides.

Restless legs syndrome leads to unpleasant sensations in the limbs.

Different patients experience different sensations, with some describing the feelings as either tingling, aching, crawling, painful, burning, prickling, pulling, or itching.

These unpleasant feelings are relieved by movement, leading to a strong urge to constantly move your legs, pace, or toss and turn at night.

Symptoms of restless legs syndrome most often arise during periods of inactivity.

Discomfort usually starts in the evening or around bedtime.

Symptoms can worsen throughout the night but usually go away by the morning.

Symptoms can range from minimal to debilitating.

Symptoms can also vary from day to day.

Clinicians sometimes categorize Restless legs syndrome symptoms based on how often they occur.

These categories include:

• Intermittent RLS: when untreated, symptoms have occurred less than twice a week for the past year and have appeared at least five times in total.
• Chronic persistent RLS: when untreated, symptoms have happened at least twice a week for the past year.

The restless sensations are relieved by initiating movement.

As you can imagine, this medical condition can result in sleep deprivation.

What causes restless leg syndrome (RLS)?

Experts do not fully understand the underlying mechanisms that cause primary RLS.

However, we do know of six genes that contribute to primary RLS.

These genes include BTEBD9, PTPRD, MAP2K5, MEIS1, SKOR1, and TOX3.

Primary RLS sometimes occurs within families, supporting the theory that the condition can be genetic and hereditary.

Roughly 63 percent of individuals with RLS have a first-degree family member with the disorder.

Additionally, iron and dopamine (a chemical messenger in the brain) can be out of balance in the brain.

Secondary RLS

Secondary RLS is when another condition causes RLS.

Examples of causes of potential include:

• Low iron
• Vitamin B12/folate deficiency
• Pregnancy
• End-stage renal disease (ESRD)
• Peripheral neuropathy (nerve damage to the hands and feet, usually caused by diabetes)
• Parkinson’s disease
• Fibromyalgia
• Rheumatoid arthritis
• Charcot-Marie-Tooth disease

The video below from my YouTube channel reviews the hidden signs of Vitamin B12 deficiency:

RLS also commonly occurs when you have other neurological conditions.

These conditions include stroke, migraine, and multiple sclerosis.

You can reverse certain disorders that cause secondary RLS and alleviate symptoms.

Examples of reversible conditions include pregnancy, renal disease, and low iron.

The video below from the Cleveland Clinic provides a nice overview of RLS triggers, home remedies, and treatment:

What is your body lacking when you have RLS?

A significant risk factor for RLS is iron deficiency.

In the central nervous system, iron and dopamine affect one another.

For instance, dopamine production requires iron.

This explains why animals with low levels of iron have dysfunctional dopamine transporters.

As discussed in the article, Dopamine can contribute to RLS symptoms.

The interplay between dopamine and iron, therefore, is critical.

Individuals with RLS can have low iron levels in the brain.

Roughly 15 percent of individuals with RLS have low iron levels (defined as a serum ferritin level of less than 50 mcg/L).

If you have low iron and RLS symptoms, you may benefit from iron supplementation.

Increasing your iron levels may improve or eliminate RLS symptoms.

Only your doctor can determine if your iron levels are low through blood work and if you need to start taking iron supplementation.

Please do not start taking iron without discussing it with your doctor.

Having too much iron in your system can be dangerous to your health.

If you have been taking iron without your doctors’ knowledge and start experiencing vomiting, vomiting blood, diarrhea, abdominal pain, drowsiness, irritability, headache, fever, dizziness, shortness of breath, yellowing of the skin, or your skin turns grayish or bluish, call your doctor immediately!

RLS vs. PLMS

Periodic Limb Movements of Sleep

Periodic Limb Movements of Sleep (PLMS), also known as Periodic Limb Movement Disorder, is a condition like RLS.

PLMS is when you have repeated limb movements, usually during the first few hours of sleep.

However, they can also occur before sleep or when awake.

Experts define a PLMS cluster as a minimum of four movements separated by five to 90 seconds.

Movements can include things such as kicking or twitching of the extremities.

The difference between restless legs syndrome and periodic limb movements of sleep

The difference between RLS and PLMS is when these movement disruptions occur.

For PLMS, limb movements usually occur during sleep. For RLS, limb movements typically occur at rest, which is frequently around bedtime and before sleep.

Approximately 80 percent of patients with RLS will also have PLMS.

How is someone diagnosed with restless legs syndrome (RLS)?

There are no tests that can definitively confirm the presence of RLS.

Instead, your provider will assess subjective information such as your symptoms and medical history.

They may also perform blood tests to help support an RLS diagnosis or understand the underlying cause.

Clinicians diagnose RLS based on your medical history and a neurological exam.

If you have RLS, your neurological exam should be normal.

These details are essential as they will help exclude other potential conditions that could be causing your symptoms.

Other conditions commonly confused with RLS include leg cramps at night, muscle pain, restlessness, habitual foot tapping, and positional discomfort.

Conditions involving your blood vessels can also cause symptoms similar to RLS. These include things such as leg swelling.

Diagnosis of RLS can be based on the International Restless Legs Syndrome Study Group (IRLSSG) and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.

These criteria can confirm a diagnosis if the following five situations occur:

1. An overwhelming urge to move your legs with or due to an uncomfortable sensation in the legs

2. Symptoms only occur or worsen at times of rest or inactivity

3. Movement, such as walking, resolves symptoms for as long as the movement continues

4. Symptoms only occur or worsen at nighttime

5. The previous four symptoms are not the result of another medical or behavioral disorder

Your provider will likely run a blood test if they suspect RLS.

A blood test can help to rule out potential secondary causes of RLS, as they are seeing if there is an underlying condition that could be causing your symptoms.

For example, if your blood test indicates that you are deficient in iron, your low iron levels may be causing RLS.

Examples of blood tests that may rule out secondary RLS include:

• Iron tests (e.g., serum ferritin level)
• Serum vitamin B12 and folic acid
• Serum glucose and HbA1C
• Full blood count
• Serum creatinine (a measure of kidney function)
• Urea and electrolytes
• Thyroid function tests

Your provider may also prescribe a dose of levodopa to “test” your RLS diagnosis.

Levodopa is a medication that treats Parkinson’s Disease and RLS.

It works by acting as dopamine to relieve symptoms.

If you have symptom improvement with a dose of levodopa, you will likely benefit from RLS treatment.

Dopamine’s role in RLS will be discussed next in the article.

Depending on your symptoms, you may require other diagnostic tests.

For example, if you experience insomnia symptoms, your clinician may recommend a sleep study.

Role of dopamine in RLS

As stated above, patients can use levodopa to treat RLS.

Levodopa is a medication that mimics the natural substance dopamine and stimulates the dopamine system in the brain.

Levodopa’s efficacy in alleviating RLS symptoms would suggest that the brain does not make enough dopamine.

However, it is the opposite. Brain imaging indicates that with RLS, the nervous system exhibits increased levels of dopamine.

Restless legs syndrome treatment guidelines

Currently, there are no treatments that cure RLS or change the course of the disease.

There are treatments available, though, that can help relieve your symptoms.

There are multiple non-medication options that you can try, such as implementing specific lifestyle changes.

The best treatment will depend on your specific symptoms, including how severe and frequent they are.

If your symptoms are minimal, you can manage your RLS with behavioral changes alone.

More severe symptoms may need medication to improve or resolve.

We will discuss available treatment options in the rest of this article.

Non-Prescription Management

Reverse the underlying cause

Certain causes of RLS are reversible. This means that treating the underlying condition will help to alleviate RLS symptoms.

For example, patients with End-stage renal disease (ESRD) commonly have RLS.

In the instance of ESRD, a successful kidney transplant may help to relieve symptoms.

Another example includes iron deficiency.

Treatment of iron deficiency will be discussed in the pharmacologic treatment section.

Remove offending medications

Your doctor should review your medication list to see if any medications could be causing or worsening your RLS symptoms.

If you are on a medication that can worsen RLS, your provider might be able to discontinue the drug, reduce your dose, switch you to another medication, or add another agent to help symptoms.

For example, if you take an SSRI for depression, your provider may recommend switching to bupropion.

Bupropion affects dopamine and is thus considered first-line for patients with RLS and depression.

Other Management Strategies

Non-medication treatment can be used alone or with medication to alleviate RLS symptoms.

For example, physical activity, specifically lower body resistance and aerobic exercise, can benefit.

Some patients may benefit from walking, stretching, and relaxation methods like yoga.

Other techniques include massaging your legs and bathing in cold or hot water.

Avoid caffeine, nicotine, and alcohol, which can worsen symptoms.

Proper sleep hygiene can also be of benefit.

Practicing good sleep hygiene means maintaining a routine and eliminating distractions to ensure a restful night’s sleep.

For example, you should maintain a comfortable and quiet sleeping environment.

Additionally, maintaining a regular sleep schedule (e.g., having the same bedtime and wake-up time daily) can improve sleep quality.

What are the best medications to treat RLS?

Various medications are available to help with RLS symptoms. The American Academy of Neurology (AAN) recommends pramipexole, rotigotine, and gabapentin enacarbil as first-line treatments for RLS.

Other options include ropinirole, pregabalin, or IV ferric carboxymaltose.

A brief overview of treatments available, doses, and important points are summarized in the table below:

Carbidopa/Levodopa

Carbidopa/levodopa is an efficacious agent; however, clinicians do not consider it first-line therapy because of augmentation.

Augmentation, which we will discuss later, is when your symptoms worsen than when you started treatment.

Augmentation occurs in 50 to 80 percent of patients taking carbidopa/levodopa.

When indicated, carbidopa/levodopa is used for intermittent RLS and taken at a maximum of two to three times weekly.

You should avoid taking carbidopa/levodopa daily.

Additionally, abrupt discontinuation of carbidopa/levodopa can cause withdrawal symptoms and neuroleptic malignant syndrome (NMS).

NMS refers to a rare reaction to certain drugs.

Dopamine Agonists

Dopamine agonists include pramipexole, ropinirole, and the rotigotine transdermal patch.

Pramipexole and ropinirole are the most effective in the class and potential first-line agents.

Augmentation can occur with dopamine agonists but not as much as carbidopa/levodopa.

With the rotigotine patch, rotate the application site to avoid adverse effects.

Ropinirole also has special considerations for those who smoke.

If you are a smoker and stop smoking while on ropinirole, you may see increased adverse effects.

Therefore, your doctor may need to adjust your dose.

6 to 17 percent of patients taking dopamine agonists have impulse control issues.

These problems include hypersexuality or the urge to binge eat, spend money, or gamble.

If you experience these effects, you may benefit from switching to a non-dopamine-acting agent.

See the medication table above for options to discuss with your doctor.

Alpha-2-Delta Calcium Channel Ligands

Gabapentin enacarbil is a “prodrug” of gabapentin.

This means that gabapentin enacarbil is converted to gabapentin in the body.

The benefit of these agents is that they do not cause augmentation.

You should swallow gabapentin enacarbil whole and take it with food.

DO NOT chew the contents or sprinkle them over applesauce or food.

While other medications in capsule form can be taken this way, gabapentin enacarbil cannot.

Additionally, you should use caution when operating machinery, as drowsiness can occur.

Benzodiazepines & Opioids (off-label)

Benzodiazepines and opioids can treat RLS but are “off-label” medications.

This means the FDA has not formally approved these drugs to treat RLS specifically. This does not mean that this practice is illegal.

Physicians have the legal privilege to prescribe these medications if they have assessed their patients and concluded that the off-label drug would benefit them clinically.

Benzodiazepines, like clonazepam, do not treat RLS symptoms but instead, help facilitate sleep and treat insomnia.

Opioids can treat severe augmentation or RLS that does not respond to other treatments.

Iron supplementation

Between 25 to 35 percent of people with iron deficiency anemia will have RLS.

Iron supplementation, therefore, may improve symptoms.

Guidelines currently suggest iron replacement therapy for RLS patients with a ferritin level of less than 75 ng/mL.

Patients usually start with oral iron therapy but can receive intravenous (IV) iron if required.

After starting iron therapy, your doctor should check your ferritin levels to ensure they are within range.

What Is Augmentation?

Augmentation is when your symptoms get worse from when you started treatment.

Augmentation can present as:

• Greater intensity of symptoms
• Symptoms start earlier in the night or day (sometimes happening 24/7)
• Quicker symptom onset after stopping activity
• Spreading of symptoms to other areas of the body

Augmentation is a significant concern with medications that act on the body’s dopamine system, specifically carbidopa/levodopa.

Augmentation occurs in 73% percent of individuals on levodopa therapy.

In comparison, the risk of augmentation with pramipexole is seven percent per year.

Therefore, the current AAN guidelines suggest starting an alpha-2-delta calcium channel ligand agent (e.g., gabapentin enacarbil) as a first-line treatment instead of a dopamine agent.

High doses of dopamine agents increase your risk of experiencing augmentation.

If you use a dopamine agent such as carbidopa/levodopa, your physician will likely keep your dose as low as possible to prevent augmentation.

Additionally, your provider should continuously monitor you for signs of augmentation.

What Non-prescription and Prescription Medications Cause RLS?

Certain medicines can worsen RLS symptoms.

If you receive an RLS diagnosis, your provider should review your medication history to identify any medications that may aggravate your symptoms.

• Medications that may cause or worsen RLS symptoms include:
• Antihistamines (specifically sedating antihistamines, such as diphenhydramine)
• Antipsychotic drugs (e.g., paliperidone, risperidone, and quetiapine)
• Other dopamine-receptor blockers (e.g., promethazine and metoclopramide)
• Selective serotonin reuptake inhibitors (SSRIs) (e.g., escitalopram, citalopram, and sertraline)
• Beta-blockers (e.g., metoprolol, carvedilol, bisoprolol)
• Lithium

In addition, caffeine and alcohol can worsen symptoms.

Summary

There are several key takeaways about RLS that you should remember:

• RLS is when you have uncomfortable sensations in your limbs, causing uncontrollable movements (likely in your legs)
• Iron deficiency is common in patients with RLS and may require supplementation
• Augmentation makes it challenging to treat RLS and maintain control over symptoms
• Alpha-2-delta calcium channel ligands like gabapentin enacarbil are first-line agents for RLS
• Dopamine agents can be first line, but providers should monitor signs of augmentation