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NI FEATURE: THE EDITORIAL DEBATE III-- PROS AND CONS
Year : 2019  |  Volume : 67  |  Issue : 3  |  Page : 657-659

Restless leg syndrome in patients with liver cirrhosis: Waiting for the shoe to drop


1 Department of Neurology, Christian Medical College, Ludhiana, Punjab; Department of Neurology, University Hospitals, Birmingham, United Kingdom
2 Department of Neurology, University Hospitals, Birmingham; Institute of Immunology and Immunotherapeutics, University of Birmingham, United Kingdom

Date of Web Publication23-Jul-2019

Correspondence Address:
Dr. Saiju Jacob
Honorary Reader, Institute of Immunology and Immunotherapeutics, University of Birmingham, and Consultant Neurologist, University Hospitals Birmingham B15 2TH
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.263218

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How to cite this article:
Bose S, Jacob S. Restless leg syndrome in patients with liver cirrhosis: Waiting for the shoe to drop. Neurol India 2019;67:657-9

How to cite this URL:
Bose S, Jacob S. Restless leg syndrome in patients with liver cirrhosis: Waiting for the shoe to drop. Neurol India [serial online] 2019 [cited 2019 Dec 10];67:657-9. Available from: http://www.neurologyindia.com/text.asp?2019/67/3/657/263218




Restless leg syndrome (RLS) or Willis–Ekbom disease is a sleep-related movement disorder, first described by Sir Thomas Willis in 1685 and published by Ekbom in the 1940s as his doctoral thesis. Patients present with an irresistible urge to move their limbs with symptoms improving partially or fully on movement. It is a poorly recognized and hence underreported condition. Epidemiological studies suggest that RLS affects around 10% of the general population. The first study on the Indian population, done as a questionnaire-based survey in Bangalore in 2007, reported the prevalence of RLS to be as low as 2.1%.[1] In this study, a delay in sleep onset correlated with the presence of RLS, and the duration in delay of sleep onset was associated with the severity of RLS. Another study done in 2012 demonstrated the prevalence to be 2.9%.[2] The reasons for such a low prevalence in India could be the lack of awareness of the condition, or a misdiagnosis of RLS as positional discomfort, akathisia, cramps, physiological leg movements in sleep, leg pain, and volitional leg movements. The diagnosis of RLS is based on history. There are no other tests required to confirm the diagnosis, unless there is a doubt, in which case a polysomnography could help in identifying periodic limb movements in sleep (PLMS). However, PLMS are not specific to the diagnosis of RLS. The International Restless Legs Syndrome Study Group has given the diagnostic criteria (revised in 2012), which involve the presence of all five patterns of symptoms that include an urge to move the legs which may or may not be accompanied by abnormal sensation in the legs, worsening of manifestations during rest, partial or total relief of the symptoms by movement, occuring of movements only or mostly in the evening or night, and the manifestations not being explained by any other cause such as arthritis, leg edema, and venous stasis. It defines chronic persistent RLS as occurring on an average more than twice weekly for the past 1 year, and intermittent RLS as occurring less than twice weekly for the past 1 year but with at least five lifetime events.[3]

RLS could be differentiated into the primary and secondary varieties. Primary RLS is considered in patients with a positive family history. A positive family history can be obtained in 30-60% of patients.[4] Iron deficiency states, chronic kidney disease, hypothyroidism, peripheral neuropathy, spinal cord pathology, and pregnancy are conditions commonly associated with RLS. [Figure 1] (adapted from Byrne et al.,[5]), outlines the common conditions linked to RLS.
Figure 1: Clinical classification of restless leg syndrome (adapted from Byrne et al.[5])

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The earliest report of RLS in patients with chronic liver disease was by Franco et al., in 2008.[6] In this study, there was no correlation between the severity of liver dysfunction or the presence of cirrhosis to RLS. There have been many studies now showing a positive correlation between the prevalence of RLS in patients with cirrhosis. Thus, the prevalence of RLS in the latter cohort is found to be higher than that of the general population. A study by Goel et al.,[7] demonstrated that the prevalence of RLS in patients with cirrhosis was 6.6% in the Indian population (lower than that reported in the Caucasian population).

Both RLS and cirrhosis have a negative impact on the quality of life (QoL), and therefore, it could be hypothesized that both could have a synergistic effect on worsening the QoL when present concomitantly in a patient. It would hence be imperative to find out a correlation between the two conditions and also establish whether the severity of liver cirrhosis has any association with the prevalence of RLS. Reports on Indian patients in this regard have been conflicting. Goel et al.,[7] established no relation of RLS with the severity of cirrhosis. The authors comment on the possibility of mild RLS being underreported in the general population as being the possible cause for such an observation. Rajender et al., on the other hand, proved the contrary.[8] RLS was more common in patients with a higher Child–Pugh score and in those with ethanol-induced cirrhosis.

The various pathophysiological mechanisms for RLS in patients with cirrhosis include the following:

First, low iron levels have been a well-known risk factor for RLS. Patients with decompensated cirrhosis often have low iron stores. They are also prone to have low folic acid, vitamin B12, and vitamin D levels. This can be attributed to a decreased intake, poor absorption, and chronic occult blood loss. All these factors may contribute to RLS. Low iron levels in the central nervous system may cause dysfunction or decrease in the number of dopamine receptors in the striatum which could be a potential cause for RLS. Animal studies have shown that there is an increase in the activity of tyrosine hydroxylase in the substantia nigra.[9] There is an associated decrease in the dopamine transporter function at the cell membrane level leading to an excess of extracellular dopamine, which correlates with RLS severity. The hyperdopaminergic state leads to post synaptic desensitization, which overcompensates at evening or night when the dopamine levels are lower compared to the rest of the day.[10],[11] Fluid overload states or altered electrolyte levels (hypokalemia, hyponatremia, hypomagnesemia, which can occur as an effect of diuretics) may be another contributory factor for the occurrence of RLS.[10]

Second, neuropathy due to various etiological reasons may be seen in patients with cirrhosis. RLS is known to be prevalent in patients with neuropathy.

Third, there has been a clear association between small intestinal bacterial overgrowth, which is commonly present in cirrhosis, and RLS. However, there have been contrasting reports on the association of serum ammonia and RLS.

In the study by Franco et al.,[6] 16.3% of patients with cirrhosis had RLS unaccounted by associated risk factors such as kidney disease, anemia, iron deficiency, neuropathy, and medications.

In this edition of Neurology India, Halkurike-Jayadevappa and colleagues have attempted to explore this question again.[12] This particular study, akin to some other studies, did not find any correlation between the prevalence of RLS and the severity of cirrhosis.[12] In contrast to the previous studies, this study assessed the presence of RLS in all patients with cirrhosis, hence dissolving the possible effect of underreporting. The approach to the diagnosis of RLS was thorough. The authors corroborated the fact that the prevalence of RLS in India is less than that reported in other parts of the world. Also, patients with cirrhosis had moderate-to-severe RLS as opposed to the general population where RLS presents as a milder disease and runs a benign course.

The study excluded patients with sudden liver function worsening in the preceding 4 weeks. This group might have contributed to analyzing the severity or occurrence of RLS in decompensated cirrhosis, as would have those patients admitted with decompensated cirrhosis who were not included in the study. But as the authors rightly point out, the symptoms are likely to be dominated by other features (and potentially masks RLS), in such acutely decompensated patients.

Important correlations to the severity of RLS worth investigating were serum iron and ammonia levels. Low iron levels may not always be synonymous with low hemoglobin, and vice versa. It would also have been worthwhile to have looked into serum ammonia as a primary risk factor of RLS in cirrhosis. The relationship between alcoholic liver disease and RLS, however, could not be established as it contradicted that reported by another study.[8]

Larger multicenter studies would be needed to substantiate the present hypothesis. A study comparing the quality of life of patients with cirrhosis with and without RLS may be beneficial. Studies looking at serum ferritin, iron levels, and blood urea nitrogen in patients with cirrhosis who also have RLS may help in understanding the pathophysiology better.



 
  References Top

1.
Rangarajan S, Rangarajan S, D'Souza GA. Restless legs syndrome in an Indian urban population. Sleep Med 2007;9:88-93.  Back to cited text no. 1
    
2.
Panda S, Taly AB, Sinha S, Gururaj G, Girish N, Nagaraja D. Sleep-related disorders among a healthy population in South India. Neurol India 2012;60:68.  Back to cited text no. 2
[PUBMED]  [Full text]  
3.
Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. and 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. 3
    
4.
Ondo W, Jankovic J. Restless legs syndrome: Clinicoetiologic correlates. Neurology 1996;47:1435-41.  Back to cited text no. 4
    
5.
Byrne R, Sinha S, Chaudhuri KR. Restless legs syndrome: Diagnosis and review of management options. Neuropsychiatr Dis Treat 2006;2:155.  Back to cited text no. 5
    
6.
Franco RA, Ashwathnarayan R, Deshpandee A, Knox J, Daniel J, Eastwood D, et al. The high prevalence of restless legs syndrome symptoms in liver disease in an academic-based hepatology practice. J Clin Sleep Med2008;4:45-9.  Back to cited text no. 6
    
7.
Goel A, Jat SL, Sasi A, Paliwal VK, Aggarwal R. Prevalence, severity, and impact on quality of life of restless leg syndrome in patients with liver cirrhosis in India. Indian J Gastroenterol 2016;35:216-21.  Back to cited text no. 7
    
8.
Rajender A, Mathur S, Choudhary P, Upadhyay S, Gaurav R, Bhargava R, et al. Restless leg syndrome a common undiagnosed comorbidity of clinical significance in cirrhosis. Gastroenterol Hepatol Bed Bench 2019;12:13-6.  Back to cited text no. 8
    
9.
Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT, et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 2009;132:2403-12.  Back to cited text no. 9
    
10.
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.  Back to cited text no. 10
    
11.
Salas RE, Gamaldo CE, Allen RP. Update in restless legs syndrome. Curr Opin Neurol 2010;23:401.  Back to cited text no. 11
    
12.
Halkurike-Jayadevappa VK, 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. 12
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