Causes and Risk Factors of Restless Legs Syndrome

Restless legs syndrome (RLS) is a disorder thought to be caused by poor communication between the central nervous system and peripheral nervous system, often affecting the limbs. The exact cause has not yet been identified, but several genes, medications, and other medical conditions have been linked to restless legs syndrome. 

Genetic RLS, commonly called primary RLS, is the most common cause of RLS. Symptoms of primary RLS can begin at any time in life, but may be worsened by taking certain types of drugs, including antidepressant, antipsychotic, and antihistamine medications.

RLS with no genetic basis may also be induced by these drugs or may be provoked by a nutritional deficiency, most commonly iron deficiency. In addition, a deficiency in vitamin B12 or folate may cause symptoms due to the inability to adequately produce red blood cells.

Significant physiological changes can also cause RLS (or RLS-like symptoms) in people without a known genetic factor. These changes may include pregnancy, neurological diseases like Parkinson’s disease and multiple sclerosis, and other disorders affecting the nervous system, kidneys, and legs.

Common Causes

To better understand the causes of RLS, it is helpful to divide them into primary and secondary causes:

Primary

The most common cause of restless legs syndrome (RLS) is familial RLS, also known as primary RLS. Primary RLS is heritable and almost two-thirds of people experiencing RLS have an immediate family member who also has symptoms. This may be a parent, sibling, or child who is similarly affected.

The various genes thought to be responsible for the condition likely cause RLS through a few different mechanisms related to iron regulation and the function of dopamine in the brain. The “Genetics” section below explains the genetic contributions of primary RLS in more detail.

Secondary

Secondary RLS occurs from a non-genetic cause and is often related to another medical condition.

The most common causes of secondary RLS are:

• Iron deficiency
• Pregnancy (notably in the third trimester)
• End-stage renal disease

Iron Deficiency or Pregnancy

RLS caused by iron deficiency or pregnancy has been linked to inadequate iron stores, as measured by the serum ferritin level. If the ferritin level is less than 70, the condition may be improved with iron replacement.

Iron supplements may be taken with vitamin C to improve absorption. Alternatively, dietary changes including eating more red meat or dark leafy vegetables (such as spinach) may be helpful.

End-Stage Renal Disease

End-stage renal disease, also known as chronic kidney disease, increases the risk of developing restless legs syndrome. This is especially true if someone is dependent upon dialysis. It is unclear what exactly contributes to the risk, but it may relate to anemia or iron deficiency.

Neurological Disease

Beyond these contributors, it is known that some neurological diseases can induce secondary RLS or RLS-like symptoms. Parkinson’s disease directly disrupts the dopaminergic pathway, while multiple sclerosis decreases the connectivity of neurons by damaging the myelin sheaths that insulate the nerves and speed conduction.

Because Parkinson’s disease and multiple sclerosis both affect the nervous system by disrupting brain communication important for limb movement, they are able to cause the symptoms associated with RLS.

Unfortunately, medications taken to treat these two diseases may also increase the risk of RLS. It should be noted that some disorders that affect the spinal cord or peripheral nerves may also cause RLS.

Diabetes

Diabetes and RLS are strongly correlated. In several studies, people with diabetes experience RLS two to three times more often than the general population. Among people with diabetes, complications from diabetes, such as damage affecting the peripheral nerves that extend into the limbs, are a common cause of secondary RLS.

Other Conditions

Damage to blood vessels of the legs can also lead to secondary RLS. Usually varicose veins are merely bothersome due to the cosmetic appearance, but (in the case of uncomfortable varicose veins) the pain and discomfort may coincide with symptoms of RLS. 

Rheumatic diseases—including rheumatoid arthritis, Sjogren’s syndrome, and fibromyalgia—are associated with the development of secondary RLS.

Interestingly, disruption of sleep may further exacerbate RLS symptoms. This may occur in the context of sleep deprivation or due to underlying sleep disorders that affect sleep quality, like untreated sleep apnea. 

Genetics

The role of the various genes that may be linked to primary RLS is not fully understood. The exact mechanisms are not known, and this is likely complicated by the different contributions to the condition.

There are several RLS-causing gene mutations that appear to affect iron storage. The gene BTBD9, for example, appears to be important for iron storage throughout the body. The presence of a mutated BTBD9 gene causes unusually low serum ferritin levels, indicative of iron deficiency and potentially contributing to anemia. 

However, many cases of genetically-linked RLS have less to do with iron storage and more to do with its regulation. MEIS1 is linked to the regulation of iron inside the brain. People with a malfunctioning MEIS1 variant may have normal iron levels in their blood, yet still have decreased iron availability in parts of their brain.

Other genes identified with an increased RLS risk include:

• PTPRD
• SKOR1
• MAP2K5
• TOX3
• rs6747972

It is expected that more relevant genes will be identified in future research.

Inheritance Pattern

Inheritance of primary RLS is often autosomal dominant, so the child of a parent with primary RLS may receive the gene and, if present, would be likely to exhibit symptoms at some point in their life. 

Familial RLS also often exhibits a pattern called “genetic anticipation.” This is due to the fact that sections of the mutant gene may be further duplicated and passed on, enhancing the effect of the change in subsequent generations. As a result, each subsequent generation with the altered RLS gene may experience their first RLS symptoms at a younger age.

The symptoms of primary RLS are generally first experienced from early adulthood to the early 40s, but may also occur during childhood, especially in the context of genetic anticipation. Medications, including some used to treat RLS, may also flare up or intensify RLS symptoms. 

Lifestyle Risk Factors

There are a number of important lifestyle risk factors that may exacerbate symptoms of restless legs syndrome. Changes in behaviors—including activity levels and substance and medication use—may alleviate the condition. Declining physical health may also have a negative effect on RLS.

Inactivity (such as while traveling) may aggravate symptoms of restless legs syndrome, as can excessive caffeine consumption and smoking. Exercise or stretching may be helpful to provide relief.

Reducing the intake of coffee, tea, chocolate, soda pop, or energy drinks may be needed. For myriad reasons, smoking cessation is advised.

Medications

Unfortunately, many medications (including prescription and over-the-counter drugs) may worsen RLS symptoms. It may be important to review the medications being taken with a pharmacist or prescribing medical provider to ensure they are not playing a role.

Antidepressants can affect the dopaminergic pathway in the brain in a way that may provoke RLS. The following antidepressants increase the risk of RLS:

• Escitalopram
• Mirtazapine 
• Fluoxetine
• Sertraline

In addition, some antipsychotic medications used to treat psychiatric conditions by reducing the effects of dopamine may contribute to symptoms of RLS. These include: 

• Olanzapine
• Haloperidol
• Phenothiazine 
• Lithium
• Prochlorperazine

There are a handful of other drug classes and specific medications that may also lead to RLS, such as:

• Antihistamines: Common sources are cold and allergy medications, such as Benadryl (diphenhydramine).
• Opioids: Painkillers like tramadol may worsen the condition, but longer-acting agents may actually be an effective treatment for intractable symptoms.
• Levothyroxine: Used to treat hypothyroidism, it may aggravate symptoms.
• Metoclopramide: Often prescribed as an anti-nausea medication, it is a dopamine agonist.
• Sinemet: This treatment of Parkinson’s, available as the generic levodopa/carbidopa, affects dopamine levels and may lead to augmentation.

If symptoms are thought to be due to a medication side effect, it is important to discuss changes in the medication with a healthcare provider. In some cases, it may be necessary to taper the dosing as part of discontinuation to avoid additional problems.

A Word From Verywell

It is important for someone experiencing RLS symptoms to potentially get testing and receive a diagnosis before attempting to treat it. This may require evaluation by a board-certified sleep physician and lab work, such as a serum ferritin level.

If it is determined that an underlying nutritional deficiency is present, this should be corrected prior to starting other medications. If the symptoms persist, it may be necessary to use RLS medications such as dopamine agonists for relief. Fortunately, improvement is typically possible, regardless of the underlying cause.

When symptoms are bothersome, seek expert evaluation to ensure safe and sustainable treatments that may provide long-term improvements in quality of life.