Restless legs syndrome pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

Overview

Pathophysiology

Pathogenesis

Generally most scientists consider restless legs syndrome(RLS) as a central nervous system (CNS)-related disorder, but no specific lesion has been found to be associated with the syndrome.^[1]

It is thought that RLS is the result of central nervous system anatomic lesions.^[1]
Findings in imaging of CNS witch suggest the relation between the anatomic lesions in CNS and RLS include:^[1]^[2]^[3]^[4]
- Presence of morphologic changes in the somatosensory cortex, motor cortex and thalamic gray matter in MRI
- Abnormal bilateral cerebellar and thalamic activation during the manifestation of sensory symptoms, with additional red nucleus and reticular formation activity during periodic leg movements (PLMS), in functional MRI study
- Evidences of the role of the limbic and opioid systems in SPECT and PET studies
- Low brain iron concentrations and dysfunction of iron metabolism and intracellular iron
  - The “iron-dopamine model” explains that iron deficiency in the brain causes an abnormality in the dopaminergic system leading to manifestation of RLS.

RLS symptoms seem to depend on abnormal spinal sensorimotor integration at the spinal cord level and abnormal central somatosensory processing
In animal models, studies suggest that the All dopaminergic system and the D3 receptor participates in RLS symptoms

Genetics

Genes involved in the pathogenesis of RLS include: RLS 1: 12q and RLS 2: 14q and RLS 3: 9p and RLS 4: 2q and RLS 5: 20p.^[1]
40% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.

Associated Conditions

Conditions which may be associated with RLS include:^[5]^[6]^[7]

Microscopic Pathology

The exact neuroanatomical substrate imbalance which causes restless legs syndrome (RLS) is unknown.^[8]
Chronic ischemic changes were found in some brain tissue samples of patients whit RLS.^[8]

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Miyamoto M, Miyamoto T, Iwanami M, Suzuki K, Hirata K (2009). “[Pathophysiology of restless legs syndrome]”. Brain Nerve. 61 (5): 523–32. PMID 19514512.
↑ Li X, Allen RP, Earley CJ, Liu H, Cruz TE, Edden RAE; et al. (2016). “Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla”. Sleep Med. 22: 75–82. doi:10.1016/j.sleep.2016.05.001. PMC 4992945. PMID 27544840.
↑ Etgen T, Draganski B, Ilg C, Schröder M, Geisler P, Hajak G; et al. (2005). “Bilateral thalamic gray matter changes in patients with restless legs syndrome”. Neuroimage. 24 (4): 1242–7. doi:10.1016/j.neuroimage.2004.10.021. PMID 15670702.
↑ Guo S, Huang J, Jiang H, Han C, Li J, Xu X; et al. (2017). “Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management”. Front Aging Neurosci. 9: 171. doi:10.3389/fnagi.2017.00171. PMC 5454050. PMID 28626420.
↑ Katsi V, Katsimichas T, Kallistratos MS, Tsekoura D, Makris T, Manolis AJ; et al. (2014). “The association of Restless Legs Syndrome with hypertension and cardiovascular disease”. Med Sci Monit. 20: 654–9. doi:10.12659/MSM.890252. PMC 3999161. PMID 24747872.
↑ Cotter PE, O’Keeffe ST (2006). “Restless leg syndrome: is it a real problem?”. Ther Clin Risk Manag. 2 (4): 465–75. PMC 1936366. PMID 18360657.
↑ Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J (2016). “Restless legs syndrome associated with major diseases: A systematic review and new concept”. Neurology. 86 (14): 1336–43. doi:10.1212/WNL.0000000000002542. PMC 4826337. PMID 26944272.
↑ ^8.0 ^8.1 Pittock SJ, Parrett T, Adler CH, Parisi JE, Dickson DW, Ahlskog JE (2004). “Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology”. Mov Disord. 19 (6): 695–9. doi:10.1002/mds.20042. PMID 15197711.

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[pmid19514512-1] 1.0 ^1.1 ^1.2 ^1.3 Miyamoto M, Miyamoto T, Iwanami M, Suzuki K, Hirata K (2009). “[Pathophysiology of restless legs syndrome]”. Brain Nerve. 61 (5): 523–32. PMID 19514512.

[pmid27544840-2] Li X, Allen RP, Earley CJ, Liu H, Cruz TE, Edden RAE; et al. (2016). “Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla”. Sleep Med. 22: 75–82. doi:10.1016/j.sleep.2016.05.001. PMC 4992945. PMID 27544840.

[pmid15670702-3] Etgen T, Draganski B, Ilg C, Schröder M, Geisler P, Hajak G; et al. (2005). “Bilateral thalamic gray matter changes in patients with restless legs syndrome”. Neuroimage. 24 (4): 1242–7. doi:10.1016/j.neuroimage.2004.10.021. PMID 15670702.

[pmid28626420-4] Guo S, Huang J, Jiang H, Han C, Li J, Xu X; et al. (2017). “Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management”. Front Aging Neurosci. 9: 171. doi:10.3389/fnagi.2017.00171. PMC 5454050. PMID 28626420.

[pmid24747872-5] Katsi V, Katsimichas T, Kallistratos MS, Tsekoura D, Makris T, Manolis AJ; et al. (2014). “The association of Restless Legs Syndrome with hypertension and cardiovascular disease”. Med Sci Monit. 20: 654–9. doi:10.12659/MSM.890252. PMC 3999161. PMID 24747872.

[pmid18360657-6] Cotter PE, O’Keeffe ST (2006). “Restless leg syndrome: is it a real problem?”. Ther Clin Risk Manag. 2 (4): 465–75. PMC 1936366. PMID 18360657.

[pmid26944272-7] Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J (2016). “Restless legs syndrome associated with major diseases: A systematic review and new concept”. Neurology. 86 (14): 1336–43. doi:10.1212/WNL.0000000000002542. PMC 4826337. PMID 26944272.

[pmid15197711-8] 8.0 ^8.1 Pittock SJ, Parrett T, Adler CH, Parisi JE, Dickson DW, Ahlskog JE (2004). “Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology”. Mov Disord. 19 (6): 695–9. doi:10.1002/mds.20042. PMID 15197711.

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