Elsevier

Sleep Medicine Reviews

Volume 22, August 2015, Pages 15-22
Sleep Medicine Reviews

Clinical review
Restless legs syndrome in multiple sclerosis

https://doi.org/10.1016/j.smrv.2014.10.002Get rights and content

Summary

Restless legs syndrome (RLS) is a sleep-related sensory-motor disorder characterized by an irresistible urge to move the legs accompanied by unpleasant sensations in the lower extremities. According to many recent studies patients with multiple sclerosis (MS) suffer frequently from symptoms of RLS. The prevalence of RLS in MS patients varies 13.3%–65.1%, which is higher than the prevalence of RLS in people of the same age in the general population. MS patients with RLS have higher scores in the Expanded Disability Status Scale compared to MS patients without RLS. Presence of RLS has a negative impact on sleep quality and fatigue of MS patients. Iron deficiency and chronic inflammation may be factors contributing to development of RLS in MS. The relationship between the course and treatment of MS and RLS requires further prospective studies.

Introduction

Restless legs syndrome (RLS) is a sleep-related sensory-motor disorder characterized by an irresistible urge to move the legs during rest. This is usually accompanied by unpleasant sensations and discomfort of the lower extremities. The symptoms appear or increase in the evening or night and during periods of rest. Moving the legs brings total or partial relieve [1]. The essential, supportive and additional clinical features of RLS, published in 2003 by the International Restless Legs Syndrome Study Group (IRLSSG) are presented in Table 1. RLS is frequently accompanied by periodic limb movements (PLMs) which are sleep-related rhythmic, repetitive movements of the legs that may resemble the Babinski sign. PLMs are present in most RLS patients but can also be found in many other sleep and wake disorders [2].

In adults, the prevalence of symptoms of RLS vary between five and 15% and the prevalence of clinically significant RLS is between one and five percent [3]. The prevalence is higher in women and it increases with age [4], [5].

There are two forms of RLS, idiopathic and secondary RLS. In idiopathic RLS the first symptoms of RLS appear usually before the age of 50 y, while secondary RLS starts often later in life. In idiopathic RLS 40–90% of patients report a positive family history indicating a strong genetic influence [6]. Four genes have been associated with RLS in genome-wide association studies: BTBD9, MEIS1, PTPRD and MAP2KP/SCOR1. However, the possible role of these genes in determining the clinical course of RLS is unknown [7], [8], [9]. There is a strong line of evidence linking RLS to decreased iron stores in the brain. This central iron deficiency may cause disturbances in the metabolism of dopamine [10]. Disordered dopaminergic transmission is probably one of the most important components in pathophysiology of RLS, as concluded from the efficiency of dopaminergic drugs and from studies of animal models of RLS [11]. It has been postulated recently that the dopaminergic neurons located in the A11 region, which are probably the only source of dopaminergic pathways for the spinal cord, are involved in the pathology of RLS [12]. Deregulation of spinal dopaminergic transmission may lead to hyperexcitability of spinal motor and sensory pathways and cause the symptoms of RLS and PLMs [13], [14].

The conditions that cause secondary RLS include iron deficiency [15], pregnancy [16], and end-stage kidney disease [17]. The prevalence of RLS is increased in many diseases, such as neuropathies [18], primary headaches [19], myasthenia gravis [20], rheumatoid arthritis [21], celiac disease [22] or liver diseases [23].

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system. Its etiology is not completely understood. It is characterized by appearance of relapsing or progressing focal neurological deficits. An association of MS with sleep disorders, such as narcolepsy, REM sleep behavior disorder, sleep disordered breathing or insomnia, has been described [24].

Sensory symptoms, and also symptoms of RLS are common in MS as noted for the first time by Rae-Grant and collaborators in 1999 [25]. Patients with MS describe their painful symptoms as burning, itching, electric or formicatory pain, resembling pain described by patients with RLS. Patients with MS localize their symptoms to legs and feet, trunk, arms and hands. The first epidemiological study on the occurrence of RLS in multiple sclerosis (MS) was reported by Auger et al. in 2005 [26]. Since that time numerous papers focusing on the relation between RLS and MS have been published [27], ∗[28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. The aim of this review is to analyze the available data on the epidemiology and etiology of RLS in MS patients and to suggest future directions of research.

Section snippets

Epidemiological data

The prevalence of RLS in MS reported by the studies published to date ranges from 13.3% to 65.1% (Table 2). The data available from these studies are presented in Table 2. All published papers (with one exception [38]) showed that RLS is significantly more prevalent in MS patients than in the general population.

RLS in the general population is characterized by the following traits: a higher prevalence among women and in older individuals and a high prevalence of subjects with a positive family

Relationship between the clinical course of MS and RLS

In most cases, RLS develops after the diagnosis of MS. It suggests a causal relationship between demyelination and RLS symptoms. It must be remembered that the prevalence of RLS increases with age which may explain the chronology of symptom development.

MS is an autoimmunological inflammatory disease. RLS is highly prevalent in inflammatory and immunological disorders and the possible connections between inflammation and immunological alterations and development of RLS were discussed recently in

Genes or anatomy?

The studies published suggest that MS may lead to secondary RLS. The low percentage of patients with a positive family history, development of RLS after the diagnosis of MS, a higher prevalence than that of the general population and a relationship between the presence of RLS and higher scores on the EDSS suggest that RLS is secondary to MS. However, the possible pathological link between MS and RLS remains unclear.

The link between the two disorders may be of a genetic nature. For some reason,

Conflict of interests

The authors have no conflict of interests to declare.

References (84)

  • L.B. Weinstock et al.

    Restless legs syndrome – theoretical roles of inflammatory and immune mechanisms

    Sleep Med Rev

    (2012)
  • W. Paulus et al.

    Dopamine and the spinal cord in restless legs syndrome: does spinal cord physiology reveal a basis for augmentation?

    Sleep Med Rev

    (2006)
  • T. Yokota et al.

    Sleep-related periodic leg movements (nocturnal myoclonus) due to spinal cord lesion

    J Neurol Sci

    (1991)
  • S.C.L. Telles et al.

    Periodic limb movements during sleep and restless legs syndrome in patients with ASIA A spinal cord injury

    J Neurol Sci

    (2011)
  • P.J. Wrigley et al.

    Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury

    Pain

    (2009)
  • S.M.H.A. Araujo et al.

    Restless legs syndrome in end-stage renal disease: clinical characteristics and associated comorbidities

    Sleep Med

    (2010)
  • P.-H. Chen et al.

    Risk factors and prevalence rate of restless legs syndrome among pregnant women in Taiwan

    Sleep Med

    (2012)
  • S.L. Clardy et al.

    Ferritin subunits in CSF are decreased in restless legs syndrome

    J Lab Clin Med

    (2006)
  • C.J. Earley et al.

    MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome

    Sleep Med

    (2006)
  • L.C. Jellen et al.

    Iron deficiency alters expression of dopamine-related genes in the ventral midbrain in mice

    Neuroscience

    (2013)
  • J.R. Connor et al.

    Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome

    Sleep Med

    (2011)
  • H. Stefansson et al.

    A genetic risk factor for periodic limb movements in sleep

    N Engl J Med

    (2007)
  • J. Winkelmann et al.

    Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions

    Nat Genet

    (2007)
  • B. Schormair et al.

    PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome

    Nat Genet

    (2008)
  • R.P. Allen et al.

    The role of iron in restless legs syndrome

    Mov Disord

    (2007)
  • S. Clemens et al.

    Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective

    Neurology

    (2006)
  • S. Qu et al.

    Locomotion is increased in a11-lesioned mice with iron deprivation: a possible animal model for restless legs syndrome

    J Neuropathol Exp Neurol

    (2007)
  • W. Bara-Jimenez et al.

    Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex

    Neurology

    (2000)
  • R.P. Allen et al.

    The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia

    Am J Hematol

    (2013)
  • M. Manconi et al.

    Restless legs syndrome and pregnancy

    Neurology

    (2004)
  • J. Lee et al.

    The prevalence of restless legs syndrome across the full spectrum of kidney disease

    J Clin Sleep Med

    (2013)
  • Y.A. Rajabally et al.

    Restless legs syndrome in chronic inflammatory demyelinating polyneuropathy

    Muscle Nerve

    (2010)
  • F. D' Onofrio et al.

    Restless legs syndrome and primary headaches: a clinical study

    Neurol Sci

    (2008)
  • M. Sieminski et al.

    Increased frequency of restless legs syndrome in myasthenia gravis

    Eur Neurol

    (2012)
  • R.M. Taylor-Gjevre et al.

    Restless legs syndrome in a rheumatoid arthritis patient cohort

    J Clin Rheumatol

    (2009)
  • M. Moccia et al.

    Restless legs syndrome is a common feature of adult celiac disease

    Mov Disord

    (2010)
  • R.A. Franco et al.

    The high prevalence of restless legs syndrome symptoms in liver disease in an academic-based hepatology practice

    J Clin Sleep Med

    (2008)
  • A.D. Rae-Grant et al.

    Sensory symptoms of multiple sclerosis: a hidden reservoir of morbidity

    Mult Scler

    (1999)
  • C. Auger et al.

    Increased frequency of restless legs syndrome in a French-Canadian population with multiple sclerosis

    Neurology

    (2005)
  • M. Manconi et al.

    High prevalence of restless legs syndrome in multiple sclerosis

    Eur J Neurol

    (2007)
  • M. Manconi et al.

    Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study

    Sleep

    (2008)
  • N.C.V. Moreira et al.

    Restless leg syndrome, sleep quality and fatigue in multiple sclerosis patients

    Braz J Med

    (2008)
  • Cited by (33)

    • Restless legs syndrome in multiple sclerosis is related to retinal thinning

      2022, Photodiagnosis and Photodynamic Therapy
      Citation Excerpt :

      Depending on the affected area in the central nervous system, various clinical signs and symptoms may develop, including motor, sensory, autonomic, and cognitive disorders [5]. The prevalence of RLS in MS patients is between 13.3 and 65.1%, and it is more common than in the general population with a more severe course [6–8]. Optical Coherence Tomography (OCT) is a non-invasive imaging method that uses optical back-reflection of near-infrared light views the retina, similar to histological sections [9].

    • Restless legs syndrome in pediatric onset multiple sclerosis

      2021, Multiple Sclerosis and Related Disorders
    • Restless legs syndrome in people with multiple sclerosis: An updated systematic review and meta-analyses

      2021, Multiple Sclerosis and Related Disorders
      Citation Excerpt :

      Minár et al., 2017) Although, it has been shown that RLS appears more frequently in women, the elderly, and in people with a family history of RLS, it is still unknown if this occurs in PwMS. ( Sieminski et al., 2015) Thus, the aim of this systematic review and meta-analyses was to (i) provide updated information as to the prevalence and clinical characteristics of RLS amongst PwMS and (ii) clarify RLS-related factors in PwMS. MEDLINE (PubMed), Scopus, and EMBASE were searched from their inception through April 2021 for the following keywords used independently and in combination: ‘restless legs syndrome’ or ‘RLS’ and ‘multiple sclerosis' or ‘MS’.

    • Restless Legs Syndrome in Multiple Sclerosis: Risk factors and effect on sleep quality – a case-control study

      2021, Multiple Sclerosis and Related Disorders
      Citation Excerpt :

      Restless Legs Syndrome (RLS) was first described in 1945 by the Swedish neurologist Karl-Axel Ekbom and is classified as an extrapyramidal hyperkinesia or, according to the German Society for Sleep Research and Sleep Medicine (DGSM), as a sleep-related movement disorder (EKBOM, 1945, S3-Leitlinie Nicht erholsamer Schlaf 2011). Moreover, there are two forms of RLS, idiopathic and secondary RLS (Sieminski et al., 2015). According to the revised diagnostic criteria of the International Restless Legs Syndrome Study Group (IRLSSG), RLS is characterized by a strong urge to move limbs with accompanying unpleasant sensations, worsening at rest and in the evening, improvement or complete disappearance with movement and excluded mimics (Allen et al., 2014).

    View all citing articles on Scopus

    The most important references are denoted by an asterisk.

    View full text