Materiały źródłowe

• #1 Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5454050/

  Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. […] Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. […] It is widely accepted that the local brain iron level plays an important role in RLS pathophysiology, however, the mechanism is still unclear. Recent studies demonstrated that the iron deficiency in brain was related to the function of blood-brain interface, as BBBs endothelial cells acted as an iron reservoir for the brain. […] A large number of pharmacological studies and clinical findings have provided evidence for the important role of dopaminergic system dysfunction in RLS.

• #2 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  The aim of this overview was to outline the pathophysiology, common comorbidities and current therapeutic modalities in the treatment/management of restless legs syndrome (RLS) a sensorimotor neurological disorder. […] An understanding of the etiopathogenesis of RLS by examining both endogenous and exogenous factors, such as CNS dopaminergic and iron deficiency hypotheses as the etiologic hallmarks of RLS has enhanced our clinical understanding of this disorder, and contributed to the improvement of diagnostic and therapeutic approaches. […] One hypothesis concerning RLS establishes that underlying the condition there is a regional brain iron deficiency and/or specific genetic factors that disturb the neurotransmission of dopamine in the subcortical brain areas. […] The pharmacological treatment of RLS is limited to symptomatic medication, since etiological forms of therapy have not been developed.

• #2 Restless Legs Syndrome: Current Concepts about Disease Pathophysiology | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.322

  The most consistently found biological abnormality in RLS is a deficiency of brain iron in the substantia nigra, red nucleus, putamen, caudate, and thalamus. Ferritin in the blood of RLS patients is commonly low, but iron measures themselves are often normal in RLS. The sum of these findings suggests an impairment of iron transport into the brain, and more specifically into neuromelanin-containing cells of the substantia nigra. Iron, itself, is an essential cofactor for tyrosine hydroxylase in the enzymatic conversion of L-tyrosine to L-dopa, the main precursor to dopamine. […] Hypoxia, by activating HIF-1, leads to upregulation of tyrosine hydroxylase and a dopamine transporter. Hypoxia in RLS is suggested by increased muscle microvascularization and increased vascular endothelial growth factor in muscle of RLS patients. Furthermore, increased HIF-1 immunoreactivity has been found in the substantia nigra of RLS patients.

• #3 Frontiers | Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

  https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2017.00171/full

  Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. […] Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. […] The pathophysiology of RLS is still partially understood. The most accepted pathways include genetics variants, abnormal iron metabolisms, dopaminergic dysfunction, and central opiate system. […] It’s widely accepted that the local brain iron level plays an important role in RLS pathophysiology, however, the mechanism is still unclear. Recent studies demonstrated that the iron deficiency in brain was related to the function of blood-brain interface, as BBBs endothelial cells acted as an iron reservoir for the brain.

• #3 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Rather, a hallmark of RLS appears to be brain iron deficiency, documented by several separate studies which discovered low cerebrospinal fluid (CSF) ferritin in RLS patients. […] Two major pathophysiological consequences of low brain iron are hypoxia and demyelination. […] The findings of high 3-orthomethyl dopamine (3-OMD) in the CSF correlated with an increased level of the dopamine metabolite, homovanillic acid (HVA), is suggestive of an increase in tyrosine hydroxylase activity leading to high dopamine production. […] Furthermore, the decreased fluoro-l-dopa (f-DOPA) uptake suggests a fast turnover of dopamine, consistent with its increased production. […] Thirdly and most importantly, decreased dopamine-transporter (DAT), mostly the membrane-bound one, and decreased D2 receptors were identified in iron-deficient rodents, similar to RLS ones.

• #4

  https://journals.lww.com/md-journal/fulltext/2022/12160/exploration_of_restless_legs_syndrome_under_the.45.aspx

  Brain iron deficiency (BID) has been recognized as a major initial pathogenesis in the development of RLS. […] The almost immediate improvement of RLS symptoms with small doses of most dopaminergic agents supports the pathophysiological role of the dopamine system; however, the opposite effect, exacerbation of symptoms, occurs with dopamine antagonists. […] Alterations in the dopaminergic system, that is, the presynaptic hyperdopaminergic state, appear to be involved in causing PLMS, and alterations in the glutamate neurotransmitter, that is, the presynaptic hyperglutamate state, are involved in causing excessive anxiety and PLMS.

• #5 Frontiers | Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

  https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2017.00171/full

  Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. […] Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. […] The pathophysiology of RLS is still partially understood. The most accepted pathways include genetics variants, abnormal iron metabolisms, dopaminergic dysfunction, and central opiate system. […] It’s widely accepted that the local brain iron level plays an important role in RLS pathophysiology, however, the mechanism is still unclear. Recent studies demonstrated that the iron deficiency in brain was related to the function of blood-brain interface, as BBBs endothelial cells acted as an iron reservoir for the brain.

• #6 Neurochemistry of Idiopathic Restless Legs Syndrome – touchNEUROLOGY

  https://touchneurology.com/movement-disorders/journal-articles/neurochemistry-of-idiopathic-restless-legs-syndrome/

  The same group found decreased concentrations of ferritin, divalent metal transporter 1 (DMT1), ferroportin and transferrin receptor, decreased activities of total iron regulatory proteins (IRP) and IRP1, decreased IRP1 protein levels, increased concentrations of transferrin and normal IRP2 protein levels in the neuromelanin cells of four iRLS patients compared with four controls. […] These results were interpreted by the authors to suggest that RLS could arise from a defect in IRP1 in neuromelanin cells promoting destabilisation of the transferrin receptor mRNA, leading to cellular iron deficiency. […] Several recent works have called attention to the possible role of vitamin D deficiency in the aetiology of iRLS. This is a new interesting observation, for depletion of 25-hydroxyvitamin D may lead to dopaminergic dysfunction.

• #7 Neurochemistry of Idiopathic Restless Legs Syndrome – touchNEUROLOGY

  https://touchneurology.com/movement-disorders/journal-articles/neurochemistry-of-idiopathic-restless-legs-syndrome/

  The same group found decreased concentrations of ferritin, divalent metal transporter 1 (DMT1), ferroportin and transferrin receptor, decreased activities of total iron regulatory proteins (IRP) and IRP1, decreased IRP1 protein levels, increased concentrations of transferrin and normal IRP2 protein levels in the neuromelanin cells of four iRLS patients compared with four controls. […] These results were interpreted by the authors to suggest that RLS could arise from a defect in IRP1 in neuromelanin cells promoting destabilisation of the transferrin receptor mRNA, leading to cellular iron deficiency. […] Several recent works have called attention to the possible role of vitamin D deficiency in the aetiology of iRLS. This is a new interesting observation, for depletion of 25-hydroxyvitamin D may lead to dopaminergic dysfunction.

• #8 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Rather, a hallmark of RLS appears to be brain iron deficiency, documented by several separate studies which discovered low cerebrospinal fluid (CSF) ferritin in RLS patients. […] Two major pathophysiological consequences of low brain iron are hypoxia and demyelination. […] The findings of high 3-orthomethyl dopamine (3-OMD) in the CSF correlated with an increased level of the dopamine metabolite, homovanillic acid (HVA), is suggestive of an increase in tyrosine hydroxylase activity leading to high dopamine production. […] Furthermore, the decreased fluoro-l-dopa (f-DOPA) uptake suggests a fast turnover of dopamine, consistent with its increased production. […] Thirdly and most importantly, decreased dopamine-transporter (DAT), mostly the membrane-bound one, and decreased D2 receptors were identified in iron-deficient rodents, similar to RLS ones.

• #9

  https://link.springer.com/article/10.1007/s13311-021-01019-4

  However, it is more complex than the relative amount of these molecules. […] These findings suggest that dopamine deficiency per se is not the predominant mechanism underlying RLS, but rather dopamine dysregulation leads to RLS symptoms. […] The strong causal relationship between OSA and cardiovascular disease is thought to be primarily related to hypoxemia, although there may be an increased risk in cardiovascular disease inherently related to disturbance of sleep and sleep disorders in general, including RLS. […] Iron deficiency may cause activation of the hypoxia pathway, and since oxygen transport requires iron to be effective, hypoxic pathway activation could affect the regulatory transport mechanisms of iron across the blood-brain barrier.

• #10 Restless Legs Syndrome: Current Concepts about Disease Pathophysiology | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.322

  The most consistently found biological abnormality in RLS is a deficiency of brain iron in the substantia nigra, red nucleus, putamen, caudate, and thalamus. Ferritin in the blood of RLS patients is commonly low, but iron measures themselves are often normal in RLS. The sum of these findings suggests an impairment of iron transport into the brain, and more specifically into neuromelanin-containing cells of the substantia nigra. Iron, itself, is an essential cofactor for tyrosine hydroxylase in the enzymatic conversion of L-tyrosine to L-dopa, the main precursor to dopamine. […] Hypoxia, by activating HIF-1, leads to upregulation of tyrosine hydroxylase and a dopamine transporter. Hypoxia in RLS is suggested by increased muscle microvascularization and increased vascular endothelial growth factor in muscle of RLS patients. Furthermore, increased HIF-1 immunoreactivity has been found in the substantia nigra of RLS patients.

• #11 Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5454050/

  Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. […] Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. […] It is widely accepted that the local brain iron level plays an important role in RLS pathophysiology, however, the mechanism is still unclear. Recent studies demonstrated that the iron deficiency in brain was related to the function of blood-brain interface, as BBBs endothelial cells acted as an iron reservoir for the brain. […] A large number of pharmacological studies and clinical findings have provided evidence for the important role of dopaminergic system dysfunction in RLS.

• #12 Frontiers | Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

  https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2017.00171/full

  A large number of pharmacological studies and clinical findings have provided evidence for the important role of dopaminergic system dysfunction in RLS. […] Studies demonstrate a strong relationship between genetic predisposition and early-onset RLS, of which more than 60% reveal a positive familial history.

• #13 Genetics and Pathogenesis of Restless Legs Syndrome

  https://www.medscape.org/viewarticle/572098

  The findings of this study are consistent with what we know about the disorder clinically. […] It’s thought that iron may somehow interact with dopamine to cause a dopamine-deficient state, or at least exacerbate a dopamine-deficient state. […] There is a lot of information on both dopamine and iron and their involvement, or potential involvement, in the pathogenesis of RLS. […] The largest amount of the collective data suggests that in the evening, we have a normal nadir or drop in how much dopamine is available in the brain. […] We know from numerous studies that patients with RLS have depressed iron. […] It’s attractive to think about the gene variant providing some risk that you’re born with and that various environmental or medical insults represent so-called „second hits,” one example of which would be low iron.

• #14 Neurochemistry of Idiopathic Restless Legs Syndrome – touchNEUROLOGY

  https://touchneurology.com/movement-disorders/journal-articles/neurochemistry-of-idiopathic-restless-legs-syndrome/

  The pathogenesis of idiopathic restless legs syndrome (iRLS) is not well established, but the most important hypothesis suggests dopaminergic dysfunction and iron deficiency. […] Although the exact pathophysiology of idiopathic RLS (iRLS) is not well established, dopaminergic dysfunction and brain iron insufficiency are the most accepted theories. […] The excellent therapeutic response of RLS to dopaminergic drugs, together with some neuropathological, neuroimaging, biochemical and experimental data, supports the possible role of the dopaminergic system in the pathophysiology of RLS. […] Because the alterations found in the study by Connor et al. are similar to those found in animal and cell models of iron insufficiency, the authors hypothesised that dopaminergic abnormality in iRLS was owing to a primary iron insufficiency.

• #15 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Rather, a hallmark of RLS appears to be brain iron deficiency, documented by several separate studies which discovered low cerebrospinal fluid (CSF) ferritin in RLS patients. […] Two major pathophysiological consequences of low brain iron are hypoxia and demyelination. […] The findings of high 3-orthomethyl dopamine (3-OMD) in the CSF correlated with an increased level of the dopamine metabolite, homovanillic acid (HVA), is suggestive of an increase in tyrosine hydroxylase activity leading to high dopamine production. […] Furthermore, the decreased fluoro-l-dopa (f-DOPA) uptake suggests a fast turnover of dopamine, consistent with its increased production. […] Thirdly and most importantly, decreased dopamine-transporter (DAT), mostly the membrane-bound one, and decreased D2 receptors were identified in iron-deficient rodents, similar to RLS ones.

• #16 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Rather, a hallmark of RLS appears to be brain iron deficiency, documented by several separate studies which discovered low cerebrospinal fluid (CSF) ferritin in RLS patients. […] Two major pathophysiological consequences of low brain iron are hypoxia and demyelination. […] The findings of high 3-orthomethyl dopamine (3-OMD) in the CSF correlated with an increased level of the dopamine metabolite, homovanillic acid (HVA), is suggestive of an increase in tyrosine hydroxylase activity leading to high dopamine production. […] Furthermore, the decreased fluoro-l-dopa (f-DOPA) uptake suggests a fast turnover of dopamine, consistent with its increased production. […] Thirdly and most importantly, decreased dopamine-transporter (DAT), mostly the membrane-bound one, and decreased D2 receptors were identified in iron-deficient rodents, similar to RLS ones.

• #17 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Treating the already excessive brain dopamine in RLS with levodopa would appear counterintuitive, but the key to understanding it lies in the circadian rhythm of both dopaminergic activity and RLS/WED symptoms. […] The key here is to use long-acting medication such as transdermal rotigotine in order to reduce the risk of debilitating augmentation. […] A total of 13 different genes implicated in RLS have been identified as single nucleotide polymorphisms on chromosomes 6p21.2 (BTBD9), 2p14 (MEIS1), 9p24.1-p23 (PTPRD), 15q23 (MAP2K5/SKOR1) and 16q12.1 (TOX3/BC034767) based on GWAS. […] The functions of these genes are in close connection to the neurological development of the embryonic limbs even if the pathophysiological functions are not yet clear.

• #18

  https://www.nhs.uk/conditions/restless-legs-syndrome/causes/

  In many cases, the exact cause of restless legs syndrome is unknown. […] Research has identified specific genes related to restless legs syndrome, and it can run in families. […] There’s evidence to suggest restless legs syndrome is related to a problem with part of the brain called the basal ganglia. […] The basal ganglia uses a chemical (neurotransmitter) called dopamine to help control muscle activity and movement. […] If nerve cells become damaged, the amount of dopamine in the brain is reduced, which causes muscle spasms and involuntary movements. […] Dopamine levels naturally fall towards the end of the day, which may explain why the symptoms of restless legs syndrome are often worse in the evening and during the night. […] Restless legs syndrome can sometimes occur as a complication of another health condition, or it can be the result of another health-related factor. […] You can develop secondary restless legs syndrome if you have iron deficiency anaemia (low levels of iron in the blood can lead to a fall in dopamine, triggering restless legs syndrome).

• #19 Restless Legs Syndrome: Current Concepts about Disease Pathophysiology | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.322

  The most consistently found biological abnormality in RLS is a deficiency of brain iron in the substantia nigra, red nucleus, putamen, caudate, and thalamus. Ferritin in the blood of RLS patients is commonly low, but iron measures themselves are often normal in RLS. The sum of these findings suggests an impairment of iron transport into the brain, and more specifically into neuromelanin-containing cells of the substantia nigra. Iron, itself, is an essential cofactor for tyrosine hydroxylase in the enzymatic conversion of L-tyrosine to L-dopa, the main precursor to dopamine. […] Hypoxia, by activating HIF-1, leads to upregulation of tyrosine hydroxylase and a dopamine transporter. Hypoxia in RLS is suggested by increased muscle microvascularization and increased vascular endothelial growth factor in muscle of RLS patients. Furthermore, increased HIF-1 immunoreactivity has been found in the substantia nigra of RLS patients.

• #20 Restless Legs Syndrome | AAFP

  https://www.aafp.org/pubs/afp/issues/2008/0715/p235.html

  Restless legs syndrome may be a primary condition, or it may be secondary to iron deficiency, renal failure, pregnancy, or the use of certain medications. […] Research has identified abnormalities in dopamine and iron function in the central nervous system in individuals with RLS, although these relationships are not fully understood. […] Two studies have demonstrated enhanced circadian variation in dopamine activity in those with RLS compared with control patients. […] Iron content in the sub-stantia nigra and the putamen were lower in those with RLS than in control patients. […] The levels of ferritin in the cerebrospinal fluid were significantly lower in patients with RLS than in controls, although serum levels were similar between the two groups. […] Further, serum iron stores (measured by serum ferritin) have been shown to correlate inversely with RLS severity. […] Iron is a cofactor in tyrosine hydroxylase, the rate-limiting enzymatic step in the conversion of tyrosine to dopamine.

• #21 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Rather, a hallmark of RLS appears to be brain iron deficiency, documented by several separate studies which discovered low cerebrospinal fluid (CSF) ferritin in RLS patients. […] Two major pathophysiological consequences of low brain iron are hypoxia and demyelination. […] The findings of high 3-orthomethyl dopamine (3-OMD) in the CSF correlated with an increased level of the dopamine metabolite, homovanillic acid (HVA), is suggestive of an increase in tyrosine hydroxylase activity leading to high dopamine production. […] Furthermore, the decreased fluoro-l-dopa (f-DOPA) uptake suggests a fast turnover of dopamine, consistent with its increased production. […] Thirdly and most importantly, decreased dopamine-transporter (DAT), mostly the membrane-bound one, and decreased D2 receptors were identified in iron-deficient rodents, similar to RLS ones.

• #22 Diagnosis and Treatment of Restless Legs Syndrome in Psychiatric Practice

  https://www.psychiatrictimes.com/view/diagnosis-and-treatment-restless-legs-syndrome-psychiatric-practice

  A polygenetic disorder with its phenotype contributed by a number of variants, RLS is a highly familial trait with heritability estimates of about 50%. […] Many studies have established the role of dopaminergic pathology in RLS. […] The underlying cause for the high prevalence of comorbidities between RLS and depression is unclear. […] An underlying shared pathophysiological mechanism between RLS and MDD might be responsible for the comorbidity. […] Diminished dopamine release from presynaptic neurons or impaired signal transduction has been implicated. […] Neuroimaging studies have shown reduced dopamine transmission and compensatory up-regulation of D2 receptors.

• #23 Frontiers | Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

  https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2017.00171/full

  A large number of pharmacological studies and clinical findings have provided evidence for the important role of dopaminergic system dysfunction in RLS. […] Studies demonstrate a strong relationship between genetic predisposition and early-onset RLS, of which more than 60% reveal a positive familial history.

• #24 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Treating the already excessive brain dopamine in RLS with levodopa would appear counterintuitive, but the key to understanding it lies in the circadian rhythm of both dopaminergic activity and RLS/WED symptoms. […] The key here is to use long-acting medication such as transdermal rotigotine in order to reduce the risk of debilitating augmentation. […] A total of 13 different genes implicated in RLS have been identified as single nucleotide polymorphisms on chromosomes 6p21.2 (BTBD9), 2p14 (MEIS1), 9p24.1-p23 (PTPRD), 15q23 (MAP2K5/SKOR1) and 16q12.1 (TOX3/BC034767) based on GWAS. […] The functions of these genes are in close connection to the neurological development of the embryonic limbs even if the pathophysiological functions are not yet clear.

• #25 Restless Legs Syndrome across the Lifespan: Symptoms, Pathophysiology, Management and Daily Life Impact of the Different Patterns of Disease Presentation

  https://www.mdpi.com/1660-4601/17/10/3658

  Iron deficiency and dopamine metabolism are the two main pathophysiological mechanisms underlying RLS symptoms, but a link to genetics does exist. […] Some genome-wide association studies (GWAS) have identified RLS risk alleles on five specific genomic regions (MEIS1, BTBD9, PTPRD, MAP2k/SKOR1, and TOX3/BC034767) and on an intergenic region on chromosome 2 (rs6747972). […] Iron pathophysiology has been extensively studied. It is based on the observation that decreased peripheral iron and iron-deficient anemia are strongly associated with RLS. […] However, normal serum ferritin is found in most RLS patients, suggesting the presence of possible different pathophysiological mechanisms involving iron metabolism. […] The main consequences of brain iron deficiency are hypoxia and myelin loss.

• #26 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Treating the already excessive brain dopamine in RLS with levodopa would appear counterintuitive, but the key to understanding it lies in the circadian rhythm of both dopaminergic activity and RLS/WED symptoms. […] The key here is to use long-acting medication such as transdermal rotigotine in order to reduce the risk of debilitating augmentation. […] A total of 13 different genes implicated in RLS have been identified as single nucleotide polymorphisms on chromosomes 6p21.2 (BTBD9), 2p14 (MEIS1), 9p24.1-p23 (PTPRD), 15q23 (MAP2K5/SKOR1) and 16q12.1 (TOX3/BC034767) based on GWAS. […] The functions of these genes are in close connection to the neurological development of the embryonic limbs even if the pathophysiological functions are not yet clear.

• #27 Genetics and Pathogenesis of Restless Legs Syndrome

  https://www.medscape.org/viewarticle/572098

  Restless legs syndrome (RLS) is a prevalent disorder that has a significant impact on patient quality of life. Recent studies have identified gene variants that confer a significant amount of risk for developing the disorder. […] There is also a growing amount of information related to the pathophysiology of RLS, specifically regarding the roles of iron and dopamine. […] A better understanding of the genetics and pathophysiology of RLS will help in the development of better screening techniques and management strategies. […] These studies together are significant because they identify, for the first time, specific genes and variants of those genes that are associated with a risk for RLS. […] The BTBD9 gene accounts for about 50% of the entire population risk for RLS and is significant in terms of the size of the effect.

• #28 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Treating the already excessive brain dopamine in RLS with levodopa would appear counterintuitive, but the key to understanding it lies in the circadian rhythm of both dopaminergic activity and RLS/WED symptoms. […] The key here is to use long-acting medication such as transdermal rotigotine in order to reduce the risk of debilitating augmentation. […] A total of 13 different genes implicated in RLS have been identified as single nucleotide polymorphisms on chromosomes 6p21.2 (BTBD9), 2p14 (MEIS1), 9p24.1-p23 (PTPRD), 15q23 (MAP2K5/SKOR1) and 16q12.1 (TOX3/BC034767) based on GWAS. […] The functions of these genes are in close connection to the neurological development of the embryonic limbs even if the pathophysiological functions are not yet clear.

• #29

  https://journals.lww.com/md-journal/fulltext/2022/12160/exploration_of_restless_legs_syndrome_under_the.45.aspx

  Restless leg syndrome (Restless legs syndrome, RLS) is a common neurological disorder. The pathogenesis of RLS remains unknown, and recent pathophysiological developments have shown the contribution of various genetic markers, neurotransmitter dysfunction, and iron deficiency to the disease, as well as other unidentified contributing mechanisms, particularly chronic renal dysfunction. […] Many studies have attempted to identify the genes involved in the basic molecular mechanisms of this disease, but no single cause of RLS has been identified. […] The pathophysiological functions of these genomic loci are yet to be defined, but their main functions appear to be related to the neural development of the limb during the embryonic period. […] The iron deficiency hypothesis remains the most important in the pathophysiology of RLS, although oral and intravenous iron therapies have different efficacies in the treatment of RLS.

• #30

  https://omim.org/entry/612853

  Spieler et al. (2014) found that the G risk allele of rs12469063 in the MEIS1 gene alters enhancer function in the developing telencephalon. The G risk allele of rs12469063, located in a highly conserved noncoding region (617), showed decreased reporter gene expression in the neural tube compared to the A protective allele. Decreased enhancer function of the risk allele was also observed in embryonic mouse brain, particularly in the ganglionic eminences, but not in the adult brain. Affinity chromatography identified CREB1 (123810) as an upstream binding factor of rs12469063, binding stronger to the risk allele where it may act as a transcriptional repressor. Adult heterozygous Meis1-deficient mice showed hyperactivity, resembling the RLS phenotype. Spieler et al. (2014) postulated a loss-of-function mechanism that causes a neurodevelopmental defect affecting the basal ganglia with possible age-dependent development of RLS.

• #31 Restless Legs Syndrome: Current Concepts about Disease Pathophysiology | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.322

  RLS is a neurologic sensorimotor disorder that involves pathology, most notably iron deficiency, in motor and sensory brain areas. Brain areas not subserving movement or sensation such as the cingulate cortex and cerebellum are also involved. Other biological systems including the dopaminergic, oxygensensing, opioid, glutamatergic, and serotonergic systems are involved. Further research is needed to determine which of these anatomic locations or biological systems are affected primarily, and which are affected in a secondary response. […] Stepping back from neuroanatomy, much investigation has taken place to identify a pathophysiologic substrate of RLS. Biological systems that have been studied include the dopaminergic, opioid, iron, serotonergic, and glutamatergic systems. It is likely that activation and or abnormalities seen in different brain regions result from a primary disturbance of some biological system that in turn drives the symptoms and thus the entity of RLS.

• #32 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20190404/Study-Pathogenetic-downregulation-of-adenosine-linked-to-restless-leg-syndrome.aspx

  Researchers have identified a common mechanism implicating adenosine in the cause of restless leg syndrome (RLS) symptoms the periodic limb movements characteristic of RLS and the state of enhanced arousal that both disrupt sleep. […] A combination of preclinical and clinical findings has shown that brain iron deficiency (BID) is an early factor in the pathophysiology of RLS and that BID in rodents causes downregulation of A1Rs in the brain. […] „Based on these results,” Editor-in-Chief of Journal of Caffeine and Adenosine Research, Sergi Ferr, MD, PhD, and his research colleagues in the Integrative Neurobiology Section, National Institute on Drug Abuse, National Institutes of Health (Baltimore, MD), „have hypothesized that a hypoadenosinergic state secondary to A1R downregulation could be mostly responsible for the hyperglutamatergic and hyperdopaminergic states of RLS that determine the sensorimotor symptoms of RLS as well as the hyperarousal component.”

• #33 Istradefylline for Restless Legs Syndrome Associated with Parkinson’s Disease | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.429

  Current studies have indicated that adenosine receptors play a significant role in both brain iron deficiency and sleep disorders in RLS. […] One study demonstrated a significant downregulation of adenosine A1 receptors and upregulation of adenosine A2A receptors in RLS. […] Thus, inhibiting adenosine A2A receptors may directly improve RLS, although this hypothesis remains speculative.

• #34

  https://journals.lww.com/md-journal/fulltext/2022/12160/exploration_of_restless_legs_syndrome_under_the.45.aspx

  Brain iron deficiency (BID) has been recognized as a major initial pathogenesis in the development of RLS. […] The almost immediate improvement of RLS symptoms with small doses of most dopaminergic agents supports the pathophysiological role of the dopamine system; however, the opposite effect, exacerbation of symptoms, occurs with dopamine antagonists. […] Alterations in the dopaminergic system, that is, the presynaptic hyperdopaminergic state, appear to be involved in causing PLMS, and alterations in the glutamate neurotransmitter, that is, the presynaptic hyperglutamate state, are involved in causing excessive anxiety and PLMS.

• #35 Restless Legs Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1188327-overview

  The pathogenesis of restless legs syndrome (RLS) is unclear. The most widely accepted mechanism involves a genetic component, along with abnormalities in the central subcortical dopamine pathways and impaired iron homeostasis. […] When centrally acting dopamine receptor antagonists are administered to patients with the syndrome, symptoms are reactivated. Results of single-photon emission computed tomography (SPECT) have suggested a deficiency of dopamine D2 receptors. Iron homeostasis abnormalities have been implicated through cerebrospinal fluid (CSF) iron profile measures. […] In addition, investigators have shown an increased severity of RLS with decreasing availability of serotonin transporter in the brainstem, which supports the hypothesis that increasing serotonin transmission in the brain may exacerbate RLS. RLS can also be genetic and run in families. Various chromosomes have been implicated to date, including 12q, 14q, 9p, 20p, 4q, and 17p, in autosomal dominant and recessive fashion.

• #36 The pathophysiology of restless legs syndrome

  https://inis.iaea.org/search/search.aspx?orig_q=RN:40080301

  Restless legs syndrome (RLS) is generally considered to be a central nervous system (CNS)-related disorder although no specific lesion has been found to be associated with the syndrome. […] Reduced intracortical inhibition has been demonstrated in RLS by transcranial magnetic stimulation. […] The results of single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies showed that the limbic and opioid systems also play important roles in the pathophysiology of RLS. […] RLS symptoms seem to depend on abnormal spinal sensorimotor integration at the spinal cord level and abnormal central somatosensory processing. […] PLMS appears to depend on increased excitability of the spinal cord and a decreased supraspinal inhibitory mechanism from the A11 diencephalic dopaminergic system.

• #37 Neurochemistry of Idiopathic Restless Legs Syndrome – touchNEUROLOGY

  https://touchneurology.com/movement-disorders/journal-articles/neurochemistry-of-idiopathic-restless-legs-syndrome/

  The expression of NO synthase1 (NOS1, neuronal NOS or nNOS) and nitrotyrosine have been found increased in the substantia nigra of four out of six iRLS patients and in none of six controls in a immunohistochemical study. […] These data suggest a possible role of NO and oxidative stress in the pathophysiology of iRLS.

• #38 Understanding Restless Leg Syndrome (RLS) – Causes and Treatments

  https://www.hearthousenj.com/conditions/peripheral-vascular/restless-leg-syndrome

  Restless leg syndrome (RLS) is a common condition causing uncomfortable leg sensations and an irresistible urge to move the legs. […] While we still have more to learn, research suggests vascular mechanisms may play a significant role in restless leg syndrome (RLS) for many patients. […] For instance, there is some evidence that restless leg syndrome (RLS) and peripheral vascular disease (PVD) may be linked. […] The study also found that people with RLS who had PVD were more likely to have severe RLS symptoms. […] One possibility is that both conditions are caused by damage to the nerves that control blood flow to the legs. […] Another possibility is that both conditions are caused by inflammation. […] Studies reveal decreased leg circulation in RLS patients, especially at night when symptoms worsen.

• #39 Researchers Study Biomarkers in Patients with Restless Legs Syndrome – Medical Update

  https://medicalupdate.pennstatehealth.org/neurology-neurosurgery/researchers-study-biomarkers-in-patients-with-restless-legs-syndrome/

  Idiopathic restless legs syndrome (RLS) can severely affect quality of life and disturb sleep, often requiring pharmacological treatment. […] The study sought to determine whether changes in blood flow occurred in the femoral artery of RLS subjects, and if hypoxia attenuated the increased blood flow response in RLS patients compared to subjects without the condition. […] This activation has been tied to increased expression of proteins involved in iron homeostasis. Key to this hypothesis was the proposition that increased nitric oxide levels underlie the mechanism that generates this pathway activation. […] The resulting data, which demonstrated that subjects with RLS showed only a 1.7 percent increase in femoral artery blood flow during hypoxic insult, while control subjects showed a 7.2 percent increase when challenged with hypoxia, strongly supported the link between RLS, hypoxia and altered peripheral blood flow.

• #40 Researchers Study Biomarkers in Patients with Restless Legs Syndrome – Medical Update

  https://medicalupdate.pennstatehealth.org/neurology-neurosurgery/researchers-study-biomarkers-in-patients-with-restless-legs-syndrome/

  It appears that in RLS, there is already maximum blood flow in the periphery and blood flow cannot adjust to decreased oxygen availability in various situations, including airplanes, sleep onset or high altitudessituations known to increase RLS symptoms. […] Patton adds that the link between RLS and cardiovascular disease is increasingly recognized, as well as its high correlation to other hypoxic conditions, such as sleep apnea and chronic obstructive pulmonary disease. This deeper understanding may lead to a more multifactorial approach to treating these disease states.

• #41 Researchers Study Biomarkers in Patients with Restless Legs Syndrome – Medical Update

  https://medicalupdate.pennstatehealth.org/neurology-neurosurgery/researchers-study-biomarkers-in-patients-with-restless-legs-syndrome/

  It appears that in RLS, there is already maximum blood flow in the periphery and blood flow cannot adjust to decreased oxygen availability in various situations, including airplanes, sleep onset or high altitudessituations known to increase RLS symptoms. […] Patton adds that the link between RLS and cardiovascular disease is increasingly recognized, as well as its high correlation to other hypoxic conditions, such as sleep apnea and chronic obstructive pulmonary disease. This deeper understanding may lead to a more multifactorial approach to treating these disease states.

• #42 Does Restless Legs Syndrome Have a Different Pathomechanism in Premotor and Motor Parkinson’s Disease?

  https://www.e-jmd.org/journal/view.php?doi=10.14802/jmd.20160

  There is a long-standing debate regarding the comorbid association of Parkinsons disease (PD) and restless legs syndrome (RLS) in the same patients. […] This issue is directly connected to the hitherto unresolved question concerning whether RLS is a risk factor for the subsequent development of PD or vice versa. […] This unbalanced prevalence of RLS onset between the premotor and motor phases of PD raises the question that different pathomechanisms might underlie RLS depending on the timing of its onset. […] However, this finding does not explain whether RLS and PD are linked by a common pathomechanism and whether the pathomechanism involved in RLS occurring in the setting of PD differs from that of primary RLS. […] Overall, these data support the view that the impairments in somatosensory epidermal C fibers may occur early in the neurodegenerative process and, thereby, enlarge the spectrum of small fiber dysfunction in the prodromal phase of PD that, to date, is believed to affect nearly exclusively the autonomic sympathetic terminal axons.

• #43 Does Restless Legs Syndrome Have a Different Pathomechanism in Premotor and Motor Parkinson’s Disease?

  https://www.e-jmd.org/journal/view.php?doi=10.14802/jmd.20160

  If this hypothesis is correct, then the sensory-motor disorder emerging in the motor phase of PD should be considered centrally mediated and DA-dependent. […] On the basis of these concepts, RLS in the setting of PD should be regarded as a heterogeneous disorder likely due to the different pathomechanisms, i.e., peripherally or centrally mediated, underlying its development depending on whether onset occurs in the premotor or motor phase of PD. […] If this hypothesis is correct, then it is expected that the two subtypes of RLS emerging in premotor and motor PD may show different clinical phenotypes and courses and possibly different therapeutic responses. […] Therefore, although specific pharmacotherapeutic guidelines for treating RLS in PD patients have not yet been established, it is advisable to take into account the postulated heterogeneous pathomechanisms underlying RLS based on the timing of its onset, i.e., in the premotor or motor phase of PD.

• #44 The pathophysiology of restless legs syndrome

  https://inis.iaea.org/search/search.aspx?orig_q=RN:40080301

  The symptoms of RLS are aggravated in those with iron deficiency, and iron treatment ameliorates the symptoms in some patients. […] Neuroimaging studies, analysis of the cerebrospinal fluid, and studies on postmortem tissue and use of animal models have indicated that low brain iron concentrations and dysfunction of iron metabolism and intracellular iron may play key roles in the pathogenesis 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. […] In conclusion, disturbances in the central dopaminergic system, disturbances in iron metabolism, and genetics seem to be the primary factors in the pathophysiology of RLS.

• #45

  https://www.e-jsm.org/journal/view.php?number=383

  Restless legs syndrome is a prevalent sensorimotor sleep disorder that worsens the quality of life. Dopamine agonists are widely used to relieve the symptoms of restless legs syndrome, even though these patients are in a hyperdopaminergic state. This treatment paradox inevitably leads to augmentation syndrome. Here, we review the pathophysiological basis of this deterioration in patients treated with dopamine agonists. […] The underlying mechanism in RLS is thought to include a dysfunction in the dopaminergic system and a brain iron deficiency in genetically predisposed individuals. Brain iron deficiency sometimes has a peripheral cause and is revealed by anemia and/or hypoferritinaemia. The main consequence of brain iron deficiency is hypoxia, which leads to 1) a presynaptic hyperdopaminergic state (with an increase in the synthesis, liberation, and turnover of dopamine), and 2) myelin loss and white matter alterations. These intracerebral disorders lead to the dysfunction of the sensorimotor loop at various levels of integration. The descending dopaminergic system (which inhibits the posterior horn of the spinal cord) is particularly affected. It is thought that the inhibitory control of sensory afferents is impaired in individuals with RLS. This impairment results in various sensory disorders, which are partially corrected by movement. Predominantly, lumbosacral spinal hyperexcitability causes periodic movement during wakefulness.

• #46

  https://www.e-jsm.org/journal/view.php?number=383

  In RLS, a presynaptic hyperdopaminergic state might lead to the internalization of postsynaptic D2 receptors; the more the dopaminergic system is stimulated (for example, by high doses of DAs), the more postsynaptic D2 receptors are internalized. A preferential decrease in the number of D2 receptors on the postsynaptic cell membrane induces an increase in the number of D1 receptors. This imbalance in the D1/D2 synergism leads to the proliferation of D1 receptors. Chronic hyperstimulation of D1 receptors and unstable dopamine metabolism might lead to an impairment in the descending dopaminergic pathway (involving the dorsoposterior hypothalamus and the spinal cord) or greater sensorymotor cortex excitability and thus the appearance of AS. […] However, dopamine receptor function is very complex, and other factors may affect susceptibility to disease or an individual patients response to medications. These factors include polymorphisms in genes encoding dopamine receptors and other proteins involved in dopamine transmission (such as G proteins, dopamine receptor-interacting proteins, G protein-coupled receptor kinases, and arrestins).

• #47

  https://www.e-jsm.org/journal/view.php?number=383

  In RLS, a presynaptic hyperdopaminergic state might lead to the internalization of postsynaptic D2 receptors; the more the dopaminergic system is stimulated (for example, by high doses of DAs), the more postsynaptic D2 receptors are internalized. A preferential decrease in the number of D2 receptors on the postsynaptic cell membrane induces an increase in the number of D1 receptors. This imbalance in the D1/D2 synergism leads to the proliferation of D1 receptors. Chronic hyperstimulation of D1 receptors and unstable dopamine metabolism might lead to an impairment in the descending dopaminergic pathway (involving the dorsoposterior hypothalamus and the spinal cord) or greater sensorymotor cortex excitability and thus the appearance of AS. […] However, dopamine receptor function is very complex, and other factors may affect susceptibility to disease or an individual patients response to medications. These factors include polymorphisms in genes encoding dopamine receptors and other proteins involved in dopamine transmission (such as G proteins, dopamine receptor-interacting proteins, G protein-coupled receptor kinases, and arrestins).

• #48

  https://www.e-jsm.org/journal/view.php?number=383

  Restless legs syndrome is a prevalent sensorimotor sleep disorder that worsens the quality of life. Dopamine agonists are widely used to relieve the symptoms of restless legs syndrome, even though these patients are in a hyperdopaminergic state. This treatment paradox inevitably leads to augmentation syndrome. Here, we review the pathophysiological basis of this deterioration in patients treated with dopamine agonists. […] The underlying mechanism in RLS is thought to include a dysfunction in the dopaminergic system and a brain iron deficiency in genetically predisposed individuals. Brain iron deficiency sometimes has a peripheral cause and is revealed by anemia and/or hypoferritinaemia. The main consequence of brain iron deficiency is hypoxia, which leads to 1) a presynaptic hyperdopaminergic state (with an increase in the synthesis, liberation, and turnover of dopamine), and 2) myelin loss and white matter alterations. These intracerebral disorders lead to the dysfunction of the sensorimotor loop at various levels of integration. The descending dopaminergic system (which inhibits the posterior horn of the spinal cord) is particularly affected. It is thought that the inhibitory control of sensory afferents is impaired in individuals with RLS. This impairment results in various sensory disorders, which are partially corrected by movement. Predominantly, lumbosacral spinal hyperexcitability causes periodic movement during wakefulness.

• #49 Restless Legs Syndrome across the Lifespan: Symptoms, Pathophysiology, Management and Daily Life Impact of the Different Patterns of Disease Presentation

  https://www.mdpi.com/1660-4601/17/10/3658

  Restless legs syndrome is a common but still underdiagnosed neurologic disorder, characterized by peculiar symptoms typically occurring in the evening and at night, and resulting in sleep disruption and daily functioning impairment. […] The pathophysiology of this disorder offers an interesting example of interaction between genetics and the environment, considering strong iron metabolism involvement and its interaction with recognized individual genetic factors. […] The role of peripheral nerve damage in the causality and severity progression for RLS patients remains unclear. […] However, the subdivision of RLS in two entities, primary or secondary to another disease, has recently become a matter of debate, after the discovery of genetic data and studies of hypoxic pathway activation and iron deficiency, providing further insights into the pathophysiology of the disease.

• #50 Genetics and Pathogenesis of Restless Legs Syndrome

  https://www.medscape.org/viewarticle/572098

  The potential role of dopamine in the pathogenesis of RLS suggests why some classes of medication, such as dopamine antagonists, may worsen symptoms. […] There are certainly medicines that can interact with the effects of dopamine or antagonize the effects of dopamine that clearly make RLS worse in many patients. […] The major foods or beverages that exacerbate RLS symptoms are red wines and dark-colored liquors. […] We also have limited data that caffeine or caffeinated beverages such as colas or teas can worsen restless legs as well. […] The gene variants associated with RLS, particularly the BTBD9 variant, are common in the „normal” population, being present in 65% of white patients, and nearly 50% of the „normal” population is carrying 2 copies of the risk variant (ie, a homozygous state). […] What „second hit” or other exacerbating factor pushes one over a threshold to translate this genetic diathesis into the development of symptoms remains unknown.

• #51 Periodic Limb Movement Disorder (PLMD) and Restless Legs Syndrome (RLS) – Neurologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/neurologic-disorders/sleep-and-wakefulness-disorders/periodic-limb-movement-disorder-plmd-and-restless-legs-syndrome-rls

  The mechanism is unclear but may involve abnormalities in dopamine neurotransmission in the central nervous system (CNS). […] In primary RLS, heredity may be involved; more than one-third of patients with primary RLS have a family history of it. […] Disorders that can contribute include iron deficiency anemia, uremia, neuropathy, pregnancy, Parkinson disease, MS, and spinal cord disorders.

• #52 Restless Leg Syndrome – Life Extension

  https://www.lifeextension.com/protocols/neurological/restless-leg-syndrome?srsltid=AfmBOorbLer1OKTyyWIyQjyf5jVlFyVBVCz-_RenWystfsXW0TrhJN1w

  Secondary RLS is a common complication of end-stage kidney disease. Estimates indicate that up to 60% of patients on dialysis have RLS. People with diabetes or impaired glucose tolerance are more likely to have RLS, and RLS is a prominent part of diabetic peripheral neuropathy. Chronic venous disorders are a major contributor to secondary RLS. […] The main pharmacologic agents used to treat primary RLS are dopamine agonists, levodopa (L-DOPA), benzodiazepines, gabapentin, and opioids. However, treatment of primary RLS should not be considered until possible causes of secondary RLS are ruled out, especially venous disorders. […] Iron deficiency or altered brain iron metabolism have been linked to RLS; supplementation is often recommended for RLS patients who have been tested and shown to be deficient. Iron supplementation has been shown to significantly improve symptoms in iron-deficient RLS patients.

• #53 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  The aim of this overview was to outline the pathophysiology, common comorbidities and current therapeutic modalities in the treatment/management of restless legs syndrome (RLS) a sensorimotor neurological disorder. […] An understanding of the etiopathogenesis of RLS by examining both endogenous and exogenous factors, such as CNS dopaminergic and iron deficiency hypotheses as the etiologic hallmarks of RLS has enhanced our clinical understanding of this disorder, and contributed to the improvement of diagnostic and therapeutic approaches. […] One hypothesis concerning RLS establishes that underlying the condition there is a regional brain iron deficiency and/or specific genetic factors that disturb the neurotransmission of dopamine in the subcortical brain areas. […] The pharmacological treatment of RLS is limited to symptomatic medication, since etiological forms of therapy have not been developed.

• #54 Restless Legs Syndrome: Detection and Management in Primary Care | AAFP

  https://www.aafp.org/pubs/afp/issues/2000/0701/p108.html

  RLS has been reported in association with spinal cord and peripheral nerve lesions, although an exact pathologic mechanism has not been identified. […] Some evidence from published case reports indicates that RLS symptoms may be induced or exacerbated by medications such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), lithium and dopamine antagonists. […] The diagnosis of RLS is based primarily on the patient’s history. […] RLS symptoms are generally worse in the evening and night and less severe in the morning. […] The criteria for the diagnosis of RLS are based on those developed by the International Restless Legs Syndrome Study Group. The involuntary, repetitive, periodic, jerking movements refer to periodic limb movements (PLM), also known as PLMS (periodic limb movements of sleep) or nocturnal myoclonus, which may be associated with RLS. PLMS are stereotyped, repetitive flexions of the limbs (legs alone or legs more than arms) usually occurring during sleep. They occur periodically on an average of every 20 seconds. […] Dopaminergic agents are the first-line drugs for most RLS patients.

• #55 Restless legs syndrome: An overview of pathophysiology, comorbidities and therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2021.11108

  Treating the already excessive brain dopamine in RLS with levodopa would appear counterintuitive, but the key to understanding it lies in the circadian rhythm of both dopaminergic activity and RLS/WED symptoms. […] The key here is to use long-acting medication such as transdermal rotigotine in order to reduce the risk of debilitating augmentation. […] A total of 13 different genes implicated in RLS have been identified as single nucleotide polymorphisms on chromosomes 6p21.2 (BTBD9), 2p14 (MEIS1), 9p24.1-p23 (PTPRD), 15q23 (MAP2K5/SKOR1) and 16q12.1 (TOX3/BC034767) based on GWAS. […] The functions of these genes are in close connection to the neurological development of the embryonic limbs even if the pathophysiological functions are not yet clear.

• #56 Restless Leg Syndrome – Life Extension

  https://www.lifeextension.com/protocols/neurological/restless-leg-syndrome?srsltid=AfmBOorbLer1OKTyyWIyQjyf5jVlFyVBVCz-_RenWystfsXW0TrhJN1w

  Secondary RLS is a common complication of end-stage kidney disease. Estimates indicate that up to 60% of patients on dialysis have RLS. People with diabetes or impaired glucose tolerance are more likely to have RLS, and RLS is a prominent part of diabetic peripheral neuropathy. Chronic venous disorders are a major contributor to secondary RLS. […] The main pharmacologic agents used to treat primary RLS are dopamine agonists, levodopa (L-DOPA), benzodiazepines, gabapentin, and opioids. However, treatment of primary RLS should not be considered until possible causes of secondary RLS are ruled out, especially venous disorders. […] Iron deficiency or altered brain iron metabolism have been linked to RLS; supplementation is often recommended for RLS patients who have been tested and shown to be deficient. Iron supplementation has been shown to significantly improve symptoms in iron-deficient RLS patients.

• #57 Restless Legs Syndrome: Detection and Management in Primary Care | AAFP

  https://www.aafp.org/pubs/afp/issues/2000/0701/p108.html

  RLS has been reported in association with spinal cord and peripheral nerve lesions, although an exact pathologic mechanism has not been identified. […] Some evidence from published case reports indicates that RLS symptoms may be induced or exacerbated by medications such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), lithium and dopamine antagonists. […] The diagnosis of RLS is based primarily on the patient’s history. […] RLS symptoms are generally worse in the evening and night and less severe in the morning. […] The criteria for the diagnosis of RLS are based on those developed by the International Restless Legs Syndrome Study Group. The involuntary, repetitive, periodic, jerking movements refer to periodic limb movements (PLM), also known as PLMS (periodic limb movements of sleep) or nocturnal myoclonus, which may be associated with RLS. PLMS are stereotyped, repetitive flexions of the limbs (legs alone or legs more than arms) usually occurring during sleep. They occur periodically on an average of every 20 seconds. […] Dopaminergic agents are the first-line drugs for most RLS patients.

• #58 Restless Legs Syndrome: Detection and Management in Primary Care | AAFP

  https://www.aafp.org/pubs/afp/issues/2000/0701/p108.html

  RLS has been reported in association with spinal cord and peripheral nerve lesions, although an exact pathologic mechanism has not been identified. […] Some evidence from published case reports indicates that RLS symptoms may be induced or exacerbated by medications such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), lithium and dopamine antagonists. […] The diagnosis of RLS is based primarily on the patient’s history. […] RLS symptoms are generally worse in the evening and night and less severe in the morning. […] The criteria for the diagnosis of RLS are based on those developed by the International Restless Legs Syndrome Study Group. The involuntary, repetitive, periodic, jerking movements refer to periodic limb movements (PLM), also known as PLMS (periodic limb movements of sleep) or nocturnal myoclonus, which may be associated with RLS. PLMS are stereotyped, repetitive flexions of the limbs (legs alone or legs more than arms) usually occurring during sleep. They occur periodically on an average of every 20 seconds. […] Dopaminergic agents are the first-line drugs for most RLS patients.

• #59 Restless Legs Syndrome: Detection and Management in Primary Care | AAFP

  https://www.aafp.org/pubs/afp/issues/2000/0701/p108.html

  RLS has been reported in association with spinal cord and peripheral nerve lesions, although an exact pathologic mechanism has not been identified. […] Some evidence from published case reports indicates that RLS symptoms may be induced or exacerbated by medications such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), lithium and dopamine antagonists. […] The diagnosis of RLS is based primarily on the patient’s history. […] RLS symptoms are generally worse in the evening and night and less severe in the morning. […] The criteria for the diagnosis of RLS are based on those developed by the International Restless Legs Syndrome Study Group. The involuntary, repetitive, periodic, jerking movements refer to periodic limb movements (PLM), also known as PLMS (periodic limb movements of sleep) or nocturnal myoclonus, which may be associated with RLS. PLMS are stereotyped, repetitive flexions of the limbs (legs alone or legs more than arms) usually occurring during sleep. They occur periodically on an average of every 20 seconds. […] Dopaminergic agents are the first-line drugs for most RLS patients.

• #60 Istradefylline for Restless Legs Syndrome Associated with Parkinson’s Disease | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.429

  Current studies have indicated that adenosine receptors play a significant role in both brain iron deficiency and sleep disorders in RLS. […] One study demonstrated a significant downregulation of adenosine A1 receptors and upregulation of adenosine A2A receptors in RLS. […] Thus, inhibiting adenosine A2A receptors may directly improve RLS, although this hypothesis remains speculative.

• #61 Potential Effect of Vortioxetine on Restless Leg Syndrome

  https://www.cpn.or.kr/journal/view.html?volume=21&number=3&spage=599

  Considering the efficacy of vortioxetine on both dopamine and gaba, its may have had a positive effect on RLS symptoms. […] Taken together, vortioxetine may be considered a candidate for the treatment of patients with RLS. […] In conclusion, we believe that studies should be conducted to investigate the efficacy of vortioxetine in the treatment of RLS. Therefore, randomized controlled studies are needed to determine the effect and safety of vortioxetine on RLS symptoms.

• #62 Treatment with selenium in restless legs syndrome | 49448

  https://www.iomcworld.org/proceedings/treatment-with-selenium-in-restless-legs-syndrome-49448.html

  A highly researched area in order to find an etiology and treatment for restless legs syndrome (RLS) is the brain dopamine system. […] It might be hypothesized that selenium may reduce the symptoms of RLS as selenium may work on the function of the dopaminergic system. […] It is known that RLS-patients are under oxidative stress. Thus, given the fact, that selenium is a potent antioxidant, its mechanism of action could as well be related to its ability to neutralize the reactive intermediates. Another possible working mechanism could be through the positive effect selenium has on endothelial function.

• #63 Use of potassium citrate in restless leg syndrome (RLS) – MedCrave online

  https://medcraveonline.com/PPIJ/use-of-potassium-citrate-in-restless-leg-syndrome-rls.html

  The secondary forms of RLS strongly support an iron deficiency abnormality for RLS, further documented by several other studies. […] On analyzing the information the beneficial effect of pot-citrate in RLS may be due to […] Neutralization of acidosis and or […] Potassium influx into muscle cells thereby hyperpolarizing the muscles resulting in decreased contraction. More scientific researchers are suggested to exclude or include this hypothesis. […] Though there are very few references in support of the results of this study, potassium citrate is significantly effective in relieving RLS.

• #64 Restless Legs Syndrome: Current Concepts about Disease Pathophysiology | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.322

  It is still unclear which areas are affected primarily by a pathologic process that causes RLS, as opposed to affected secondarily as a consequence of either chronic sleep loss or sensorimotor disturbances. It is likely that within these differing neuroanatomic regions, various biological systems are involved in producing the RLS state, including the dopaminergic, opioid, iron, serotonergic, and glutamatergic systems.

• #65 Restless Legs Syndrome: Known Knowns and Known Unknowns

  https://www.mdpi.com/2076-3425/12/1/118

  Growing evidence supports the view of RLS as a derangement of sensorimotor interaction. […] A central origin of the symptoms has therefore been hypothesized, likely due to a decreased supraspinal inhibitory influence on the spinal cord, resulting in increased spinal excitability. […] Two mechanisms that may have an important role in altered somatosensory processing in RLS are BID and dopaminergic dysfunction. […] The hypothesis that RLS may represent a network disorder, rather than a purely dopaminergic one, is also supported by recent evidence coming from functional connectivity studies. […] RLS is a puzzling disorder that remains poorly understood from both clinical and pathophysiological perspectives. […] In conclusion, we propose that RLS should be viewed as a circadian sensorimotor disorder, rather than a sleep-related MD.

• #66

  https://step2.medbullets.com/evidence/33880737

  Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. […] The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. […] RLS significantly impacts patients’ quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies.

• #67 Restless Legs Syndrome: Current Concepts about Disease Pathophysiology | Tremor and Other Hyperkinetic Movements

  https://tremorjournal.org/articles/10.5334/tohm.322

  RLS is a neurologic sensorimotor disorder that involves pathology, most notably iron deficiency, in motor and sensory brain areas. Brain areas not subserving movement or sensation such as the cingulate cortex and cerebellum are also involved. Other biological systems including the dopaminergic, oxygensensing, opioid, glutamatergic, and serotonergic systems are involved. Further research is needed to determine which of these anatomic locations or biological systems are affected primarily, and which are affected in a secondary response. […] Stepping back from neuroanatomy, much investigation has taken place to identify a pathophysiologic substrate of RLS. Biological systems that have been studied include the dopaminergic, opioid, iron, serotonergic, and glutamatergic systems. It is likely that activation and or abnormalities seen in different brain regions result from a primary disturbance of some biological system that in turn drives the symptoms and thus the entity of RLS.

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