As asserted by davew, there is evidence that RLS is caused by general bodily inflammation (1, 2, 3). However, after researching the topic, I believe RLS is more plausibly caused by one specific type of inflammation: that of the Central Nervous System (CNS).
There isn’t any hard proof that CNS inflammation causes RLS (if there was, I wouldn’t need to spend my time writing this), but there is a considerable amount of incidental evidence. The purpose of this post is to demonstrate a correlative, and perhaps causative, link between CNS inflammation and RLS. I will present three arguments: first, that my inflammatory-RLS theory is consistent with what we know about RLS pathology; second, that my theory is consistent with what we know about RLS treatment; and third, that my theory is consistent with what we know about other related diseases.
RLS Pathology
RLS patients have irregularities in a variety of biological systems. Problems with these same systems can sometimes be caused by inflammation. Consider the following facts:
- RLS has been linked to decreased iron levels in the CNS, even when RLS patients have normal blood iron levels (4). Iron deficiency is associated with inflammation (5).
- RLS has been linked to dysfunction in patients’ dopaminergic circuitry (6). Abnormalities in mesolimbic and mesostriatal dopamine is associated with inflammation (7).
- RLS has been linked to impairment of patients’ endogenous opioid systems (8). Debility of the opioid system is associated with inflammation (9).
- RLS has been linked to elevated glutamate levels in the brain. Heightened glutamate levels may worsen sleep quality without a proportional increase in daytime sleepiness, symptoms which present in many RLS patients (10). Elevated glutamate levels are associated with inflammation (11).
- RLS has been linked to dysregulation of serotonergic neurotransmission (12). Serotonergic imbalance is associated with inflammation (13).
- Injecting rabbits with quinolinic acid has precipitated seizures and disturbed sleep (16).
- Injecting quinolinic acid into the brains of mice has precipitated seizures (17, 18).
- Quinolinic acid “can increase glutamate release by neurons, inhibit its uptake by astrocytes and inhibit astroglial glutamine synthetase leading to excessive microenvironment glutamate concentrations and neurotoxicity” (14).
- Other neurological diseases, including multiple sclerosis and Parkinson’s disease, are associated with quinolinic acid (19, 20). I discuss the connection of RLS to multiple sclerosis and Parkinson’s disease below.
Just as a variety of biological systems are implicated in RLS symptoms, a variety of treatments are used to soothe those symptoms. These same treatments are used to fight inflammation.
- Hydrocortisone, which fights inflammation, has been used as an effective treatment for RLS (21, 22).
- Vitamin D and folate can reduce RLS symptoms (23, 24). Both substances can also be used to treat inflammation (25, 26).
- Magnesium is effective in treating some RLS patients (27). Magnesium has been shown to block NMDA receptors (28), tempering the effects of high quinolinic acid caused by neuroinflammation.
- The drug ketamine has shown promising results in RLS case studies (29). Ketamine has anti-inflammatory properties and is a powerful NMDA antagonist (30).
RLS has comorbidity with other diseases that affect the CNS. Our knowledge of most neurological diseases is in an embryonic state, but research ties some of these diseases to inflammation.
- RLS has well-documented comorbidity with multiple sclerosis (31). Of particular interest is the fact that RLS can either precede or proceed the onset of multiple sclerosis (32), suggesting that neither disease causes the other, but that they are caused by the same lurking condition. The current scientific consensus is that multiple sclerosis is caused by immune-mediated inflammation of the CNS (33), which is consistent with my theory that CNS inflammation also causes RLS. Additionally, atrophy of the corpus callosum (found in both RLS (34) and multiple sclerosis (35) patients) has been associated with inflammation (36).
- RLS has comorbidity with Parkinson’s disease. As is the case in multiple sclerosis, RLS may either precede or proceed the outbreak of Parkinson’s disease symptoms (37). The cause of Parkinson’s disease has not yet been fully elucidated, but CNS inflammation is thought to be an important component (38).
- RLS has comorbidity with epilepsy (39), which research indicates is caused in part by inflammation (40).
The theory that CNS inflammation causes RLS is consistent with our knowledge of RLS pathology, treatment, and related diseases. I am unaware of any significant research refuting this hypothesis.
Thank you for taking the time to read this meandering, dilettante post. I welcome all critiques of this inflammatory-RLS theory, especially those from persons with scientific or medical backgrounds. It seems to me that any competing theory would have difficulty collating and justifying the available RLS pathology and treatment data, especially in offering explanations for the effectiveness of hydrocortisone and the non-causal RLS comorbidity with multiple sclerosis.
1. Restless Legs Syndrome--Theoretical Roles of Inflammatory and Immune Mechanisms, https://pubmed.ncbi.nlm.nih.gov/22258033/
2. Elevated C-reactive Protein Is Associated With Severe Periodic Leg Movements of Sleep in Patients With Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/22750520/
3. Polymorphisms of Interleukin-1 Beta and Interleukin-17Alpha Genes Are Associated With Restless Legs Syndrome, https://journals.sagepub.com/doi/abs/10 ... 8827?rss=1
4. Causes of Restless Legs Syndrome, https://www.hopkinsmedicine.org/neurolo ... auses.html
5. Iron Homeostasis and the Inflammatory Response, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108097
6. Restless Legs Syndrome: Current Concepts about Disease Pathophysiology, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961894/
7. Inflammation Effects on Motivation and Motor Activity: Role of Dopamine, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143486/
8. Does the Endogenous Opiate System Play a Role in the Restless Legs Syndrome? A Pilot Post-Mortem Study, https://pubmed.ncbi.nlm.nih.gov/19167016/
9. Alteration in Endogenous Opioid Systems Due to Chronic Inflammatory Pain Conditions, https://pubmed.ncbi.nlm.nih.gov/11821033/
10. Thalamic glutamate/glutamine in restless legs syndrome, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716406/
11. Inflammation-induced changes in peripheral glutamate receptor populations, https://www.sciencedirect.com/science/a ... 9398013286
12. Availability of Brain Serotonin Transporters in Patients With Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/20142619/
13. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression, https://www.nature.com/articles/4002006
14. Quinolinic Acid, the Inescapable Neurotoxin, https://febs.onlinelibrary.wiley.com/do ... 12.08485.x
15. Quinolinic Acid in Vivo Synthesis Rates, Extracellular Concentrations, and Intercompartmental Distributions in Normal and Immune-Activated Brain as Determined by Multiple-Isotope Microdialysis, https://pubmed.ncbi.nlm.nih.gov/9422373/
16. Effect of Quinolinic Acid on Wakefulness and Sleep in the Rabbit, https://pubmed.ncbi.nlm.nih.gov/2144974/
17. Stimulant and Convulsive Effects of Kynurenines Injected Into Brain Ventricles in Mice, https://pubmed.ncbi.nlm.nih.gov/641543/
18. Quinolinic Acid Promotes Seizures and Decreases Glutamate Uptake in Young Rats: Reversal by Orally Administered Guanosine, https://pubmed.ncbi.nlm.nih.gov/15262204/
19. Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290739/
20. Alternations of Metabolic Profile and Kynurenine Metabolism in the Plasma of Parkinson's Disease, https://pubmed.ncbi.nlm.nih.gov/29294246/
21. Low-dose Hydrocortisone in the Evening Modulates Symptom Severity in Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/18443313/
22. Oral glucocorticosteroids: Effective in a case of restless legs syndrome resistant to other therapies, https://www.sciencedirect.com/science/a ... via%3Dihub
23. The Effect of Vitamin D Supplements on the Severity of Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/25148866/
24. Restless Legs Syndrome: Pathophysiology and the Role of Iron and Folate, https://pubmed.ncbi.nlm.nih.gov/17604457/
25. Vitamin D and inflammatory diseases, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070857/
26. Folic Acid Is Able to Polarize the Inflammatory Response in LPS Activated Microglia by Regulating Multiple Signaling Pathways, https://www.hindawi.com/journals/mi/2016/5240127/
27. Magnesium Therapy for Periodic Leg Movements-Related Insomnia and Restless Legs Syndrome: An Open Pilot Study, https://pubmed.ncbi.nlm.nih.gov/9703590/
28. The mechanism of magnesium block of NMDA receptors, https://www.sciencedirect.com/science/a ... 6584710128
29. Oral Ketamine: A Promising Treatment for Restless Legs Syndrome, https://journals.lww.com/anesthesia-ana ... ss.34.aspx
30. The Anti-Inflammatory Effects of Ketamine: State of the Art, https://pubmed.ncbi.nlm.nih.gov/21612145/
31. Association of multiple sclerosis with restless legs syndrome and other sleep disorders in women, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345617/
32. High Prevalence of Restless Legs Syndrome in Multiple Sclerosis, https://pubmed.ncbi.nlm.nih.gov/17437613/
33. Chronic inflammation in multiple sclerosis — seeing what was always there, https://www.nature.com/articles/s41582-019-0240-y
34. Involvement of the Central Somatosensory System in Restless Legs Syndrome: A Neuroimaging Study, https://pubmed.ncbi.nlm.nih.gov/29695597/
35. Corpus Callosum Atrophy May Be an Effective MRI Marker for Long-Term Disease Progression in MS, https://www.mdedge.com/multiplesclerosi ... ective-mri
36. Inflammation Is Related to Corpus Callosum Integrity and Executive Functions in Healthy Older Adults, https://n.neurology.org/content/78/1_Su ... /IN4-1.006
37. Restless Legs Syndrome and Parkinson Disease: A Causal Relationship Between the Two Disorders?, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066514/
38. Inflammation in Parkinson's Disease, https://pubmed.ncbi.nlm.nih.gov/22814707/
39. Epilepsy and Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/28109988/
40. The role of inflammation in the development of epilepsy, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952578/