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*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.
*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.


* It is thought that RLS is the result of central nervous system anatomic lesions.
* It is thought that RLS is the result of central nervous system anatomic lesions.<ref name="pmid19514512">{{cite journal| author=Miyamoto M, Miyamoto T, Iwanami M, Suzuki K, Hirata K| title=[Pathophysiology of restless legs syndrome]. | journal=Brain Nerve | year= 2009 | volume= 61 | issue= 5 | pages= 523-32 | pmid=19514512 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19514512  }} </ref>
* Findings in imaging of CNS witch suggest the relation between the anatomic lesions in CNS and RLS include:
* Findings in imaging of CNS witch suggest the relation between the anatomic lesions in CNS and RLS include:<ref name="pmid19514512">{{cite journal| author=Miyamoto M, Miyamoto T, Iwanami M, Suzuki K, Hirata K| title=[Pathophysiology of restless legs syndrome]. | journal=Brain Nerve | year= 2009 | volume= 61 | issue= 5 | pages= 523-32 | pmid=19514512 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19514512  }} </ref><ref name="pmid27544840">{{cite journal| author=Li X, Allen RP, Earley CJ, Liu H, Cruz TE, Edden RAE et al.| title=Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla. | journal=Sleep Med | year= 2016 | volume= 22 | issue=  | pages= 75-82 | pmid=27544840 | doi=10.1016/j.sleep.2016.05.001 | pmc=4992945 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27544840  }} </ref><ref name="pmid15670702">{{cite journal| author=Etgen T, Draganski B, Ilg C, Schröder M, Geisler P, Hajak G et al.| title=Bilateral thalamic gray matter changes in patients with restless legs syndrome. | journal=Neuroimage | year= 2005 | volume= 24 | issue= 4 | pages= 1242-7 | pmid=15670702 | doi=10.1016/j.neuroimage.2004.10.021 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15670702  }} </ref><ref name="pmid28626420">{{cite journal| author=Guo S, Huang J, Jiang H, Han C, Li J, Xu X et al.| title=Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management. | journal=Front Aging Neurosci | year= 2017 | volume= 9 | issue=  | pages= 171 | pmid=28626420 | doi=10.3389/fnagi.2017.00171 | pmc=5454050 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28626420  }} </ref>
** Presence of morphologic changes in the somatosensory cortex, motor cortex and thalamic gray matter in MRI
** 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.
** 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
** 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
** Low brain iron concentrations and dysfunction of iron metabolism and intracellular iron
Line 21: Line 21:


==Genetics==
==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.
*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.<ref name="pmid19514512">{{cite journal| author=Miyamoto M, Miyamoto T, Iwanami M, Suzuki K, Hirata K| title=[Pathophysiology of restless legs syndrome]. | journal=Brain Nerve | year= 2009 | volume= 61 | issue= 5 | pages= 523-32 | pmid=19514512 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19514512  }} </ref>
*40% of cases of RLS are familial and are inherited in an [[autosomal dominant]] fashion with [[variable penetrance]].
*40% of cases of RLS are familial and are inherited in an [[autosomal dominant]] fashion with [[variable penetrance]].


==Associated Conditions==
==Associated Conditions==


===Restless Legs Syndrome and Acidosis===
Conditions which may be associated with RLS include:<ref name="pmid24747872">{{cite journal| author=Katsi V, Katsimichas T, Kallistratos MS, Tsekoura D, Makris T, Manolis AJ et al.| title=The association of Restless Legs Syndrome with hypertension and cardiovascular disease. | journal=Med Sci Monit | year= 2014 | volume= 20 | issue=  | pages= 654-9 | pmid=24747872 | doi=10.12659/MSM.890252 | pmc=3999161 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24747872  }} </ref><ref name="pmid18360657">{{cite journal| author=Cotter PE, O'Keeffe ST| title=Restless leg syndrome: is it a real problem? | journal=Ther Clin Risk Manag | year= 2006 | volume= 2 | issue= 4 | pages= 465-75 | pmid=18360657 | doi= | pmc=1936366 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18360657  }} </ref><ref name="pmid26944272">{{cite journal| author=Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J| title=Restless legs syndrome associated with major diseases: A systematic review and new concept. | journal=Neurology | year= 2016 | volume= 86 | issue= 14 | pages= 1336-43 | pmid=26944272 | doi=10.1212/WNL.0000000000002542 | pmc=4826337 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26944272  }} </ref>
Another possible explanation of RLS is acidosis, though this claim needs to be explored further. RLS as a result of acidosis/insufficient oxygen being circulated to the legs (which reduces acid build up) would explain why symptoms worsen when the legs are at rest, and why moving them (increasing circulation) offers some relief. The fact that iron offers relief for many can be explained by its vital role in hemoglobin, which is responsible for oxygen dispersion to the tissues. The legs would be more prone to the restless condition since they are furthest from the heart and lungs. Additionally, one may see below that many of the "lifestyle changes and other non-medicinal approaches" are related in some way or form to circulation (e.g. heat, stretching, movement), acid build up (e.g. too much exercise, ketosis from high-fat diets), or the amount of oxygen being dispersed in the blood (e.g. deep breathing, iron levels). It should be noted that this potential causal relationship between RLS and acidosis is purely speculative the time being, as far as the contributing editor is aware. If this causal relationship holds true, then finding the cause of the acidosis would most likely lead to the best treatment.
*Hypertension
 
*cardiovascular deseases
Some experts believe RLS and periodic limb movement disorder are strongly associated with ADHD in some children. Both conditions are hereditary and dopamine is believed to be involved. Many types of medication for both conditions are affecting the dopamine levels in the brain.<ref>http://www.umm.edu/patiented/articles/other_disorders_associated_with_attention-deficit_disorder_000030_5.htm</ref>
*Anxiety
 
*Depression
==Gross Pathology==
*Iron deficiency
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
*Anemia
*Kidney diseases
*Stroke
*Parkinson disease
*Polyneuropathy
*Multiple sclerosis


==Microscopic Pathology==
==Microscopic Pathology==
*The exact neuroanatomical substrate imbalance which causes restless legs syndrome (RLS) is unknown.
*The exact neuroanatomical substrate imbalance which causes restless legs syndrome (RLS) is unknown.<ref name="pmid15197711">{{cite journal| author=Pittock SJ, Parrett T, Adler CH, Parisi JE, Dickson DW, Ahlskog JE| title=Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology. | journal=Mov Disord | year= 2004 | volume= 19 | issue= 6 | pages= 695-9 | pmid=15197711 | doi=10.1002/mds.20042 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15197711  }} </ref>
*Chronic ischemic changes were found in some brain tissue samples of patients whit RLS
*Chronic ischemic changes were found in some brain tissue samples of patients whit RLS.<ref name="pmid15197711">{{cite journal| author=Pittock SJ, Parrett T, Adler CH, Parisi JE, Dickson DW, Ahlskog JE| title=Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology. | journal=Mov Disord | year= 2004 | volume= 19 | issue= 6 | pages= 695-9 | pmid=15197711 | doi=10.1002/mds.20042 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15197711  }} </ref>


==References==
==References==

Revision as of 18:27, 30 March 2018

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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.
  • 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]

  • Hypertension
  • cardiovascular deseases
  • Anxiety
  • Depression
  • Iron deficiency
  • Anemia
  • Kidney diseases
  • Stroke
  • Parkinson disease
  • Polyneuropathy
  • Multiple sclerosis

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. ↑ 1.0 1.1 1.2 Miyamoto M, Miyamoto T, Iwanami M, Suzuki K, Hirata K (2009). "[Pathophysiology of restless legs syndrome]". Brain Nerve. 61 (5): 523–32. PMID 19514512.
  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.
  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.
  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.
  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.
  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.
  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.
  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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