Reviewed by Sahil Chopra, MD, and Stacey Gunn, MD.

Research by Savit Malhotra and Theresa Do.

Introduction

For our second article in the RLS crash course series, our focus will be on the underlying causes and pathophysiology of restless leg syndrome. Now that we know the basics of RLS, its symptoms, and its prevalence, we will be delving into what research knows about why RLS may happen in the first place. Throughout the article, we will introduce the two types of RLS based on their etiology, or causes. From there, we will also discuss how RLS may be connected to dopamine through the dopaminergic pathway in the brain. This pathway revolves around the neurotransmitter dopamine and its receptors. When there are dysfunctions in the system, it is hypothesized to lead to the development of RLS. 

Primary vs. Secondary RLS: Identifying the Underlying Causes

To understand the causes of RLS, it is helpful to discuss two etiological categories: primary RLS and secondary RLS. Primary RLS typically occurs earlier in life (usually before age 45), and often has a genetic basis, with many patients having a family history of the disease.[1] Secondary RLS usually occurs later in life, with symptoms progressing more quickly, and it is typically associated with medical problems, including iron deficiency, end-stage kidney disease, or pregnancy. It should be noted that primary and secondary RLS have been previously thought of as separate entities, but newer models suggest that they may represent a spectrum of gene-environment interactions.[2]

About half of the people diagnosed with RLS have a family member who also has the condition. Studies of twins suggest that genetics may account for up to 70% of the risk for developing RLS. However, RLS is not caused by a single gene mutation. Instead, researchers have identified 164 different genetic variations that may increase the risk of developing RLS. This means that RLS does not follow a simple inheritance pattern—having a parent with RLS does not guarantee a 50% chance of developing the condition, as the genetic picture is much more complex.[3]

Even when blood iron levels are normal, people with RLS often have low iron levels in specific parts of the brain.[3][4] Iron plays an important role in producing dopamine, a chemical messenger that helps control movement.[3] Research suggests that problems with iron metabolism and dopamine signaling in the brain contribute to RLS symptoms.[3][4]

RLS can occur on its own or develop in connection with other medical conditions. Several health issues are strongly associated with RLS, including Iron deficiency and anemia (about 24% of people with iron deficiency anemia experience RLS symptoms at least twice weekly), pregnancy (RLS affects approximately 22% of pregnant women overall, with the highest rates occurring in the third trimester. For most women, symptoms resolve within one month after delivery). Kidney disease (about 24% of people with end-stage kidney disease have RLS), peripheral neuropathy (approximately 21.5% of people with nerve damage experience RLS, though distinguishing nerve pain from RLS symptoms can sometimes be challenging, and other conditions like multiple sclerosis (27.5%), Parkinson's disease (20%), and during opioid withdrawal (up to 50%).[3]

Certain medications can trigger RLS symptoms or make existing symptoms worse, including some antidepressants, antihistamines (like diphenhydramine), and medications that block dopamine.[3] 

Dopaminergic Dysfunction and Basal Ganglia Involvement

Primarily, dopamine serves as the brain’s reward chemical, helping us to feel good after completing certain tasks.[5] Dopamine is produced in an area of the brain called the substantia nigra, which is part of the basal ganglia. Sleep literature has documented that RLS is a dopamine-dependent disorder, with dopaminergic stimulation lessening symptoms and dopamine blockade worsening them.[6]

However, RLS does not appear to be a simple dopamine deficiency (such as in neurodegenerative conditions, like Parkinson’s disease, where dopamine-producing neurons become dysfunctional). Instead, RLS related domanergic mechanisms appear to be due to dysregulations in the dopamine signaling pathways within the basal ganglia circuits.[7] Through animal models, neuroimaging, and response patterns to treatment, it seems as though the actual functionality of dopamine receptors and the functionality of these pathways impact the severity of RLS more than how much dopamine is actually present.[7] 

In regard to the receptors, abnormalities in the D2-subtype receptor have been observed in patients with RLS.[6] Mitchell et. al. help prove the idea that receptor regulation, not just the level of dopamine, plays a role in the development of RLS symptoms. This is also seen at a genetic level. The typical genetic risk variants associated with RLS appear to be due to issues with the dopaminergic pathways, which directly influence dopamine turnover, receptor expression, and the nigrostriatal signaling pathway (the key pathway of the substantia nigra).[8]

The characteristic urge to move and corresponding motor restlessness can be explained by improper inhibition of these pathways. D1 receptors tend to promote excitatory signaling, whereas D2/D3 pathways provide inhibitory balance. It has been theorized that RLS symptoms are due to a shift toward excitatory dopaminergic activity, meaning that the D1 receptor pathway is favored over the D2/D3 pathway.[8] This imbalance may also help explain augmentation, a paradoxical phenomenon where long-term dopaminergic therapy worsens symptoms over time.‍

Conclusion

RLS is a complex disorder, and we’ve only scratched the surface thus far. Dopaminergic mechanisms have been widely accepted to be the most important mechanism in RLS, but there are a number of other factors that can also play into this mechanism (such as iron dysregulation and everyday triggers) and help explain RLS’s etiology. In future articles, we will continue to explore these different mechanisms to better understand how RLS presents in the way it does. Understanding the mechanisms provides the background necessary to understand the new treatments available to counter RLS.

As we continue to explore RLS, we encourage you to reach out to a provider if you yourself have RLS that is preventing you from getting the quality sleep that you need each night. The team at Empower Sleep is always ready to help you get your sleep back on track!

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