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Restless legs syndrome in multiple sclerosis
Sleep Medicine Reviews 22 (2015) 15e22
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CLINICAL REVIEW
Restless legs syndrome in multiple sclerosis Mariusz Sieminski a, *, Jacek Losy b, c, Markku Partinen d, e a
Department of Adult Neurology, Medical University of Gdansk, Gdansk, Poland Department of Clinical Neuroimmunology, Chair of Neurology, Poznan University School of Medicine, Poznan, Poland c Neuroimmunlogical Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Poznan, Poland d Helsinki Sleep Clinic, Vitalmed Research Centre, Helsinki, Finland e Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland b
a r t i c l e i n f o
s u m m a r y
Article history: Received 28 June 2014 Received in revised form 2 October 2014 Accepted 3 October 2014 Available online 12 October 2014
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%e65.1%, 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. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Restless legs syndrome Multiple sclerosis Demyelination Iron metabolism
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]. Abbreviations: RLS, restless legs syndrome; PLMS, periodic limb movements in sleep; MS, multiple sclerosis; EDSS, expanded disability status scale; NAWM, normally appearing white matter; sTfR, soluble transferrine receptor; NO, nitric oxide; NOS, nitric oxide synthase; TNF-a, tumor necrosis factor alpha; REMS, The Restless Legs Syndrome in Multiple Sclerosis Study; Il-6, interleukine - 6; CNS, central nervous system; REM, rapid eye movement; MRI, magnetic resonanse imaging; MBP, myelin basic protein; PLP, proteolipid protein; CNPase, cyclic nucleotide phosphohydrolase; MOG, myelin oligodendrocyte glycoprotein; nNOS, neuronal nitric oxide synthase; IRLSS, International Restless Legs Syndrome Severity Scale; IRLSSG, International Restless Legs Syndrome Study Group; FSS, Fatigue Severity Scale. * Corresponding author. Tel.: þ48 606 292 536. E-mail address: [email protected] (M. Sieminski). http://dx.doi.org/10.1016/j.smrv.2014.10.002 1087-0792/© 2014 Elsevier Ltd. All rights reserved.
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 40e90% 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 [7e9]. 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
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Table 1 Clinical features of restless legs syndrome (RLS) (Allen et al., 2003).[1]. Essential diagnostic criteria 1) An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs (sometimes the urge to move is present without the uncomfortable sensations and sometimes the arms or other body parts are involved in addition to the legs) 2) The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting 3) The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues 4) The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night (when symptoms are very severe, the worsening at night may not be noticeable but must have been previously present Supportive clinical features 1) The prevalence of RLS among first-degree relatives of people with RLS is 3e5 times greater than in people without RLS 2) Nearly all people with RLS show at least an initial positive therapeutic response to either L-dopa or a dopamine-receptor agonist 3) Periodic limb movements in sleep occur in at least 85% of cases Associated features 1) When the age of onset of RLS symptoms is less than 50 y, the onset is often more insidious; when the age of onset is greater than 50 y, the symptoms often occur more abruptly and more severely 2) Disturbed sleep is a common major morbidity for RLS 3) The physical examination is generally normal and does not contribute to the diagnosis, except for those conditions that may be comorbid or secondary causes of RLS.
[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 [27,28e37]. 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.
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 history. This pattern was not fully replicated in studies of RLS in MS patients. A significant relationship with the female sex was found in only two studies [28,35] and MS patients with RLS were older than patients without RLS in only five studies [27,28,32,35,37]. Li et al. analyzed the menopausal status of the female patients with MS. The authors found that premenopausal women are at higher risk (OR ¼ 5.08) of developing RLS than postmenopausal women (OR ¼ 2.00). The authors hypothesized that this is a consequence of lower iron levels resulting from menstrual loss of blood [36]. The authors of some of the published papers focused on the prevalence of RLS in the families of MS patients. A positive family history of RLS was found in 2.4%e27.1% of the patients with MS having also RLS [27,28,34,35,37,39], which is significantly less than the occurrence of family history in idiopathic RLS in the general population [6]. The most prominent fact regarding the studies of the occurrence of RLS in MS patients is the wide range of results. There are few reasons for those discrepancies. All groups that performed those studies applied the 2003 diagnostic criteria of RLS proposed by the IRLSSG. Nonetheless the publications differed regarding the mode of application of the criteria. The authors used patient-filled questionnaires, interviews and structured interviews. The highest RLS prevalence rates were found in studies using patient-filled questionnaires. Some symptoms of RLS are difficult to explain in the form of a short question included in a questionnaire. Some symptoms of MS (paraesthesias in the limbs, sensory symptoms as described by Rae-Grant et al. [25] and also spastic symptoms) can resemble the symptoms of RLS. Ideally, the exact nature of the RLS symptoms should be verified in an interview and neurological examination by a physician with experience in RLS. Personal interviews with the patients are preferred to patient filled questionnaires. The patients who participated in the study performed by Deriu et al. filled a questionnaire (which gave a prevalence rate of 45%) and then underwent an interview that reduced the frequency of the diagnosis of RLS to 27% [30]. These results suggest that the application of a self-administered questionnaire may lead to numerous false-positive diagnoses. Also personal
Table 2 Prevalence of RLS in MS patients according to published studies. Publication: First author (year of publication)
Number of MS patients/controls
Method
Prevalence of RLS in MS (%)
Prevalence of RLS in controls (%)
Auger (2005) [26] Manconi (2007) [27] mez-Choco (2007) [38] Go Manconi (2008) [28] Moreira (2008) [29] Deriu (2009) [30] Douay (2009) [33] Aydar (2011) [32] Fragoso (2011) [31] vrov Va a (2012) [35] Li (2012) [36] Miri (2012) [34] Shaygannejad (2013) [37]
200/100 156/135/118 861/649 44/202/212 242/98/129 80/180 765/264/65280 205/126/126
PtQ Int, NeurEx. Int Int, PtQ, PtQ, Int, PtQ Int Int Int PtQ Int PtQ
37.5 32.7 13.3 19 27 14.6 18 27.6 57.5 32 15.5 27.8 65.1
16 NA 9.3 4.2 NA 2.8 NA 10.1 18.3 NA 6.4 NA 12.7
PtQ: patient-filled questionnaire; Int: interview; NeurEx: neurological examination.
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interviews without neurological examinations may give false positive results. Symptoms of RLS may be also misdiagnosed in patients with anxiety and/or depression if anxiety and depression have not been tested properly [40]. Another methodological difference among these studies is the application of a threshold of the frequency of the symptoms. The frequency of symptoms is a reliable marker of the clinical significance and severity of RLS. Including such a threshold in the diagnostic interview reduces the risk of false-positive diagnoses. Some groups applied a threshold of two days with RLS symptoms per week, or more than four days with RLS symptoms per month. In other studies no frequency threshold was used. The restless legs syndrome in multiple sclerosis study (REMS study) performed by Manconi et al., which used a threshold of two days/week, reported a prevalence of 19% [28]and the study performed by Vavrova et al., which did not apply a threshold, reported a prevalence of 32% [35]. The comorbidities that cause secondary RLS or RLS-mimics were excluded in some of the studies. It is noteworthy that the prevalence of RLS was higher in studies without such an exclusion, and that many MS patients suffer from diseases that might cause secondary RLS or RLS-mimics. Auger et al. found that RLS was present in 37.5% of MS patients but almost half of RLS-positive patients had a condition related to RLS [26]. The prevalence of RLS in Turkish MS patients was 27.6%; however over one fifth of them had an RLSrelated comorbidity [32]. The validity of excluding RLS-related comorbidities is disputable. Although this helps determine whether the two diseases are related, it may reduce the overall prevalence of RLS in MS patients. In some patients with MS an idiopathic form of RLS might have developed independently of the demyelinating process. The presence of a positive family history of RLS and the appearance of RLS before the diagnosis of MS may suggest the idiopathic nature of the RLS in these cases. The REMS study reported that 22% of RLSpositive MS subjects had a positive family history of RLS (which represents 4.2% of the whole MS population) and that 13.8% of RLSpositive subjects experienced RLS symptoms before the diagnosis of MS (which represents 2.6% of the whole MS population) [28]. Similar results were obtained in the study performed by Vavrova et al., who reported that 6.4% of MS patients had RLS symptoms before the onset of MS and that 2.4% of MS patients had a positive family history and experienced RLS before the diagnosis of MS [35]. These data allow a crude estimation of the prevalence of idiopathic RLS in MS patients at 2.4e13.5%, which is comparable with prevalence of idiopathic RLS in the general population. It is noteworthy that none of the studies implemented validated diagnostic questionnaires for the diagnosis of RLS, such as the RLS diagnostic index or the John Hopkins telephone questionnaire. Moreover, no additional diagnostic procedure, such as the L-dopa test or the suggested immobilization test were used. The use of those tools might have eliminated false positives and RLS mimics, and thus led to a more precise determination of RLS prevalence. 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 an extensive review [41]. Nevertheless, there are no data on the inflammatory status of RLS-positive patients with MS in the studies published so far. The question whether the intensity of
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autoinflammatory process in MS is related to development of RLS remains to be solved. Some of the studies have reported that patients with RLS had higher scores in the expanded disability status scale (EDSS) [27e29,35,37]. There are a few possible explanations for this observation. The time dispersion between the onset of MS and the onset of RLS suggests that patients with RLS have a longer history of MS. As disability in MS accumulates with time the higher EDSS can be simply the result of the progression of MS. Another explanation is that a more severe course of the disease leading to higher EDSS facilitates the development of RLS. The third explanation is that the pathological process that leads to RLS simultaneously worsens the course of MS. Only one study found a relationship between neuroimaging data and the presence of RLS. Manconi et al. [39] found no significant differences in cerebral lesion load between RLS-positive and RLS-negative MS patients. Moreover, no difference was found in the mean diffusivity and fractional anisotropy of the brain tissues. The basal ganglia of RLS-positive and RLS-negative MS patients did not differ on MRI examination. The number of lesions in the spinal cord was similar in the two groups; however, RLS-positive MS patients had lower fractional anisotropy and a higher fractional histogram peak height in the spinal cord. These data suggest that RLS-positive MS patients suffer from more severe spinal cord degeneration. This finding was recently supported by a study published by Bruno et al. (e-publication, ahead of print). The authors compared RLS-positive and RLS-negative MS patients and found that cervical lesions are significantly more frequent and the number of lesions in the cervical spinal cord is significantly higher in the RLS-positive group [42]. None of the studies found any relationship between lesions in the brain and the presence of RLS symptoms. This finding suggests that the development of RLS symptoms is related to demyelination of the spinal motor and sensory pathways. The relationship between the type of MS and the presence of RLS was analyzed in some of the studies. Manconi et al. performed REMS study [28] and observed a significantly higher prevalence of primary progressive MS in the RLS-positive population and a lower prevalence of relapsing - remitting MS in RLS-positive subjects. A study performed by Douay et al. using a French population of MS patients found that RLS was more prevalent in relapsing e remitting MS [33]. Vavrova et al. found, that in Czech patients, RLS was most prevalent in the secondary progressive type of MS [35]. The question of whether any of the MS subtypes predisposes to the development of RLS remains unanswered, as none of the published studies reached a definite conclusion. There are no data available on the relationship between treatment of MS and prevalence of RLS. There is no study comparing the prevalence of RLS among MS patients receiving disease modifying therapy and among untreated patients. There are no data on temporal relation between initiation of disease modifying therapy of MS and development of RLS. None of the published data allows to suspect that RLS in MS may be an iatrogenic condition secondary to the therapy used. The relationships between RLS and depression, and sleep disturbances and fatigue in MS patients were analyzed in some of the studies. Insomnia was more prevalent in RLS-positive MS patients in the studies performed by Manconi et al. [27] and by Miri et al. [34]. In another study Manconi et al. found that total sleep time was significantly shorter and sleep latency was significantly longer, in RLS-positive patients [28]. Moreira et al. found that MS patients with RLS had higher scores on the Pittsburgh sleep quality index and that the score in the excessive daytime sleepiness scale was higher in RLS-positive MS patients [29]. Manconi et al. found a higher prevalence of daytime sleepiness in RLS-positive subjects [28]. Nevertheless, some studies have shown that the presence of
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RLS does not result in increased daytime sleepiness in MS patients [27,34,36]. Two studies have described a relationship between fatigue and the presence of RLS in MS patients. Moreira et al. found a higher fatigue score on the fatigue severity scale (FSS) in RLSpositive MS patients [29], and Aydar et al. [32] stated that the presence of RLS is related to fatigue, without comments on the direction of that relation. Aydar et al. checked the level of depression in RLS-negative and RLS-positive patients and found that the presence of RLS is related to depression without a more profound description of that relationship [32]. The question of whether RLS has any impact on the presence of fatigue and depression in MS patients deserves further study. None of the studies published to date has focused on the relationship between RLS and the quality of life of patients with MS. Studies performed with the participation of healthy controls allow the comparison of RLS in MS-positive and MS-negative subjects. Auger et al. performed the first study of RLS in MS and found that the symptoms of restless legs are more severe in patients with MS, although the method used to measure the severity of RLS was not published [26]. In an REMS study Manconi et al. used the International RLS severity scale (IRLSS) and found that RLS was more severe in MS patients compared with healthy controls [28]. Aydar at al. and Fragoso et al. also used the IRLSS scale, with a similar result: a higher score on the IRLSSS in MSpositive patients [31,32]. Li et al. found that in MS-positive women severe RLS was more prevalent than it was in MSnegative women [36]. The results described above suggest that RLS in MS patients has a more severe course. Conversely, it must be remembered that the sensory symptoms of MS may overlap with symptoms of RLS, thus leading to a subjective impression of more severe disease.
cases of transverse myelitis [46]. Hartmann et al. described three patients with spinal cord lesion (myelitis due to MS, posttraumatic compression of the cervical spine and cervical spondylotic myelopathy) resulting in symptomatic RLS. What is of special interest, dopaminergic treatment was successful in all of those cases [47]. Telles et al. found presence of RLS and PLMS in all subjects from a series of patients with a complete spinal cord injury [48]. The appearance of RLS and PLMS in patients with spinal cord lesions is supposed to be a result of diminished descending control over the spinal motor and sensory pathways [43]. The efficiency of dopaminergic treatment in RLS and PLMS in patients with focal spinal cord lesions suggests that impaired dopaminergic transmission is responsible for the appearance of the symptoms. The major source of the dopamine for the spinal cord is the area A11 of the hypothalamus [11]. Spinal lesion destroying the descending dopaminergic pathways results in development of the symptoms of RLS or PLMS. Lesion of spinal descending motor pathways leads to rearrangements within spinal central pattern generators which may result in development of PLMS, as it was suggested by Telles et al. [48]. Another consequence of spinal cord lesion is destruction of the ascending sensory pathways. That leads to changes within cortical and subcortical structures responsible for sensory functions as it was shown in animal models and in human subjects [49,50]. This process is responsible for the development of central neuropathic pain in patients after spinal cord injury and may be also involved in generating the sensory symptoms of RLS in patients with spinal cord lesions. The hypothesis that the degeneration of spinal pathways resulting from the demyelination process leads to the appearance of RLS symptoms is plausible. Iron deficit, inflammation and demyelination?
A possible pathological links between RLS and MS 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, genes that are related to development of RLS (BTBD9, MEIS1, PTPRD, MAP2KP/SCOR1) may be present more frequently in the population of MS patients. Vavrova et al. verified this hypothesis by performing a genetic association study in a population of patients with MS. The authors found only a weak relationship between the presence of RLS in MS and a variant of MAP2KP/SCOR1 [35]. As the relationship between the presence of the gene and the development of RLS in MS was very weak, genetic factors do not seem to explain the prevalence of RLS in MS patients. Many authors have suggested that RLS in MS patients is caused by demyelinated lesions localized in areas that are responsible for the development of RLS. These hypotheses are very speculative, as the exact anatomical background of RLS remains unclear. Manconi et al. [39] found that some MRI findings (lower fractional anisotropy and higher fractional histogram peak height) are suggestive of more intense degeneration of the spinal cord in MS patients with RLS. This finding was confirmed recently in a publication by Bruno et al. [42]. Spinal cord lesions are suggested to be an anatomopathological substrate of RLS and PLMS [43]. PLMS were observed in patients with transverse myelopathy [44] and in patients with focal spinal cord lesions [45]. RLS was observed in
RLS is strongly related to iron deficiency, both peripheral and in central nervous system (CNS). Higher prevalence of RLS was found in populations of subjects with iron-deficiency anemia [15], or in blood donors [51]. RLS is also more prevalent in conditions leading to iron deficiency, like end-stage renal disease [52,53] or pregnancy [54,55]. Serum ferritin was found decreased in RLS patients [56]. There is also an evidence for iron deficiency within the CNS. The level of iron and ferritin was decreased in cerebrospinal fluid (CSF) of patients with RLS, compared with CSF of normal controls [57e60]. It was discovered in magnetic resonance imaging studies that brain iron stores are reduced in patients with RLS [61] which was in concordance with results of a study with transcranial ultrasound assessment of substantia nigra of patients with RLS [62]. Data collected in autopsy studies also confirm the decrease of iron stores in brains of patients with RLS [63,64]. It was recently found in animal studies, that iron deficiency leads to alterations in the synthesis of dopamine within the midbrain [65]. Disorders of iron metabolism, peripheral and within the CNS were also discovered in multiple sclerosis. A higher prevalence of iron-deficiency anemia was found in patients with multiple sclerosis [66,67]. Increased level of soluble transferrine receptor (sTfR) was found in serum of patients with MS [68], which was also found in patients with RLS [69]. The increased serum level of sTfR is suggestive of iron deficiency. Iron is necessary for myelination and iron deficiency leads to disordered myelination as it was shown in animal and human studies [70,71]. In contrast to RLS, where decreased CNS iron stores were found, iron accumulation in the brain was described in patients with MS. Iron deposits were found in the deep gray matter and in the perivascular areas of the white matter of MS patients [72e74]. It was found in some studies that the iron accumulation in brains of patients with MS correlated with the duration of the disease and with
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its activity [75e77]. The iron deposits were found in the following structures: caudate nucleus, putamen, thalamus, globus pallidus and rolandic cortex [75,78]. It is noteworthy that the iron deposits were not found in the structures that are crucial for production of dopamine, such as substantia nigra or A11 area of hypothalamus. Hametner et al. recently found decreased iron load in normally appearing white matter (NAWM) in MS patients with chronic disease and increased iron load at the edges of active MS lesions. The high iron load was found in the area where demyelination and destruction of oligodendrocytes take place [79]. The results of those studies show that iron accumulation is not equally distributed over the MS brain. It has been discovered that some of the cytokines responsible for inflammation in MS, like tumor necrosis factor -a (TNF-a) or interleukin-6 may lead to retention of iron in the activated cells (e.g., astrocytes) [41,80]. This may result in a pathological intracellular accumulation of iron in some of the brain structures, simultaneously leading to local iron deficits in other
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parts of the brain. The intracellular iron deposits may act as an additional factor leading to the destruction of the cell through generation of reactive oxygen species. Results of the above cited studies suggest that alteration of brain iron metabolism caused by the inflammatory process specific for MS has various consequences. First, iron deposits accelerate neurodegeneration and formation of the plaques. Second, local iron deficit (e.g., in NAWM) inhibits remyelination, as iron is necessary for myelination. Third, intracellularly accumulated iron is not available for other metabolic processes within the brain e e.g., production of dopamine. It was discovered recently that RLS is related to decreased myelination in the central nervous system. Connor et al. analyzed postmortem brain tissues from 11 RLS patients and 11 normal controls and found decreased expression of myelin proteins: myelin basic protein (MBP), proteolipid protein (PLP), and 30 50 -cyclic nucleotide phosphohydrolase (CNPase). It was also found in that study that the levels of transferrin and H-ferritin were reduced in
Fig. 1. Hypothetical processes leading to occurrence of restless legs syndrome in multiple sclerosis. NOS: nitric oxide synthase; NO: nitric oxide;TNF-a: tumor necrosis factor alpha; Il-6: interleukine-6; MS: multiple sclerosis; RLS: restless legs syndrome.
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the myelin of RLS patients, suggesting the presence of iron deficiency in the central nervous system. Moreover, the authors found a decrease in the volume of the white matter structures: corpus callosum, anterior cingulum, and white matter surrounding the precentral gyrus in MRI brain scans of 23 RLS patients compared with 23 healthy controls [81]. These findings suggest that iron deficit in CNS is related to disorders of myelination which may lead to appearance of symptoms of RLS. The hypothesis that demyelination in the course of MS leads to the development of RLS remains in concordance with above findings. None of the studies focusing on the prevalence of RLS in MS patients has shown an increased frequency of iron metabolism disorders in RLS-positive MS patients. It must be remembered that all of these studies used only retrospective data, and that laboratory assessment of iron metabolism was not included in any of the protocols of the published studies. The “iron hypothesis” of the pathogenesis of RLS in MS patients must remain a speculation until additional data on iron metabolism in MS patients with RLS is collected. It has been recently found that neuronal nitric oxide synthase (nNOS) is up-regulated in substantia nigra of patients with RLS [82]. This finding remains in line with a previous report showing an association between NOS1 gene and RLS [83]. Those facts suggest another pathological mechanism linking RLS and MS. Nitric oxide (NO) is a well known factor contributing to the pathology of MS and recently it was found to decrease the expression of myelin proteins (MBP, PLP, CNPase and myelin oligodendrocyte glycoprotein (MOG)) in human oligodendrocytes [84]. It is of note that it was the same proteins (with an exception of MOG) that were suppressed in brains of RLS patients examined by Connor et al. [81]. Pathological activity of NOS may lead to demyelination and its symptoms typical for MS, and to decreased myelination described by Connor et al. in patients with RLS. Summarizing the above facts, it may be said that increased frequency of RLS in MS results from few pathological mechanisms that are common for both conditions. The following theory explaining the coexistence of RLS and MS can be coined: the inflammatory process of MS results in increased production of cytokines (Il-6, TNFa) and NO. The cytokines lead to intracellular retention of iron, which is a cause of destruction of the cells and of local deficits of iron in another areas of brain. The lack of available iron disturbs production of dopamine and results in decreased myelination, which in turn is responsible for development of symptoms of RLS. Simultaneously, NO suppresses the expression of myelin proteins which results in demyelination and symptoms of MS and RLS. The theory is shown in Fig. 1. The theory has weak points. There is no specific evidence for disturbances of brain iron metabolism in RLS-positive MS patients. The consequences of iron accumulation in MS and the consequences of cytokine secretion are still not clear. The existence of common pathological pathways for MS and RLS still requires more evidence.
Practice points 1) Restless legs syndrome is more prevalent in patients with MS than in the general population. 2) Clinical significance of RLS in MS patients remains unknown, nevertheless it may be assumed that it decreases the quality of life of the patients. 3) There are no data on efficacy of any specific therapies of RLS in MS
Research agenda 1) Is the course of RLS related to the course of MS? A prospective study that follows MS patients from the moment of diagnosis should be performed, as it would allow the analysis of the relationship between the appearance of RLS and the clinical status of the patients, subtype of MS, and MRI findings. 2) Is RLS influenced by disease-modifying therapies for MS? Data showing that stopping or slowing the progress of the disease with any form of treatment leads to the reduction of RLS would support the hypothesis that MS causes secondary RLS. 3) Is RLS clinically relevant in MS patients? This question requires a prospective study with follow-up of EDSS and of the presence of RLS and its severity, which would allow the assessment of whether the development of RLS causes more severe disability in the patients. 4) Does RLS in MS patients require any specific treatment? The best solution would be comparative blinded studies with various classes of drugs aiming at establishing the most effective first-line treatment for RLS in MS patients.
Conflict of interests The authors have no conflict of interests to declare.
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CLINICAL REVIEW
Restless legs syndrome in multiple sclerosis Mariusz Sieminski a, *, Jacek Losy b, c, Markku Partinen d, e a
Department of Adult Neurology, Medical University of Gdansk, Gdansk, Poland Department of Clinical Neuroimmunology, Chair of Neurology, Poznan University School of Medicine, Poznan, Poland c Neuroimmunlogical Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Poznan, Poland d Helsinki Sleep Clinic, Vitalmed Research Centre, Helsinki, Finland e Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland b
a r t i c l e i n f o
s u m m a r y
Article history: Received 28 June 2014 Received in revised form 2 October 2014 Accepted 3 October 2014 Available online 12 October 2014
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%e65.1%, 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. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Restless legs syndrome Multiple sclerosis Demyelination Iron metabolism
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]. Abbreviations: RLS, restless legs syndrome; PLMS, periodic limb movements in sleep; MS, multiple sclerosis; EDSS, expanded disability status scale; NAWM, normally appearing white matter; sTfR, soluble transferrine receptor; NO, nitric oxide; NOS, nitric oxide synthase; TNF-a, tumor necrosis factor alpha; REMS, The Restless Legs Syndrome in Multiple Sclerosis Study; Il-6, interleukine - 6; CNS, central nervous system; REM, rapid eye movement; MRI, magnetic resonanse imaging; MBP, myelin basic protein; PLP, proteolipid protein; CNPase, cyclic nucleotide phosphohydrolase; MOG, myelin oligodendrocyte glycoprotein; nNOS, neuronal nitric oxide synthase; IRLSS, International Restless Legs Syndrome Severity Scale; IRLSSG, International Restless Legs Syndrome Study Group; FSS, Fatigue Severity Scale. * Corresponding author. Tel.: þ48 606 292 536. E-mail address: [email protected] (M. Sieminski). http://dx.doi.org/10.1016/j.smrv.2014.10.002 1087-0792/© 2014 Elsevier Ltd. All rights reserved.
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 40e90% 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 [7e9]. 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
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Table 1 Clinical features of restless legs syndrome (RLS) (Allen et al., 2003).[1]. Essential diagnostic criteria 1) An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs (sometimes the urge to move is present without the uncomfortable sensations and sometimes the arms or other body parts are involved in addition to the legs) 2) The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting 3) The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues 4) The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night (when symptoms are very severe, the worsening at night may not be noticeable but must have been previously present Supportive clinical features 1) The prevalence of RLS among first-degree relatives of people with RLS is 3e5 times greater than in people without RLS 2) Nearly all people with RLS show at least an initial positive therapeutic response to either L-dopa or a dopamine-receptor agonist 3) Periodic limb movements in sleep occur in at least 85% of cases Associated features 1) When the age of onset of RLS symptoms is less than 50 y, the onset is often more insidious; when the age of onset is greater than 50 y, the symptoms often occur more abruptly and more severely 2) Disturbed sleep is a common major morbidity for RLS 3) The physical examination is generally normal and does not contribute to the diagnosis, except for those conditions that may be comorbid or secondary causes of RLS.
[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 [27,28e37]. 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.
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 history. This pattern was not fully replicated in studies of RLS in MS patients. A significant relationship with the female sex was found in only two studies [28,35] and MS patients with RLS were older than patients without RLS in only five studies [27,28,32,35,37]. Li et al. analyzed the menopausal status of the female patients with MS. The authors found that premenopausal women are at higher risk (OR ¼ 5.08) of developing RLS than postmenopausal women (OR ¼ 2.00). The authors hypothesized that this is a consequence of lower iron levels resulting from menstrual loss of blood [36]. The authors of some of the published papers focused on the prevalence of RLS in the families of MS patients. A positive family history of RLS was found in 2.4%e27.1% of the patients with MS having also RLS [27,28,34,35,37,39], which is significantly less than the occurrence of family history in idiopathic RLS in the general population [6]. The most prominent fact regarding the studies of the occurrence of RLS in MS patients is the wide range of results. There are few reasons for those discrepancies. All groups that performed those studies applied the 2003 diagnostic criteria of RLS proposed by the IRLSSG. Nonetheless the publications differed regarding the mode of application of the criteria. The authors used patient-filled questionnaires, interviews and structured interviews. The highest RLS prevalence rates were found in studies using patient-filled questionnaires. Some symptoms of RLS are difficult to explain in the form of a short question included in a questionnaire. Some symptoms of MS (paraesthesias in the limbs, sensory symptoms as described by Rae-Grant et al. [25] and also spastic symptoms) can resemble the symptoms of RLS. Ideally, the exact nature of the RLS symptoms should be verified in an interview and neurological examination by a physician with experience in RLS. Personal interviews with the patients are preferred to patient filled questionnaires. The patients who participated in the study performed by Deriu et al. filled a questionnaire (which gave a prevalence rate of 45%) and then underwent an interview that reduced the frequency of the diagnosis of RLS to 27% [30]. These results suggest that the application of a self-administered questionnaire may lead to numerous false-positive diagnoses. Also personal
Table 2 Prevalence of RLS in MS patients according to published studies. Publication: First author (year of publication)
Number of MS patients/controls
Method
Prevalence of RLS in MS (%)
Prevalence of RLS in controls (%)
Auger (2005) [26] Manconi (2007) [27] mez-Choco (2007) [38] Go Manconi (2008) [28] Moreira (2008) [29] Deriu (2009) [30] Douay (2009) [33] Aydar (2011) [32] Fragoso (2011) [31] vrov Va a (2012) [35] Li (2012) [36] Miri (2012) [34] Shaygannejad (2013) [37]
200/100 156/135/118 861/649 44/202/212 242/98/129 80/180 765/264/65280 205/126/126
PtQ Int, NeurEx. Int Int, PtQ, PtQ, Int, PtQ Int Int Int PtQ Int PtQ
37.5 32.7 13.3 19 27 14.6 18 27.6 57.5 32 15.5 27.8 65.1
16 NA 9.3 4.2 NA 2.8 NA 10.1 18.3 NA 6.4 NA 12.7
PtQ: patient-filled questionnaire; Int: interview; NeurEx: neurological examination.
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interviews without neurological examinations may give false positive results. Symptoms of RLS may be also misdiagnosed in patients with anxiety and/or depression if anxiety and depression have not been tested properly [40]. Another methodological difference among these studies is the application of a threshold of the frequency of the symptoms. The frequency of symptoms is a reliable marker of the clinical significance and severity of RLS. Including such a threshold in the diagnostic interview reduces the risk of false-positive diagnoses. Some groups applied a threshold of two days with RLS symptoms per week, or more than four days with RLS symptoms per month. In other studies no frequency threshold was used. The restless legs syndrome in multiple sclerosis study (REMS study) performed by Manconi et al., which used a threshold of two days/week, reported a prevalence of 19% [28]and the study performed by Vavrova et al., which did not apply a threshold, reported a prevalence of 32% [35]. The comorbidities that cause secondary RLS or RLS-mimics were excluded in some of the studies. It is noteworthy that the prevalence of RLS was higher in studies without such an exclusion, and that many MS patients suffer from diseases that might cause secondary RLS or RLS-mimics. Auger et al. found that RLS was present in 37.5% of MS patients but almost half of RLS-positive patients had a condition related to RLS [26]. The prevalence of RLS in Turkish MS patients was 27.6%; however over one fifth of them had an RLSrelated comorbidity [32]. The validity of excluding RLS-related comorbidities is disputable. Although this helps determine whether the two diseases are related, it may reduce the overall prevalence of RLS in MS patients. In some patients with MS an idiopathic form of RLS might have developed independently of the demyelinating process. The presence of a positive family history of RLS and the appearance of RLS before the diagnosis of MS may suggest the idiopathic nature of the RLS in these cases. The REMS study reported that 22% of RLSpositive MS subjects had a positive family history of RLS (which represents 4.2% of the whole MS population) and that 13.8% of RLSpositive subjects experienced RLS symptoms before the diagnosis of MS (which represents 2.6% of the whole MS population) [28]. Similar results were obtained in the study performed by Vavrova et al., who reported that 6.4% of MS patients had RLS symptoms before the onset of MS and that 2.4% of MS patients had a positive family history and experienced RLS before the diagnosis of MS [35]. These data allow a crude estimation of the prevalence of idiopathic RLS in MS patients at 2.4e13.5%, which is comparable with prevalence of idiopathic RLS in the general population. It is noteworthy that none of the studies implemented validated diagnostic questionnaires for the diagnosis of RLS, such as the RLS diagnostic index or the John Hopkins telephone questionnaire. Moreover, no additional diagnostic procedure, such as the L-dopa test or the suggested immobilization test were used. The use of those tools might have eliminated false positives and RLS mimics, and thus led to a more precise determination of RLS prevalence. 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 an extensive review [41]. Nevertheless, there are no data on the inflammatory status of RLS-positive patients with MS in the studies published so far. The question whether the intensity of
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autoinflammatory process in MS is related to development of RLS remains to be solved. Some of the studies have reported that patients with RLS had higher scores in the expanded disability status scale (EDSS) [27e29,35,37]. There are a few possible explanations for this observation. The time dispersion between the onset of MS and the onset of RLS suggests that patients with RLS have a longer history of MS. As disability in MS accumulates with time the higher EDSS can be simply the result of the progression of MS. Another explanation is that a more severe course of the disease leading to higher EDSS facilitates the development of RLS. The third explanation is that the pathological process that leads to RLS simultaneously worsens the course of MS. Only one study found a relationship between neuroimaging data and the presence of RLS. Manconi et al. [39] found no significant differences in cerebral lesion load between RLS-positive and RLS-negative MS patients. Moreover, no difference was found in the mean diffusivity and fractional anisotropy of the brain tissues. The basal ganglia of RLS-positive and RLS-negative MS patients did not differ on MRI examination. The number of lesions in the spinal cord was similar in the two groups; however, RLS-positive MS patients had lower fractional anisotropy and a higher fractional histogram peak height in the spinal cord. These data suggest that RLS-positive MS patients suffer from more severe spinal cord degeneration. This finding was recently supported by a study published by Bruno et al. (e-publication, ahead of print). The authors compared RLS-positive and RLS-negative MS patients and found that cervical lesions are significantly more frequent and the number of lesions in the cervical spinal cord is significantly higher in the RLS-positive group [42]. None of the studies found any relationship between lesions in the brain and the presence of RLS symptoms. This finding suggests that the development of RLS symptoms is related to demyelination of the spinal motor and sensory pathways. The relationship between the type of MS and the presence of RLS was analyzed in some of the studies. Manconi et al. performed REMS study [28] and observed a significantly higher prevalence of primary progressive MS in the RLS-positive population and a lower prevalence of relapsing - remitting MS in RLS-positive subjects. A study performed by Douay et al. using a French population of MS patients found that RLS was more prevalent in relapsing e remitting MS [33]. Vavrova et al. found, that in Czech patients, RLS was most prevalent in the secondary progressive type of MS [35]. The question of whether any of the MS subtypes predisposes to the development of RLS remains unanswered, as none of the published studies reached a definite conclusion. There are no data available on the relationship between treatment of MS and prevalence of RLS. There is no study comparing the prevalence of RLS among MS patients receiving disease modifying therapy and among untreated patients. There are no data on temporal relation between initiation of disease modifying therapy of MS and development of RLS. None of the published data allows to suspect that RLS in MS may be an iatrogenic condition secondary to the therapy used. The relationships between RLS and depression, and sleep disturbances and fatigue in MS patients were analyzed in some of the studies. Insomnia was more prevalent in RLS-positive MS patients in the studies performed by Manconi et al. [27] and by Miri et al. [34]. In another study Manconi et al. found that total sleep time was significantly shorter and sleep latency was significantly longer, in RLS-positive patients [28]. Moreira et al. found that MS patients with RLS had higher scores on the Pittsburgh sleep quality index and that the score in the excessive daytime sleepiness scale was higher in RLS-positive MS patients [29]. Manconi et al. found a higher prevalence of daytime sleepiness in RLS-positive subjects [28]. Nevertheless, some studies have shown that the presence of
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RLS does not result in increased daytime sleepiness in MS patients [27,34,36]. Two studies have described a relationship between fatigue and the presence of RLS in MS patients. Moreira et al. found a higher fatigue score on the fatigue severity scale (FSS) in RLSpositive MS patients [29], and Aydar et al. [32] stated that the presence of RLS is related to fatigue, without comments on the direction of that relation. Aydar et al. checked the level of depression in RLS-negative and RLS-positive patients and found that the presence of RLS is related to depression without a more profound description of that relationship [32]. The question of whether RLS has any impact on the presence of fatigue and depression in MS patients deserves further study. None of the studies published to date has focused on the relationship between RLS and the quality of life of patients with MS. Studies performed with the participation of healthy controls allow the comparison of RLS in MS-positive and MS-negative subjects. Auger et al. performed the first study of RLS in MS and found that the symptoms of restless legs are more severe in patients with MS, although the method used to measure the severity of RLS was not published [26]. In an REMS study Manconi et al. used the International RLS severity scale (IRLSS) and found that RLS was more severe in MS patients compared with healthy controls [28]. Aydar at al. and Fragoso et al. also used the IRLSS scale, with a similar result: a higher score on the IRLSSS in MSpositive patients [31,32]. Li et al. found that in MS-positive women severe RLS was more prevalent than it was in MSnegative women [36]. The results described above suggest that RLS in MS patients has a more severe course. Conversely, it must be remembered that the sensory symptoms of MS may overlap with symptoms of RLS, thus leading to a subjective impression of more severe disease.
cases of transverse myelitis [46]. Hartmann et al. described three patients with spinal cord lesion (myelitis due to MS, posttraumatic compression of the cervical spine and cervical spondylotic myelopathy) resulting in symptomatic RLS. What is of special interest, dopaminergic treatment was successful in all of those cases [47]. Telles et al. found presence of RLS and PLMS in all subjects from a series of patients with a complete spinal cord injury [48]. The appearance of RLS and PLMS in patients with spinal cord lesions is supposed to be a result of diminished descending control over the spinal motor and sensory pathways [43]. The efficiency of dopaminergic treatment in RLS and PLMS in patients with focal spinal cord lesions suggests that impaired dopaminergic transmission is responsible for the appearance of the symptoms. The major source of the dopamine for the spinal cord is the area A11 of the hypothalamus [11]. Spinal lesion destroying the descending dopaminergic pathways results in development of the symptoms of RLS or PLMS. Lesion of spinal descending motor pathways leads to rearrangements within spinal central pattern generators which may result in development of PLMS, as it was suggested by Telles et al. [48]. Another consequence of spinal cord lesion is destruction of the ascending sensory pathways. That leads to changes within cortical and subcortical structures responsible for sensory functions as it was shown in animal models and in human subjects [49,50]. This process is responsible for the development of central neuropathic pain in patients after spinal cord injury and may be also involved in generating the sensory symptoms of RLS in patients with spinal cord lesions. The hypothesis that the degeneration of spinal pathways resulting from the demyelination process leads to the appearance of RLS symptoms is plausible. Iron deficit, inflammation and demyelination?
A possible pathological links between RLS and MS 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, genes that are related to development of RLS (BTBD9, MEIS1, PTPRD, MAP2KP/SCOR1) may be present more frequently in the population of MS patients. Vavrova et al. verified this hypothesis by performing a genetic association study in a population of patients with MS. The authors found only a weak relationship between the presence of RLS in MS and a variant of MAP2KP/SCOR1 [35]. As the relationship between the presence of the gene and the development of RLS in MS was very weak, genetic factors do not seem to explain the prevalence of RLS in MS patients. Many authors have suggested that RLS in MS patients is caused by demyelinated lesions localized in areas that are responsible for the development of RLS. These hypotheses are very speculative, as the exact anatomical background of RLS remains unclear. Manconi et al. [39] found that some MRI findings (lower fractional anisotropy and higher fractional histogram peak height) are suggestive of more intense degeneration of the spinal cord in MS patients with RLS. This finding was confirmed recently in a publication by Bruno et al. [42]. Spinal cord lesions are suggested to be an anatomopathological substrate of RLS and PLMS [43]. PLMS were observed in patients with transverse myelopathy [44] and in patients with focal spinal cord lesions [45]. RLS was observed in
RLS is strongly related to iron deficiency, both peripheral and in central nervous system (CNS). Higher prevalence of RLS was found in populations of subjects with iron-deficiency anemia [15], or in blood donors [51]. RLS is also more prevalent in conditions leading to iron deficiency, like end-stage renal disease [52,53] or pregnancy [54,55]. Serum ferritin was found decreased in RLS patients [56]. There is also an evidence for iron deficiency within the CNS. The level of iron and ferritin was decreased in cerebrospinal fluid (CSF) of patients with RLS, compared with CSF of normal controls [57e60]. It was discovered in magnetic resonance imaging studies that brain iron stores are reduced in patients with RLS [61] which was in concordance with results of a study with transcranial ultrasound assessment of substantia nigra of patients with RLS [62]. Data collected in autopsy studies also confirm the decrease of iron stores in brains of patients with RLS [63,64]. It was recently found in animal studies, that iron deficiency leads to alterations in the synthesis of dopamine within the midbrain [65]. Disorders of iron metabolism, peripheral and within the CNS were also discovered in multiple sclerosis. A higher prevalence of iron-deficiency anemia was found in patients with multiple sclerosis [66,67]. Increased level of soluble transferrine receptor (sTfR) was found in serum of patients with MS [68], which was also found in patients with RLS [69]. The increased serum level of sTfR is suggestive of iron deficiency. Iron is necessary for myelination and iron deficiency leads to disordered myelination as it was shown in animal and human studies [70,71]. In contrast to RLS, where decreased CNS iron stores were found, iron accumulation in the brain was described in patients with MS. Iron deposits were found in the deep gray matter and in the perivascular areas of the white matter of MS patients [72e74]. It was found in some studies that the iron accumulation in brains of patients with MS correlated with the duration of the disease and with
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its activity [75e77]. The iron deposits were found in the following structures: caudate nucleus, putamen, thalamus, globus pallidus and rolandic cortex [75,78]. It is noteworthy that the iron deposits were not found in the structures that are crucial for production of dopamine, such as substantia nigra or A11 area of hypothalamus. Hametner et al. recently found decreased iron load in normally appearing white matter (NAWM) in MS patients with chronic disease and increased iron load at the edges of active MS lesions. The high iron load was found in the area where demyelination and destruction of oligodendrocytes take place [79]. The results of those studies show that iron accumulation is not equally distributed over the MS brain. It has been discovered that some of the cytokines responsible for inflammation in MS, like tumor necrosis factor -a (TNF-a) or interleukin-6 may lead to retention of iron in the activated cells (e.g., astrocytes) [41,80]. This may result in a pathological intracellular accumulation of iron in some of the brain structures, simultaneously leading to local iron deficits in other
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parts of the brain. The intracellular iron deposits may act as an additional factor leading to the destruction of the cell through generation of reactive oxygen species. Results of the above cited studies suggest that alteration of brain iron metabolism caused by the inflammatory process specific for MS has various consequences. First, iron deposits accelerate neurodegeneration and formation of the plaques. Second, local iron deficit (e.g., in NAWM) inhibits remyelination, as iron is necessary for myelination. Third, intracellularly accumulated iron is not available for other metabolic processes within the brain e e.g., production of dopamine. It was discovered recently that RLS is related to decreased myelination in the central nervous system. Connor et al. analyzed postmortem brain tissues from 11 RLS patients and 11 normal controls and found decreased expression of myelin proteins: myelin basic protein (MBP), proteolipid protein (PLP), and 30 50 -cyclic nucleotide phosphohydrolase (CNPase). It was also found in that study that the levels of transferrin and H-ferritin were reduced in
Fig. 1. Hypothetical processes leading to occurrence of restless legs syndrome in multiple sclerosis. NOS: nitric oxide synthase; NO: nitric oxide;TNF-a: tumor necrosis factor alpha; Il-6: interleukine-6; MS: multiple sclerosis; RLS: restless legs syndrome.
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M. Sieminski et al. / Sleep Medicine Reviews 22 (2015) 15e22
the myelin of RLS patients, suggesting the presence of iron deficiency in the central nervous system. Moreover, the authors found a decrease in the volume of the white matter structures: corpus callosum, anterior cingulum, and white matter surrounding the precentral gyrus in MRI brain scans of 23 RLS patients compared with 23 healthy controls [81]. These findings suggest that iron deficit in CNS is related to disorders of myelination which may lead to appearance of symptoms of RLS. The hypothesis that demyelination in the course of MS leads to the development of RLS remains in concordance with above findings. None of the studies focusing on the prevalence of RLS in MS patients has shown an increased frequency of iron metabolism disorders in RLS-positive MS patients. It must be remembered that all of these studies used only retrospective data, and that laboratory assessment of iron metabolism was not included in any of the protocols of the published studies. The “iron hypothesis” of the pathogenesis of RLS in MS patients must remain a speculation until additional data on iron metabolism in MS patients with RLS is collected. It has been recently found that neuronal nitric oxide synthase (nNOS) is up-regulated in substantia nigra of patients with RLS [82]. This finding remains in line with a previous report showing an association between NOS1 gene and RLS [83]. Those facts suggest another pathological mechanism linking RLS and MS. Nitric oxide (NO) is a well known factor contributing to the pathology of MS and recently it was found to decrease the expression of myelin proteins (MBP, PLP, CNPase and myelin oligodendrocyte glycoprotein (MOG)) in human oligodendrocytes [84]. It is of note that it was the same proteins (with an exception of MOG) that were suppressed in brains of RLS patients examined by Connor et al. [81]. Pathological activity of NOS may lead to demyelination and its symptoms typical for MS, and to decreased myelination described by Connor et al. in patients with RLS. Summarizing the above facts, it may be said that increased frequency of RLS in MS results from few pathological mechanisms that are common for both conditions. The following theory explaining the coexistence of RLS and MS can be coined: the inflammatory process of MS results in increased production of cytokines (Il-6, TNFa) and NO. The cytokines lead to intracellular retention of iron, which is a cause of destruction of the cells and of local deficits of iron in another areas of brain. The lack of available iron disturbs production of dopamine and results in decreased myelination, which in turn is responsible for development of symptoms of RLS. Simultaneously, NO suppresses the expression of myelin proteins which results in demyelination and symptoms of MS and RLS. The theory is shown in Fig. 1. The theory has weak points. There is no specific evidence for disturbances of brain iron metabolism in RLS-positive MS patients. The consequences of iron accumulation in MS and the consequences of cytokine secretion are still not clear. The existence of common pathological pathways for MS and RLS still requires more evidence.
Practice points 1) Restless legs syndrome is more prevalent in patients with MS than in the general population. 2) Clinical significance of RLS in MS patients remains unknown, nevertheless it may be assumed that it decreases the quality of life of the patients. 3) There are no data on efficacy of any specific therapies of RLS in MS
Research agenda 1) Is the course of RLS related to the course of MS? A prospective study that follows MS patients from the moment of diagnosis should be performed, as it would allow the analysis of the relationship between the appearance of RLS and the clinical status of the patients, subtype of MS, and MRI findings. 2) Is RLS influenced by disease-modifying therapies for MS? Data showing that stopping or slowing the progress of the disease with any form of treatment leads to the reduction of RLS would support the hypothesis that MS causes secondary RLS. 3) Is RLS clinically relevant in MS patients? This question requires a prospective study with follow-up of EDSS and of the presence of RLS and its severity, which would allow the assessment of whether the development of RLS causes more severe disability in the patients. 4) Does RLS in MS patients require any specific treatment? The best solution would be comparative blinded studies with various classes of drugs aiming at establishing the most effective first-line treatment for RLS in MS patients.
Conflict of interests The authors have no conflict of interests to declare.
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