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Table of Contents    
Year : 2019  |  Volume : 67  |  Issue : 3  |  Page : 660-661

Identifying risk factors for restless leg syndrome

Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi, India

Date of Web Publication23-Jul-2019

Correspondence Address:
Dr. Sanjay Pandey
Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, Academic Block, Room No 507, New Delhi - 110 002
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.263223

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How to cite this article:
Panda AK, Pandey S. Identifying risk factors for restless leg syndrome. Neurol India 2019;67:660-1

How to cite this URL:
Panda AK, Pandey S. Identifying risk factors for restless leg syndrome. Neurol India [serial online] 2019 [cited 2020 Nov 29];67:660-1. Available from:

Restless leg syndrome (RLS) is a chronic neurological disorder characterized by both sensory and motor symptoms. Willis first described it in the year 1680. The disorder was published by Ekbom in 1945, but it remains a difficult entity to diagnose owing to the absence of any biomarkers, and its varied symptomatology. RLS or Willis Ekbom disease is described as an urge to move the limbs (mainly legs, though other limbs could be affected), usually accompanied by an unpleasant sensations in the limbs.[1] The unpleasant sensations have a personal connotation and have been described as tingling, bubbling, itching, pulling, burning, or pain, among other symptoms.[2] The urge to move is predominantly in the legs (thighs or calves), but can involve the arm also (21-57% of cases). RLS has a circadian rhythm and occurs mostly in the evenings or the night-time. Even the symptoms during rest are less in the mornings rather than at night. There are about five-lifetime events that are the accepted minimum number of events that need to be present for the disease to be labelled as RLS.[3] Patients generally present with sleep disturbances, discomfort, non-specific motor activity, attention deficit hyperkinetic disorder (ADHD), and mood and cognitive dysfunction. Hence, a careful history-taking is of paramount importance. It should include the timing, frequency and severity of manifestations as well as coexisting features like 'periodic limb movements (PLMs)', sleep disturbances like inability to fall asleep, stay asleep or a poor quality sleep, and daytime sleepiness.[2] The severity can be assessed by the 'International restless leg scale (IRLS)' severity score. It is used for the categorization of patients into mild, moderate and severe RLS, thus aiding in the decision to initiate pharmacotherapy and in deciding the class of medications being administered.[3]

The diagnostic criterion for RLS has been formulated and upgraded many times for establishing the accurate diagnosis of the condition. In 2014, the 'International Restless Legs Syndrome Study Group (IRLSSG)' refined the diagnostic criteria, which, included: 1) An urge to move the limb, which is usually accompanied with unpleasant sensations but can be present without them; 2) the urge or the unpleasant sensations increase or are present only in the evening or night; 3) they worsen with periods of rest or inactivity; 4) they are partially or totally relieved by activity; 5) and, they cannot be solely explained by a medical condition. The criteria include supportive features like family history, improvement with dopaminergic medications, periodic limb movements during wakefulness or sleep, and the lack of expected daytime sleepiness. It also includes specifiers for the clinical course and the clinical significance, making it a robust and stringent criteria.[4]

RLS is a disease of all ages, occurring in children as well as adults, with an overall prevalence of 1-5%.[3] Most patients are in their middle ages at presentation. The prevalence increases with age but around 10% adults report the onset of symptoms before the age of ten years, and around 38-45%, before the age of twenty.[5] 2% - 5.9% of children between 5-17 years of age have been reported to have RLS, whereas the prevalence in adults is between 4-15%. The prevalence is high in the western countries, ranging between 5.5%-15%, whereas in the Asian populations, the prevalence varies from 0.96% in Japan and 1.4% in China to 2.9% in India.[1] In adults more than 35 years of age, women are twice more likely to be affected. Pregnancy increases the risk of RLS by two to three times (prevalence 2.9%-33.86%) when compared to nulliparous women, who have similar prevalence rates as that of men.[5]

The pathophysiology of RLS is linked to genetic abnormalities, defects in iron metabolism, dopaminergic dysfunction (both central and peripheral), and defects in the central opiate system. The genetic variants in short nucleotide polymorphisms (SNPs) like MEIS1 (chromosome 2p14), BTBD9 (chromosome 6p21.2), PTPRD (chromosome 9p24.1-p23), and MAP2K5/SCOR1 have been identified. These SNPs play important roles in iron transportation, dopamine biosynthesis and sleep regulation, axon guidance and neuroprotection of the dopaminergic neurons, respectively.[1] Iron metabolism has been implicated in RLS by various pathways, including iron deficiency in the brain especially the substantia nigra, thalamus and basal ganglia, leading to dysfunction in the dopaminergic pathways.[6] Iron is also needed for many processes like oxidative phosphorylation, oxygen transportation, synthesis and metabolism of neurotransmitters. Thus, an impairment in metabolism may lead to cellular damage. It is also a co-factor for tyrosine hydroxylase, which is a rate-limiting enzyme in dopamine synthesis.

Dopamine dysfunction in RLS leads to decreased D2 receptors and dopamine transporters, with an increased dopamine production in the striatum, leading to an increased synaptic dopamine and postsynaptic desensitization of the receptors. The normal circadian rhythm leads to a much larger day-to-night ratio of dopamine (four times than normal), and at night, the receptors overcompensate, causing symptoms.[7] Dopamine also affects the medial pain system via the medial thalamic nuclei.[1] Overall, RLS is a dopamine excessive state but dopaminergic drugs are used at night time to decrease the overcompensation of desensitized receptors.[7]

RLS is classified into idiopathic and secondary, depending upon the etiology. It is termed idiopathic when the cause is unknown, although 40-90% patients are found to have a positive family history. In the presence of comorbidities, it is termed as secondary RLS.[1] The variety of risk factors or comorbidities associated are pregnancy, iron deficiency, anemia, kidney disease, venous insufficiency, cardiovascular diseases like hypertension and stroke, chronic obstructive airway disease, chronic liver disease (CLD), migraine, multiple sclerosis, polyneuropathies, lumbosacral radiculopathy, acute spinal cord lesions-stroke, myelitis, amyotrophic lateral sclerosis,  Parkinsonism More Details, rheumatoid arthritis, alcohol abuse, vitamin deficiencies, spinal stenosis, excess caffeine or chocolate intake, diabetes mellitus, hypoglycaemia, hypothyroidism, drugs (tricyclic antidepressants, selective serotonin reuptake inhibitors, antidepressants, antiepileptic drugs, β blockers, and lithium) and obesity.[1],[8]

Despite this exhaustive list, a systemic review of literature by Trenkwalder et al., reports an increased prevalence of RLS only in iron deficiency, and kidney disease. They also report a possible association with cardiovascular disease, arterial hypertension, diabetes, migraine, and Parkinson disease. The prevalence rate of RLS in iron deficiency anaemia is 25-35% whereas that of kidney disease/end-stage renal disease is 15-68%.[8] CLD, due to the presence of iron deficiency and altered electrolytes, was investigated for its association with RLS but no correlation was found between the severity of CLD and RLS.[9] A study published in this issue of Neurology India by Vijay Kumar HJ et al., reports a prevalence of around 10% among their CLD patients. The prevalence of RLS in CLD is higher than that of normal population but it does not correlate with the severity of liver disease. This finding, according to the authors, might be due to masking of RLS in the wake of other symptoms in severe liver disease. Also, further studies might be required to ascertain whether RLS improves as liver condition worsens.[10]

In conclusion, RLS is a chronic sensorimotor neurological disorder which has genetic as well as other risk factors. The risk factors through iron metabolism defects or dopamine dysfunction lead to RLS. Although a long list of conditions can potentially cause RLS, only iron deficiency and kidney disease are reported to be associated with its increased prevalence.

  References Top

Guo S, Huang J, Jiang H, Han C, Li J, Xu X, et al. Restless legs syndrome: From pathophysiology to clinical diagnosis and management. Front Aging Neurosci 2017;9:171.  Back to cited text no. 1
Bertisch S. In the clinic. Restless legs syndrome. Ann Intern Med 2015;163:ITC1-11.  Back to cited text no. 2
Trenkwalder C, Winkelmann J, Inoue Y, Paulus W. Restless legs syndrome-current therapies and management of augmentation. Nat Rev Neurol 2015;11:434-45.  Back to cited text no. 3
Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. International Restless Legs Syndrome Study Group. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: Updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria--history, rationale, description, and significance. Sleep Med 2014;15:860-73.  Back to cited text no. 4
Srivanitchapoom P, Pandey S, Hallett M. Restless legs syndrome and pregnancy: A review. Parkinsonism Relat Disord 2014;20:716-22.  Back to cited text no. 5
Rizzo G, Li X, Galantucci S, Filippi M, Cho YW. Brain imaging and networks in restless legs syndrome. Sleep Med 2017;31:39-48.  Back to cited text no. 6
Salas RE, Gamaldo CE, Allen RP. Update in restless legs syndrome. Curr Opin Neurol 2010;23:401-6.  Back to cited text no. 7
Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases: A systematic review and new concept. Neurology 2016;86:1336-43.  Back to cited text no. 8
Moretti R, Caruso P, Tecchiolli M, Gazzin S, Tiribelli C. Management of restless legs syndrome in chronic liver disease: A challenge for the correct diagnosis and therapy. World J Hepatol 2018;10:379-87.  Back to cited text no. 9
Halkurike-Jayadevappa VJ, Goel A, Paliwal VK, Rai P, Aggarwal R. Liver disease severity is poorly related to the presence of restless leg syndrome in patients with cirrhosis. Neurol India 2019;67:732-7.  Back to cited text no. 10
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