Restless legs syndrome pathophysiology: Difference between revisions
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===Pathogenesis=== | ===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. | *Generally most scientists consider restless legs syndrome(RLS) as a [[Central nervous system|central nervous system (CNS)]]-related disorder, but no specific lesion has been found to be associated with the syndrome.<ref name="pmid19514512" /> | ||
* 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> | * 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:<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> | * 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 [[Grey matter|gray matter]] in [[Magnetic resonance imaging|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 [[Thalamus|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 system|limbic]] and [[opioid]] systems in [[Single photon emission computed tomography|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 | ||
*** The "iron-dopamine model" explains that iron deficiency in the brain causes an abnormality in the dopaminergic system leading to manifestation of RLS. | *** 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 | * 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 | * In animal models, studies suggest that the All [[dopaminergic system]] and the D3 receptor participates in RLS symptoms | ||
==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.<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> | *[[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]]. | ||
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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> | 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> | ||
*Hypertension | *[[Hypertension]] | ||
* | *[[Cardiovascular disease|Cardiovascular diseases]] | ||
*Anxiety | *[[Anxiety]] | ||
*Depression | *[[Depression]] | ||
*Iron deficiency | *[[Iron deficiency]] | ||
*Anemia | *[[Anemia]] | ||
*Kidney diseases | *[[Kidney diseases]] | ||
*Stroke | *[[Stroke (patient information)|Stroke]] | ||
*Parkinson disease | *[[Parkinson disease]] | ||
*Polyneuropathy | *[[Polyneuropathy]] | ||
*Multiple sclerosis | *[[Multiple sclerosis]] | ||
==Microscopic Pathology== | ==Microscopic Pathology== | ||
*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> | *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.<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 [[Ischemia|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 18:52, 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.[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]
- Hypertension
- Cardiovascular diseases
- 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
- ↑ 1.0 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.