Risk Factors and Treatment of Restless Legs Syndrome in Adults

Chapter 11
Risk Factors and Treatment of
Restless Legs Syndrome in Adults
John A. Gjevre and Regina M. Taylor-Gjevre
Department of Medicine University of Saskatchewan,
Canada

 

Sleep Disorders

Edited by Chris Idzikowski, ISBN 978-953-51-0293-9, 202 pages, Publisher: InTech, Chapters published March 14, 2012 under CC BY 3.0 license
DOI: 10.5772/1500
Edited Volume

1. Introduction
Restless legs syndrome (RLS) is a common clinical entity consisting of an uncomfortable
sensation in one’s legs and irresistible urge or desire to move them usually occurring in the
evening. This syndrome has been sub optimally diagnosed in the past and remains overall
misunderstood and under-recognized by many primary health care providers. However,
RLS is increasingly recognized to cause significant disease burden and decreased quality of
life (Kushida C et al., 2007). The initial modern clinical description was published by Ekbom
in 1945 but was largely ignored until the late 1980s when there was a resurgence of interest
in RLS (Walters AS & Hening W, 1987). Because of ongoing clinical confusion and the need
for more clear epidemiologic assessment, a research group was organized in 1995 and the
original IRLSSG criteria were developed (Walters AS, et al., 1995). In 2003, the International
Restless Legs Syndrome Study Group (IRLSSG) issued revised guidelines to assist in clinical
diagnosis and research of RLS (Allen RP et al., 2003).

2. RLS description and diagnosis

RLS is described by the RLS foundation as a neurological condition that is characterized by
the irresistible urge to move the legs. Patients will describe an uncomfortable itching or
“creepy-crawling” sensation on the legs in the evenings and report that it feels like “bugs
crawling under the skin.” The IRLSSG has listed 4 essential criteria to clinically diagnose
RLS. Physical examination is usually normal. There is no single test used which will make
the diagnosis although many patients suffer from iron deficiency with low ferritin levels.
While overnight polysomnography (PSG) in a sleep laboratory is helpful to assess periodic
limb movements of sleep (PLMS), a PSG is not necessary to make the clinical diagnosis of
RLS. PLMS are defined as a repetitive or periodic bursts of leg (or arm) electromyographic
(EMG) activity during sleep associated with discrete, stereotypical movements of the legs or
arms. PLMS are felt to be a related but separate disease from RLS. Although most (80%)
patients with RLS with have PLMS on PSG testing, approximately 12-20% of RLS patients
will not have evidence for PLMS (Montplaisir J et al., 1997). Approximately 30% of patients
with PLMS will have RLS symptoms. The revised 2003 IRLSSG essential criteria include 1)
An urge to move the legs accompanied or caused by uncomfortable sensations in the legs, 2)
The urge to move or unpleasant sensations beginning or worsening during periods or rest
or inactivity such as lying or sitting, 3) The urge to move or unpleasant sensations are
partially or totally relieved by movements such as walking or stretching, at least as long as
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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 (Allen RP et al.,
2003). Despite these revised guidelines, there are still difficulties in excluding mimics such
as leg cramps that can confound the diagnosis and the specificity of the 4 diagnostic criteria
is 84% (Hening WA et al., 2009). It has been suggested that the validated self-completed
Cambridge-Hopkins RLS questionnaire (CH-RLSq) is more useful with a sensitivity of
87.2% and a specificity of 94.4%. (Allen RP et al., 2008). In addition to the diagnostic criteria,
the IRLSSG developed a validated, patient-completed 10 item severity rating scale called the
IRLS severity scale or IRLSSS (Walters AS et al., 2003).

3. RLS prevalence

RLS has been mainly studied in North America and Europe and appears to have a
prevalence of 5 to 15% with up to a 2:1 female ratio (Berger K et al., 2004, Phillips B et al.,
2000). Prevalence is markedly higher in certain groups such as Icelandic women where RLS
prevalence was found to be 24.4% (Benediktsdottir B et al., 2010). Of interest, the increased
risk of RLS in women appears to be linked to parity with an increased risk of RLS directly
proportional to the number of children (Berger K et al. 2004). In contrast, nulliparous
women have the identical risk of RLS as men the same age. While, most of the epidemiology
of RLS has been researched in Europe and North America, there are studies from other
areas. Research from Asia appear to yield lower prevalence rates. (Chen NH et al., 2010).
Overall, the prevalence of RLS appears to be higher in North American/European
populations, especially in women.

4. RLS pathogenesis

The scientific basis of RLS remains unclear but appears to be related in part to the
dopaminergic pathways and iron metabolism in the substantia nigra. In 2003, Connor et.
al. published an autopsy-based study suggesting that the cause of RLS was related to a
defect in the regulation of transferrin receptors in the brain (Connor JR, et al., 2003). In
addition, MRI, PET, and SPECT imaging studies have likewise shown alterations in the
dopaminergic receptors of the brain (Michaud M et al., 2002). Recently, further evidence
has accumulated to support that there is a primary iron insufficiency leading to an overly
activated dopaminergic system (Connor JR et al., 2009, Quiroz C et al., 2010). Low iron
levels can increase extracellular dopamine and decrease D2 receptors (Earley CJ et al.,
2011). Thus, overall the pathophysiologic basis of RLS is not fully understood but there is
increasing evidence of iron deficiency related dopaminergic abnormalities. In addition to
dopamine and iron physiology, there are clear familial clusterings and genetic linkages. In
2007, researchers in Iceland reported on the first genetic variant associated with a
susceptibility to periodic limb movements of sleep (Stefansson H et al., 2007). A total of 4
main genetic variants have since been discovered which account for approximately 80% of
primary RLS.

5. Primary RLS

RLS is divided into two main categories which are primary (idiopathic) RLS and secondary
RLS. Patients with primary RLS tend to have onset at an earlier age, often under age 45. In
addition, there is a significantly higher family history of RLS (Allen RP & Earley CJ, 2000).
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6. Clinical associations with RLS or secondary RLS
6.1 RLS and multiple sclerosis
After an initial 2002 meeting presentation where data from 100 multiple sclerosis (MS)
patients with a prevalence of RLS of 32%was described, Auger et al reported a prevalence of
37.5% in their 200 French-Canadian MS patients meeting the 2003 IRRLSG criteria.
Interestingly, in their patient population, more women than men met RLS criteria and 30%
of patients reported that RLS symptoms started or worsened during pregnancy. A positive
family history for RLS was reported by 36% of these French-Canadian patients meeting RLS
criteria. They speculated whether MS plaque formation and involvement in the basal
ganglia may be pathogenic for RLS in these patients. This concept may be supported by the
therapeutic effect of dopaminergic therapeutic agents. The concept of potential common
susceptibility genes for both MS and RLS is raised by the authors (Auger C et al, 2005). The
following year, Kilfoyle et al reported a myelin protein zero (MPZ) mutation which was
associated in the individuals studied with various neurological manifestations including
RLS and MS (Kifoyle DH, et al, 2006).
In 2007, Manconi et al examined prevalence of RLS in an Italian population of MS patients.
In this population of 156 patients, 100 were female and a prevalence of 32.7% was found
who met the 2003 IRRLSG diagnostic criteria. However, in contrast to the French-Canadian
population, a positive family history for RLS was only reported by 5% of the (total)
population. In the majority of these patients (> 90%), RLS symptoms followed or were
simultaneous in onset with MS clinical features onset. The authors speculate that the coexistence
of MS and RLS may be the result of a particular lesional pattern (Manconi et al,
2007). In a subsequent study of 82 MS patients of whom 30 patients had co-existing RLS,
brain and cervical spinal cord MRIs were done. The MS and RLS patients were observed to
have a greater degree of cervical cord involvement than those MS patients without RLS. The
authors state that cervical cord damage represents a significant risk factor for RLS in MS
patients (Manconi et al, 2008).
The Italian REMS Study Group, published the ‘REstless legs syndrome in Multiple Sclerosis’
or REMS study in 2008 in the journal SLEEP. This group reported a prospective, multicenter
case-control epidemiologic survey which involved 20 sleep centers certified by the Italian
Association of Sleep Medicine and included 861 MS patients and 649 control patients. They
reported a 19% prevalence of RLS, using the IRRLSG criteria, in the MS patients compared
to a 4.2% in the control population. This provided a relative risk for RLS in the MS patients
of 5.4. Risk factors associated with RLS in the MS patients were identified as older age,
longer duration of MS, the primary progressive form of MS, higher global, pyramidal, and
sensory disability and the presence of leg jerks before sleep onset. Additionally, RLS
symptom severity was reported to be worse in the MS patient group compared to symptoms
of control group patients with RLS. The authors comment that their results strengthen the
hypothesis that MS inflammatory lesions may induce a secondary form of RLS (The Italian
REMS Study Group, 2008).
In a study of French patients with MS by Douay et al, the authors report a prospective
evaluation of 242 MS patients and found 18% met the international RLS criteria, consistent
with the REMS study report. In this French population, the authors reported RLS symptoms
to be more frequent in patients with the relapsing-remitting form of MS (Douay et al. 2009).
A Brazilian study of 44 MS patients reported by Moreira et al, found 27% of their patients
met the RLS criteria. The authors did not observe any association of specific patient
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characteristics associated with the presence of RLS compared to those MS patients not
meeting RLS criteria, in this small prevalence study (Moreira et al, 2008).
Deriu et al published a case-control study of Italian MS patients. The authors enrolled 202
MS patients and 212 age and gender matched healthy controls. Interestingly, 45% of the MS
patients met the IRRLSG diagnostic criteria for RLS, however, after neurologic review and
examination of the each patient who responded positively to the questionnaire instrument,
only 14.6% of the MS patients were felt to truly have a diagnosis of RLS. In the control
group, 16.03% were positive responders to the questionnaire criteria, but only 2.8% had a
final diagnosis of RLS following neurologic review and examination. The authors comment
on the high false positive number of questionnaire responders (Deriu et al, 2009).
In summary, there is evidence of an increased prevalence of RLS in the MS population.
Several interesting possibilities have been suggested to explain this association. The weight
of evidence seems to support the concept of a secondary RLS likely arising from strategic
geographic involvement of demyelinating lesions.
6.2 RLS and other neurologic disorders
Peripheral neuropathy has also been associated with RLS. A recent case-control study (Hattan
E et al 2009) in a Quebec population examined 245 patients with a diagnosis of peripheral
neuropathy and 245 age and gender matched controls. The authors considered a positive
response to three of the four essential criteria to be ‘screen-positive’. All ‘screen-positive’
patients were subsequently evaluated by a blinded movement disorders specialist. Of the 245
peripheral neuropathy patients, 26.5% were ‘screen-positive’, compared to 10.2% of controls.
Confirmation by neurologist, however, revealed only 46% of the ‘screen-positive’ peripheral
neuropathy patients were felt to truly have a diagnosis of RLS compared to 80% of the ‘screenpositive’
control patients. After this diagnostic confirmation, the overall prevalence of RLS did
not differ between the peripheral neuropathy patients and the control group.
The prevalence of RLS was evaluated in a cohort of 99 Italian patients with acquired diabetic
peripheral neuropathy (Gemignani et al, 2007). Using IRRLSG diagnostic criteria, RLS was
found to be present in a third of the patients in this study population (33/99). The authors
reported that of the various forms of diabetic neuropathy represented within this
population, small fiber sensory neuropathy was more common than other forms. A
prominent symptom associated with RLS was ‘burning feet’. The authors suggest that RLS
may be triggered peripherally by abnormal sensory inputs from small fibers.
A case series of 12 patients with essential mixed cryoglobulinemia and associated peripheral
neuropathy reported a frequency of RLS, using pre-2003 diagnostic measures, of one third
(4/12) (Gemignani et al, 1997).
A recent report (Bachmann CG et al 2010) suggest response to specific stimuli may be able to
distinguish between primary RLS and RLS secondary to small fiber neuropathy. In this
study of 21 primary RLS patients and 13 patients with secondary RLS related to small fiber
neuropathy, the authors describe thermal hypoesthesia to cold and warm in those with
secondary RLS compared to both the primary RLS study patients and controls. They also
suggest support for the RLS pathogenesis concept of central disinhibition of nociceptive
pathways which might be induced by conditioning afferent input from damaged small fiber
neurons in secondary RLS.
Restless legs syndrome has been reported as increased in prevalence in German hereditary
spastic paresis patients (Sperfeld AD, et al, 2007) and in Argentinian patients with Fabry’s
disease (Dominguez RO, et al, 2007). RLS has also been reported to be present in 18.1% of
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227 Charcot-Marie Tooth disease patients compared to 234 controls with a 5.6% prevalence.
RLS severity was correlated with worse sleep quality and reduced health-related quality of
life measures. Variation in prevalence was not observed between subtypes of Charcot-Marie
Tooth disease, but women were more severely affected by RLS than male patients (Boentert
M, et al 2010). A series of 28 patients with Friedreich’s Ataxia were surveyed for prevalence
of RLS with 32% meeting diagnostic criteria (Synofzik M et al, 2011). In a population of 28
chronic inflammatory demyelinating polyneuropathy (CIDP), a prevalence of 39.3% for RLS
was found, compared to 7.1% prevalence in age and gender matched control patients.
Isolated case reports of RLS symptomatology following development of
hyperparathyroidism (Agarwal P et al, 2008), administration of interferon therapy
(LaRochelle JS, et al, 2004), development of multifocal motor neuropathy (Lo Coco D, et al,
2009), and Guillain-Barré syndrome have been reported (Marin LF, et al, 2010). Additionally,
a case report has been published reporting a patient who experienced remission of severe
RLS following excision of multiple foot neuromata (Lettau LA, et al 2010).
The question has also been raised as to whether RLS in seen in a higher prevalence in
patients with Parkinson’s Disease. This has been addressed in an Italian population of 118
Parkinson’s Disease outpatients using a case-control study design. The authors report a
failure to demonstrate increased prevalence of RLS in the Parkinson’s patients in
comparison to age and gender matched control patients. They further acknowledge the RLS
prevalence assessment may be impeded by the concurrent treatment of Parkinson’s Disease
with dopaminomimetic drugs, which may also be expected to impact on RLS
symptomatology (Calzetti et al, 2009). Another study from the Netherlands in 269 nondemented
Parkinson’s Disease patients, found RLS to be present in 11% of patients. RLS
severity was noted to correlate positively with Parkinson’s Disease severity. RLS was also
significantly more common in male patients than female. The authors note the similar
prevalence of RLS in their study population to the general population and submit that this
could potentially relate to concurrent dopaminergic therapy. They also suggest that in view
of the relationship of severity of RLS to severity of Parkinson’s Disease related primarily
non-dopaminergic symptoms, that non-dopaminergic systems may play a role in any
potential relationship between RLS and Parkinson’s Disease (Verbaan D, et al, 2010).
In a reverse style of assessment, 23,119 participants in the Health Professional Follow-up study
who were free of diabetes and arthritis were surveyed. The IRRLSG diagnostic criteria were
applied and concurrent diagnoses of Parkinson’s Disease were investigated. The adjusted
odds ratios for Parkinson’s Disease in men with RLS symptoms with frequency from 5-14
times per month was 1.1, and in those with a frequency of RLS of 15 or more times per month
the odds ratio was higher at 3.09. The authors concluded that men with RLS symptomatology
were more likely to have concurrent Parkinson’s Disease (Gao X, et al, 2010).
6.3 RLS and pregnancy
Lower extremity symptoms consistent with RLS have been reported in pregnancy. In a
study of 642 pregnant Italian women, data was collected around the time of delivery and at
follow-up evaluation up to six month post-delivery. Patients were screened with the
IRRLSG diagnostic criteria. The authors reported that 26% of women acknowledged
symptoms of RLS during their pregnancy. It was most strongly related to the last trimester
of the pregnancy and tended to disappear around the time of delivery. The authors
concluded that pregnancy was associated with transient RLS. They did also observe that
women with RLS symptoms had lower hemoglobin levels and MCV compared to healthy
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subjects. (Manconi M et al, 2004). An American study of 189 nulliparous women who were
enrolled between six and 20 weeks of gestation and were followed up in the third trimester,
reported an increase in patients meeting RLS criteria from 17.5% at enrollment up to 31.2%
in the third trimester (Facco FL, et al, 2010).
In a questionnaire study of female members of the French Association of Patients with RLS,
Ghorayeb et al applied both the International RLS Severity Scale (IRLSSS) and a
questionnaire addressing reproductive behaviour and RLS history. Interestingly, women
who had had a pregnancy showed a higher mean IRLSSS score than women who had never
had a child. Worsening of symptoms during pregnancy were reported by 23% of patients,
29% of non-menopausal women reported increased severity of RLS symptoms during
menses, and 69% of women reported worsening of symptoms following menopause
(Ghorayeb I, et al, 2008). An Australian case-control study of pregnant women
demonstrated a RLS prevalence of 22.5% of 211 women. A positive family history of RLS
and of ‘growing pains’, as well as a personal childhood history of ‘growing pains’ were
associated with meeting RLS criteria in this study population (Balendran et al 2011).
In a Turkish study of 146 pregnant women, 38 were diagnosed with RLS. The authors report
lower hemoglobin levels to be a risk factor for RLS in pregnancy (Tunc et al 2007). In a study
of pregnant women in Pakistan, 81 of 271 women met diagnostic criteria for RLS. The
authors reported anemia and a positive family history of RLS to be predictive for
development of de novo RLS, whereas, a positive family history for RLS and multiparity
were predictors for pre-existing RLS with odds ratios of 12.39 and 6.84 respectively
(Sikandar R, et al, 2009). A previous pregnancy was also identified by Pantaleo NP et al as a
significant risk factor for RLS in a re-analysis of data from a prior RLS study. They observed
that in family members of RLS probands, the prevalence of RLS was significantly higher for
parous women (49.5%) than for nulliparous women (33.7%) or for men (30%). These
differences were not observed in control proband family members. The authors suggest that
in patients with a positive family history of RLS, pregnancy has a major influence on the risk
of developing RLS (Pantaleo NP, et al, 2010).
Examining hormonal influences on RLS, Dzaja et al, studied 10 pregnant German women
with RLS and nine healthy pregnant controls. Blood hormone levels of estradiol were
higher in patients with RLS than in control patients. The authors suggest estrogens may
contribute via a pathophysiological mechanism to triggering of RLS symptoms during
pregnancy (Dzaja A, et al, 2009).
Neau et al, in a cross-sectional questionnaire study of 1.022 pregnant French women from a
single town, screened for RLS using IRRLSG criteria. They found 24% of these women to be
affected by RLS during their pregnancy. The symptoms of RLS were strongly related to the
third trimester of the pregnancy. In a follow-up study of a smaller number of patients, the
authors report resolution of RLS symptoms within a short time interval following delivery
in the majority of women (Neau JP et al, 2010a, Neau JP et al, 2010b). A follow-up study of
RLS in pregnant Italian women performed after a mean lapse of 6.5 years, reported on 74
women with pregnancy associated RLS and 133 women who did not have RLS symptoms
during their pregnancy. During the time between the original study and this follow-up
investigation, the prevalence of RLS had increased to 56% person/year in women who had
experienced RLS symptoms transiently during their pregnancy and 12.6% person/year in
subjects who had not been troubled with RLS symptoms during pregnancy. The authors
conclude the transient pregnancy RLS form to be a significant risk factor for development of
a future chronic form of RLS (Cesnick et al, 2010).
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6.4 RLS and renal disease

Renal disease has been associated with RLS symptomatology. A recent hospital based study
of 301 patients, revealed a prevalence for meeting RLS criteria of 18.3%. Multivariate
analysis identified iron deficiency and chronic renal disease to be independent predictors for
RLS in this population (Quinn C et al, 2011). In a Japanese study of 490 uremic patients on
hemodialysis (HD), 12.2% were found to meet criteria for RLS. The authors found a
relationship between RLS, anxiety, anemia and high serum phosphorus level. They failed to
find evidence of previously identified risk factors including relationship to gender, longer
duration of HD therapy, frequency of HD sessions, and smoking (Takaki J et al, 2003). The
significance of an elevated serum phosphorus in RLS is unclear.
A lower frequency of RLS was observed in an Indian study of 121 HD patients and 99
controls, where only 6.6% of HD patients and 0% of controls met RLS criteria. Nerve
conduction studies conducted on RLS patients found the majority to have evidence of
sensori-motor neuropathy (Bhowmik D, et al, 2003). Another prevalence study in Brazil in
176 HD patients observed a prevalence of RLS of 14.8% (Goffredo et al, 2003). A similar
prevalence was established in 894 dialysis patients participating in the CHOICES (Choices
for Healthy Outcomes In Caring for End Stage renal disease) study, where a prevalence of
15% for ‘severe’ RLS was observed. Age and diabetes were positive predictors for RLS in
this population. The authors also report an increase in the adjusted mortality hazard ratio of
1.39 in patients with severe RLS. Reduced quality of life measures in these patients was also
observed (Unruh ML, et al, 2004). In a small study from the Netherlands, 48 patients with
renal disease and RLS were studied by polysomnogram (PSG) and questionnaire. A
prevalence of 58.3% for meeting RLS criteria was observed. In addition the authors report
nearly all RLS patients had evidence of severe periodic limb movement disorder on PSG
(Riisman RM, et al, 2004). Examining a population who were not yet dialysis dependent,
Merlino et al enrolled 138 chronic renal failure patients and 151 controls. RLS criteria were
met by 10.9% of the chronic renal failure group and 3.3% of the control population. An
association with iron deficiency and female gender was observed (Merlino et al, 2005).
6.5 RLS and rheumatic diseases
In the rheumatoid arthritis (RA) patient population, increased prevalence of RLS has been
reported by several investigators. Reynolds et al studied hospitalized RA patients
employing a ‘control’ group of osteoarthritis (OA) patients, and found a 30% prevalence of
RLS in RA compared to 3% in OA (Reynolds G et al, 1986). A subsequent study again
comparing RA and OA found comparable prevalence rates for RLS of 25% in RA and 4% in
OA (Salih AM, et al, 2004). Auger et al in their study of MS patients employed a RA patient
group for contrast, finding a prevalence rate for RLS of 31% in their RA group (Auger C, et
al, 2005). A more recent study employing the 2003 IRRLSG criteria for RLS found a
prevalence of RLS of 27.7% in RA and a prevalence of 24.4% in OA patients (Taylor-Gjevre,
et al, 2009). Increased frequency of RLS has also been reported in other rheumatic disease
populations, including Sjogren’s Syndrome, scleroderma and fibromyalgia patients (Taylor-
Gjevre, et al, 2011). A recent study of RLS in Systemic Lupus Erythematosus patients has
also suggested an increased prevalence in that population (Hassan N, et al, 2011).
6.6 RLS and Iron deficiency
An increased prevalence of anemia or iron deficiency has been observed in many RLS patient
populations. Treatment with iron supplementation has been efficacious in many cases of RLS
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in patients with low serum ferritin levels. This is discussed in greater depth in the treatment
section of this chapter. Consistent with these observations, there has been an increased
prevalence of RLS in patients with celiac disease, a disorder with associated abnormal iron
absorption (Moccia M, et al, 2010) and as mentioned previously in this chapter, many instances
of secondary RLS appear to be also associated with anemia or low iron status.
There have been several studies assessing prevalence of RLS in regular blood donors. A
large Swedish study of 946 consecutive blood donors, aged 18-64, who were evaluated for
RLS, found a gender difference in prevalence. In male blood donors 14.7% met RLS criteria,
in female donors the frequency increased to 24.7%. Further, in patients with laboratory
evidence consistent with iron-deficiency, the frequency of RLS increased to 37.5%. The
authors conclude RLS to be common amongst female blood donors (Ulfberg J, et al, 2004).
Conversely, in an American study of 144 blood donors, only a 4% prevalence of definite RLS
was appreciated. The authors comment that their relatively small sample size may influence
their results (Arunthari V, et al, 2010).
From a pathologic viewpoint, decreased iron content has been observed in the substantia
nigra which is felt to contribute to the pathophysiology of RLS (Synder AM, et al, 2009). In a
recent study, Connor et al examined expression of iron management proteins in proximity
to the blood-brain interface in brains from eleven RLS patients and in 14 control brains. The
authors report a significant decrease in heavy chain ferritin, transferrin and it’s receptor in
the microvessels in RLS patients compared to controls. Additionally, activity of an iron
regulatory protein was observed to be diminished in the RLS patients compared to controls.
These relative differences between brains from RLS patients and control patients suggest
fundamental differences in brain iron acquisition in RLS patients (Connor JR, et al, 2011)
7. Treatment options for RLS
Historically, there were a variety of treatments for RLS ranging from bloodletting to opiates.
Indeed, Sir Thomas Willis over 325 years ago described the first probable case of RLS and
used opium to alleviate the symptoms. When RLS was “rediscovered” by researchers in the
1980s, once again opioid narcotics were the treatment of choice (Hening WA, et al. 1986). In
that study, five patients with RLS were given opioid drugs which relieved their awake RLS
symptoms as well as PLMs and sleep disturbance. When counteracted with intravenous
naloxone, the RLS symptoms and findings returned leading the authors to speculate on the
endogenous opiate system playing a role in RLS pathogenesis. However, with increasing
research in the last two decades, it has become clear that the underlying pathology of RLS is
largely due to alternations in dopaminergic pathways. This has lead to the use of both nonspecific
and specific dopamine receptor agents.
7.1 Pharmacological treatments for RLS
7.1.1 Iron replacement therapy
While Ekbom did recognize the possible role of iron therapy in RLS, it was not until 1994
when O’Keeffe in Dublin did the first clinical trial of iron replacement therapy. In that study
of 18 elderly patients with 18 matched controls, iron status and RLS response to iron therapy
was observed. The researchers found that serum ferritin levels were reduced in RLS subjects
compared to the control group and that levels were inversely correlated to the severity of
RLS symptomatology. In the 15 RLS patients treated with iron replacement therapy for 2
months, there was a significant improvement in RLS symptoms (O’Keeffe ST, 1994). In a
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recent double-blinded, placebo-controlled study, Wang and colleagues showed the benefit
of iron replacement in RLS patients with low serum ferritin. In this study, 373 patients were
screened and 157 (42%) met the 2003 IRLSSG criteria for RLS. Of these, there were only 18
patients who consented to participate and met the inclusion criteria (which included having
a low-normal serum ferritin between 15-75 ng/ml). Eleven patients were randomized to iron
replacement (ferrous sulfate 325mg po bid) and 7 to placebo for 12 weeks and IRLS scores
were obtained at the start and end of the study. The researchers found a clinically significant
(p = 0.01) improvement in IRLS scores in the iron therapy group and a non-significant (p =
0.07) trend towards improvement in quality of life (Wang J, 2009).
7.1.2 Dopamine precursors
Dopamine is a catecholamine which acts as a neurotransmitter but cannot cross the bloodbrain
barrier. Levodopa (L-DOPA) is a precursor to dopamine (as well as norepinephrine
and epinephrine) and can cross the blood-brain barrier. Once in the brain, L-DOPA is
converted by DOPA decarboxylase to dopamine which can act on the dopamine receptors to
treat RLS. However, because peripheral L-DOPA is also converted to dopamine leading to
adverse effects, L-DOPA is usually given with a peripheral DOPA decarboxylase inhibitor
(usually carbidopa). There is a large body of evidence supporting the effectiveness of LDOPA
in RLS. One of earliest randomized trials was done in the USA and published in
1993. This study was a randomized, double-blind, placebo-controlled, cross-over design trial
evaluating carbidopa/levodopa with proproxyphene and placebo. The primary outcome
was PSG measurements and sleep latency tests. The researchers found that
carbidopa/levodopa normalized the PLMs and improved sleep, especially in the first 3
hours of sleep (Kaplan PW et al., 1993). However, it soon became apparent that
carbidopa/levodopa had a serious drawback in regards to augmentation or rebound of RLS
symptoms the following morning and/or early afternoon. In a report from 1996, Allen and
colleagues prospectively evaluated 46 consecutive patients being treated with
carbidopa/levodopa. They found that 82% of RLS patients and 31% of PLMS patients
experienced augmentation problems and this was severe enough to lead to medication
changes in 50% of the RLS patients (Allen RP, Earley CJ, 1996). Because of augmentation
issues, other researchers have evaluated using sustained-release L-DOPA preparations.
Trenkwalder and colleagues did an open-label extension trial of an earlier double-blinded,
cross-over study evaluating standard and sustained-release L-DOPA. In this 1 year trial they
found that 60% of patients discontinued therapy due to aggravating daytime symptoms
(Trenkwalder C et al., 2003). In a 2006 review, Paulus & Trenkwalder examined the world
literature and concluded that augmentation is a result of severely increased dopamine
concentration in the CNS and that overstimulation of the D1 receptors compared to the D2
receptors in the spinal cord may cause discomfort and PLMS. Also, iron deficiency may be a
significant predisposing factor for the development of augmentation. The researchers
concluded that therapy with L-DOPA or dopamine agonist should endeavour to be lowdose
and that iron replacement and/or opiates are the therapies of choice to use with
augmentation (Paulus W & Trenkwalder C, 2006). In summary, L-DOPA is a widely
available and inexpensive therapy for RLS which has been shown in numerous studies to be
beneficial in improving objective PSG findings as well as subjective measures of sleep and
RLS symptoms. Unfortunately, there are problems particularly linked to L-DOPA with next
morning augmentation of RLS symptoms. This does impair the usefulness of L-DOPA
especially when there are newer effective dopamine agonists with a better side effect profile.
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7.1.3 Ergot-derived dopamine agonists
Ergotamine is related to ergot alkaloids and is structurally similar to several neurotransmitters
including dopamine. Ergotamine derivatives include bromocriptine, pergolide, and
cabergoline. It most be noted that all ergot derivatives have been associated with cardiac valve
disease. In a recent Italian study, researchers found that patients taking pergolide or
cabergoline had a relative risk of 4.2 to 6.3 for valve regurgitation compared to patients using
non-ergot dopamine agonists and controls (Zanettini R, 2007). Thus it is recommended to
conduct close cardiac monitoring in patients on ergot-derived dopamine agonists.
Bromocriptine is an ergot-derivative dopamine agonist that preferentially acts on the D2
dopamine receptor. It has traditionally been used in the treatment of pituitary tumors and
Parkinson Disease but has been tried for RLS with some efficacy. In a small, double-blinded,
randomized crossover study, researchers found that 83% of patients had partial subjective
improvement in RLS symptoms but no significant change in PLMD by PSG (Walters AS,
1988). A more recent study from Europe compared bromocriptine to pramipexole (a
preferential D3 receptor agonist) showing that while both helped to improve RLS
symptoms, pramipexole was superior. In addition, pramipexole improved PSG parameters
including PLM frequency (Manconi M, 2011). Thus, bromocriptine is not commonly used as
a therapy for RLS at this time.
Pergolide is a semi-synthetic ergot-derivative that acts as a dopamine agonist at both the D2
and D1 receptors. In a major study, Trenkwalder and colleagues found pergolide
significantly improved RLS symptom severity and PLMD (Trenkwalder et al. 2004). The
researchers conducted a double-blinded, placebo-controlled, randomized study of pergolide
therapy; the Pergolide European Australian RLS (PEARLS) study. In this study, 100
patients with primary (idiopathic) RLS were randomized to either pergolide or placebo for 6
weeks. In addition, there was a 12 month follow-up phase with open-label pergolide for
placebo non-responders. PLMS were assessed by PSG and RLS symptoms by the IRLS
severity scale (IRLSSS) questionnaire. They found that pergolide significantly improved
IRLSSS results at 6 weeks. In addition, the pergolide treated patients had substantial
improvements in the 6 week and 12 month PLM index. The authors concluded that
pergolide significantly improves PLM findings as well as subjective RLS sleep disturbance.
Cabergoline is a newer, semi-synthetic, long-acting, ergot-derivative dopamine agonist that
particularly acts on the D2 receptors but also has some affinity for the D1 and D3 receptors.
One of the earliest studies examining cabergoline in RLS was from Germany in 2000. In that
study, researchers conducted a 12 week open label trial assessing efficacy with baseline and
12 week PSG and RLS subjective questionnaires. The research team found improvements in
PLMs and subjective relief of symptoms and concluded that cabergoline was effective and
well-tolerated (Stiasny K et al., 2000). A more recent randomized, double-blinded, placebocontrolled,
multicenter PSG study examined the efficacy of cabergoline in RLS (the CATOR
study). In this study, 40 patients with moderate to severe RLS were randomized to either
cabergoline or placebo for 5 weeks. Baseline and end of study PSGs were obtained as well as
IRLSSS and quality of life questionnaires. The researchers found the cabergoline group had
significant improvements in PSG parameters, IRLSSS severity scores, and the RLS quality of
life scores. They concluded that cabergoline is an efficacious and well-tolerated therapy for
RLS symptoms and associated sleep abnormalities (Oertel WH et al., 2006). Unfortunately,
like pergolide, cabergoline has been implicated in cardiac valvular heart disease and
patients treated with this agent need close cardiac monitoring.
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7.1.4 Nonergot-derived dopamine agonists
There are three newer fully-synthetic dopamine agonists that are not derived from ergot.
The three drugs include ropinirole, pramipexole, and rotigotine. As of July 2011, rotigotine
is not approved by the FDA for use for RLS in the USA. These nonergot agents are not
associated with valvular heart disease but have been associated with impulse control
disorders including pathological gambling, compulsive overeating, hypersexuality, and
pyschosis. There is increasing recognition that patients treated with these agents should be
monitored for impulse control disorders.
Ropinirole acts as a dopamine agonist primarily on the D3 as well as D2 & D4 receptors. It
was originally studied in the early 1990s for Parkinson’s Disease and later found to be
beneficial for RLS. Ondo studied 16 RLS patients in an open-label trial of ropinirole. Three
patients discontinued ropinirole use. Of the remaining 13 patients, the average duration of
use was 3.9 months and there was a 58.7% improvement in symptoms (Ondo W, 1999).
Further studies reinforced the safety and efficacy of ropinirole in RLS. The TREAT RLS 1
study (Therapy with ropinirole; efficacy and tolerability in RLS 1) was a randomized,
double-blinded, placebo-controlled trial of 12 weeks duration. 146 subjects were
randomized to the ropinirole group and 138 to the placebo group. The key endpoint was the
IRLS severity score which showed significant improvement in the ropinirole group over the
placebo group at week 12 (p=0.0036). The researchers concluded that ropinirole improves
RLS compared with placebo and was generally well-tolerated (Trenkwalder C et al. 2004).
More recent similar studies from the USA and Canada confirm the efficacy and safety of
ropinirole, including long-term duration in the Canadian study. In the USA study, Bogan
and colleagues studied 331 subjects in a multicenter, double-blinded, placebo-controlled,
flexible dose trial of 12 weeks duration. The primary endpoint was the IRLS score at week 12
which showed a significant improvement in the ropinirole group (p<0.001). In addition, the
treatment group showed improvements in subjective measures of sleep disturbance and
quantity and quality of life scores also improve. The authors concluded that ropinirole
improves RLS symptoms and was generally well-tolerated over a 12 week study period
(Bogan RK et al. 2006). In the Canadian study, researchers studied the long-term efficacy (36
weeks) of ropinirole and also evaluated for the potential of symptom relapse after drug
discontinuation. They identified 202 patients and found significantly fewer subjects relapsed
in the ropinirole arm compared to placebo (32.6% versus 57.8%, p=0.0156). In addition, the
time to relapse symptoms was longer in the ropinirole group and less patients withdrew
from lack of efficacy in that group. The authors concluded that ropinirole was highly
efficacious and well-tolerated over a 36 week period (Montplaisir J et al. 2006). In 2008, Allen
and colleagues reviewed RLS age-of-onset and the response to treatment. They observed no
relationship between the RLS symptoms age-of-onset and baseline IRLS score, and between
dose administered at week 12 and age-of-onset. The authors concluded that ropinirole
provides effective RLS symptom relief that is not affected by age of symptom onset (Allen
RP, Ritchie SY, 2008). In 2009, a large meta-analysis was conducted to evaluate the effect of
ropinirole versus placebo on sleep outcomes as measured by the Medical Outcomes Study
(MOS) sleep scale. The validated MOS sleep scale is a 12 question scale which evaluates
sleep disturbance, sleep adequacy, snoring, somnolence, quantity of sleep, and other
measures. In this review, the authors found that ropinirole improved sleep quality and
decreased daytime somnolence in patients with primary RLS (Hansen RA, et al., 2009).
Finally, researchers assessed the efficacy of ropinirole on depressive symptoms and RLS. In
a multicenter, randomized, double-blinded, placebo-controlled trial, 231 patients with
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moderate to severe primary RLS and at least mild depression were studied. Ropinirole
versus placebo was given for 12 weeks with measurements obtained at baseline and 12
weeks for the Montgomery-Asberg Depression Rating Scale, the Hamilton Scale for
Depression and Beck Depression Inventory-II score, and the Medical Outcomes Study sleep
scale. There were significant improvements in the Montgomery and Hamilton scores as well
as 3 of the 4 domains of the MOS sleep scale. The authors concluded that in patients with
RLS and mild to moderate depression, appropriate therapy for RLS should first be tried and
antidepressant medication may be needed later if the depression symptoms still persist
(Benes H et al., 2011). In summary, ropinirole is a newer nonergot-derived dopamine
agonist with a particular affinity for the D3 dopamine receptors. It has been shown to be
beneficial in RLS symptom improvement both short and long-term with improvement in
daytime somnolence and quality of life indicators.
Pramipexole is a nonergot-derived dopamine agonist that acts on the D3 as well as D2 and
D4 receptors. One of the earliest RLS studies was conducted by Lin at the Mayo Clinic in
1998. In that research, 16 patients were studied who had failed other dopaminergic therapies
for symptomatic RLS. An open-label trial showed that after 2 to 3 months usage, there was
clinically significant improvements in nocturnal leg restlessness and involuntary leg
movements. The authors proposed that pramipexole was an effective therapy for the
treatment of RLS (Lin SC et al., 1998). Following that encouraging initial report, a small
randomized trial was conducted in Quebec. Researchers studied 10 RLS subjects with PSG
and RLS symptom questionnaire using a double-blinded crossover study. They found a
significant reduction in PLMs and RLS symptoms of bedtime/nocturnal leg discomfort
(Montplaisir J et al., 1999). A larger randomized trial from Finland evaluated the efficacy
and safety of pramipexole in 2006. In this study (the PRELUDE study), 109 patients with
moderate to severe RLS (based on the IRSS severity score) were randomized in a 3 week,
double-blinded, placebo-controlled, dose-finding study. PSG measures and IRLS severity
scores were assessed. At all doses, the PLM index was reduced and IRLS severity scores
reduced. The authors concluded that pramipexole was an effective and safe therapy for
treatment of both the objective (PSG measures) and subjective (IRLS severity) aspects of RLS
(Partinen M et al., 2006) In a long-term 52 week open-label study, Japanese researchers
found that pramipexole was both effective and safe (with no RLS augmentation), especially
in patients with an IRLS score less than 20 (Inoue Y, et al., 2010). In a more recent,
multicenter trial, pramipexole was evaluated for efficacy and augmentation problems over a
6 month period. This was a 6 month, randomized, double-blinded, placebo-controlled trial in
which 321 patients were recruited. Primary endpoint for efficacy was the change in the IRLS
severity score. In addition, patients maintained a symptom diary and cases that met predefined
criteria for suspected augmentation were reviewed by a blinded panel. The study
showed that pramipexole was significantly more effective than placebo in improvements of
IRLS severity (p=0.0077). Over 6 months, the incidence of confirmed augmentation was 9.2%
in the pramipexole group versus 6.0% in placebo and the rate increased with treatment in the
intervention group but not placebo. Overall, the authors felt that pramipexole was effective
and safe but did suggest it should be studied over a longer duration for further assess
augmentation issues (Hogl B, et al., 2011). More recent trials evaluating pramipexole has
focused on comparison with other dopaminergic agonist. In a recent study by Manconi,
pramipexole (mainly a D3 receptor agonist) was compared with bromocriptine (largely a D2
receptor agent) and researchers found that pramipexole was more effective than
bromocriptine in reduction of PLMs and that while both drugs reduced RLS symptoms, the
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pramipexole group had greater symptom improvements (Manconi M et al., Neurology 2011).
The same Italian group also did a recent comparison of pramipexole to ropinirole. Researchers
found that both treatment groups improved RLS symptoms and reduced PLMs on PSG
compared to the placebo group and that there was no significant differences between the
pramipexole and ropinirole treatment arms (Manconi M et al. Mov Disorders 2011). In
summary, pramipexole is a newer nonergot-derived dopamine agonist with preferential action
on the D3 dopamine receptor site. It has been shown to be beneficial for both objective PSG
PLM findings as well as subjective improvements in RLS clinical symptoms. It is generally
well-tolerated although there may be an issue with augmentation long-term.
Rotigotine is another newer nonergot-derived dopamine agonist. It is formulated as a once
daily transdermal patch and approved to treat RLS in Europe but not FDA-approved for the
USA. It appears to mainly work on the D2, D3, and D4 receptor sites. In one of the earliest
pilot studies to show benefit for RLS patients, German researchers in 2004 evaluated 63
patients. In this randomized, multicentre, double-blind, parallel-group trial, 63 subjects were
studied using the IRLS severity score as the primary endpoint. Researchers found a significant
improvement in the treatment group and concluded that transdermal rotigotine was
efficacious and well-tolerated (Stiasny-Kolster K et al., 2004). More recently in a multicenter,
randomized, double-blind, placebo-controlled 6 month trial, 505 patients with moderate to
severe RLS were placed on placebo or rotigotine with the primary endpoints being the IRLS
severity score and the CGI-1 score. The treatment group had significantly improved IRLS and
CFI-1 outcomes. There was an overall 27% incidence of skin reactions to the transdermal
patch. Overall, the authors concluded that rotigotine significantly reduced the severity of RLS
symptoms and that treatment effectiveness was maintained throughout the 6 month study
period (Hening WA et al., 2010). Rotigotine was also recently assessed in an overnight PSG
study evaluating objective PLM measurements. This study was a multicenter, randomized,
double-blind, placebo-controlled trial that evaluated 67 subjects over a 4 week period. Baseline
and 4 week PSG and subjective questionnaires (IRLS, CGI-1, MOS-S) were obtained. The
authors found significant improvements in both the subjective questionnaires but also the
objective PSG PLM data. The researchers concluded that rotigotine was effective and well
tolerated in the 4 week treatment of both motor symptoms and subjective sleep disturbances
caused by RLS (Oertel WH et al., 2010). Finally, in a long term follow-up study, rotigotine was
shown to provide sustained effectiveness in treating moderate to severe RLS symptoms for up
to 5 years and was generally well-tolerated (Oertel W et al., 2011).
7.1.5 Other pharmacological treatments for RLS
A number of other therapies have be evaluated for RLS including opioids, gabapentin and
pregabalin, clonazepam, and case reports of melatonin, buproprion, and other agents.
Overall, there is a long experience with opioids and those drugs have been especially useful
in dopaminergic resistant RLS with augmentation problems. Clonazepam has also been
widely used but is not particularly efficacious and now has been largely replaced by
dopaminergic agents. In April 2011, the FDA approved extended release gabapentin for use
in moderate to severe RLS. This anticonvulsant agent has recently been shown to be
beneficial in RLS and may be especially useful when dopamine agents provide incomplete
resolution of RLS symptoms and/or augmentation issues arise. Please remember that the
extended release form of gabapentin gives different concentrations of drug than the shorter
acting form. Finally, it is important to note that all epilepsy drugs carry a suicide warning
label including gabapentin.
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7.2 Non-pharmacological treatments for RLS
7.2.1 Exercise
Traditionally, one of the basic clinical recommendations in treating RLS symptoms involves
exercise and stretching maneuvers. This has been endorsed by the RLS Foundation
(www.rls.org) in their latest patient brochure although the data supporting this is limited.
There have been earlier studies by suggesting that exercise close to bedtime is
counterproductive for RLS. In a large study, Ohayon assessed the prevalence of RLS and
PLMD in the general population. During the multivariate analysis of the secondary results, the
researchers (Ohayon, 2002) found that physical exercise close to bedtime (within 2 hours for at
least 15 minutes exercise 3 or more times per week) was associated with an increased risk of
RLS (OR 1.34, p<0.05) and PLMD (OR 1.43, p<0.05). However, in a conflicting study from 2000,
Phillips et al. found that a lack of exercise was significantly associated with RLS. In a telephone
survey of over 1800 participants, a single question (modified from the 1995 IRLSSG criteria)
was used to screen for RLS. In this study, there was an age-adjusted prevalence of RLS of
10.0% and a lack of exercise (less than 3 hours/month) was significantly associated with RLS
(OR 3.32). In 1996, a Brazilian study evaluated 11 volunteers with to study the effect of acute
physical activity on RLS and PLMD. In this report using a baseline PSG followed the next day
by exercise and then a repeat PSG, there was a reduction in PLMD noted on the second night
PSG (de Mello, 1996). In the only randomized-controlled trial of exercise in RLS, Aukerman
studied 28 individuals in a 12 week exercise trial. The average age was 53.7 years and 39% of
study subjects were male. Subjects were randomized to either a control group with usual
activities or to an exercise group. The exercise program consisted of 3 days a week aerobic and
lower extremity resistance/conditioning training. The IRLSSG severity scale and an RLS
ordinal severity scale were checked at 0, 3, 6, 9, and 12 weeks. Of the 28 subjects, most (23)
completed the trial with 11 in the exercise training group. The researchers found that the
exercise group had a significant improvement in RLS symptoms compared to the control
group with a p = 0.001 for the IRLSSG severity score and p < 0.001 for the RLS ordinal scale.
The research team concluded that a prescribed exercise program is effective in improving RLS
symptoms (Aukerman MM 2006).
7.2.2 Sequential compression devices
There is a hypothesis that reduced blood flow to the extremities may play a role in RLS
symptoms. Research has been undertaken to ascertain whether sequential (pneumatic)
compression devices may alleviate RLS symptomatology. In a small preliminary study from
2005, researchers from New Jersey evaluated 6 patients using enhanced external counter
pulsation (EECP) devices on the legs for one hour daily Monday to Friday for 7 weeks
(Rajaram SS, 2004). All 6 patients met the 2003 IRLSSG criteria and were assessed with the
IRLS rating scale (IRLSSS) before and after the intervention. It should be noted that 3
subjects did not complete the IRLSSS until 4-5 months after EECP treatment. Further
complicating the results, 4 of the 6 patients suffered from diabetic peripheral neuropathy
and no electromyography or nerve conduction studies were done before or after EECP
treatment to assess any potential neuropathy changes. Nevertheless, the research team
found that the IRLS rating scale was significantly improved after EECP intervention and
suggested that decreases in vascular flow may affect the nervous system (peripheral or
central) causing the sensory symptoms of RLS. In a more rigorous prospective, randomized,
double-blinded sham-controlled trial, Lettieri and Eliasson studied 35 subjects in 2009.
Consecutive patients attending a sleep clinic for RLS for approached for recruitment. 41 RLS
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patients were assessed for eligibility with 6 excluded (4 not meeting inclusion criteria and 2
refused to participate). The remaining 35 patients were randomized into either therapeutic
or sham treatment with a sequential compression device for 1 hour daily for 4 weeks.
Validated questionnaires were administrated at the start and end of the intervention. These
forms included the International Restless Legs Syndrome Study Group Severity Scale
(IRLSSS), the Johns Hopkins Restless Legs Severity Scale (JHRLSS), and the restless legs
syndrome quality of life instrument (RLS-QLI). Iron therapy and RLS pharmacological use
was similar between the sham control and intervention groups. The researchers found
significant improvements in the IRLSSS, JHRLSS, and the RLS-QLI for the intervention
group and suggest that pneumatic compression devices are a useful adjunctive or
alternative therapy for RLS (Lettieri CJ, 2009).
7.2.3 Massage therapy
Massage therapy has been long recommended as an additional therapy for RLS symptoms.
However, there is a dearth of scientific evidence to support this claim. In a case report from
2006, Russell presented a 35 year old women with RLS type symptoms. There was no
indication whether the patient actually met the 2003 IRLSSG criteria. It was noted that the
patient had previously tried ropinirole without benefit. In this case report, the patient was
treated with twice weekly massage therapy of 45 minute duration to the lower extremities for
a 3 week period and reported improvements on a subjective symptom intensity scale from
40% at baseline to 10% at the end of therapy (Russell M, 2006). Interestingly, 2 weeks following
the end of the massage intervention, the patient reported a return of her symptoms. Overall,
there is a lack of scientific evidence to routinely support the use of massage therapy in RLS.
7.2.4 Acupuncture
Acupuncture has also been recommended by some as a therapy for RLS. Nonetheless,
similar to massage therapy, there is minimal evidence to recommend acupuncture for RLS
symptoms. In a Cochrane review, the authors found out of 14 potential studies only 2 met
the inclusion criteria to be valid and both trials had methodological and/or reporting issues.
Overall, the Cochrane reviewers felt that there was no significant data to support the use of
acupuncture in RLS (Cui Y, 2008).
7.2.5 Endovenous laser ablation & sclerotherapy
Recently, Hayes and colleagues have reported on the use of endovenous laser ablation and
sclerotherapy for the treatment of RLS. They screened 89 patients for RLS using the 2003
IRLSSG criteria. A total of 35 patients met inclusion criteria with 16 assigned to the control
group and 19 to the interventional group. IRLS scores were obtained at baseline and 6 weeks
later and showed a significant symptom improvement of 80% in the interventional group.
The authors suggest that endovenous laser ablation therapy improves symptoms in RLS
patients with superficial venous insufficiency (Hayes CA, 2008). The only other study
assessing the efficacy of sclerotherapy in RLS was published by Kanter in 1995. In that
paper, 1397 patients presenting to a varicose vein clinic were screened for RLS using an
interview and a questionnaire (pre-1995 IRLSSG). Of these, 312 patients (22%) were felt to
have RLS with 113 patients receiving treatment with sclerotherapy. The vast majority of
patients (98%) reported subjective initial improvement in RLS symptoms although a
substantial minority reported recurrent symptoms at 2 year follow-up (Kanter AH, 1995).
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8. Conclusion
RLS is a common medical disorder which remains underdiagnosed. The underlying etiology
is still not fully elucidated but there is increasing understanding of some mechanisms of
disease especially in secondary RLS. Many treatment options are available although issues
of augmentation and rebound continue to cause problems with RLS control. It is highly
recommended that health care providers be aware of RLS symptoms and recognize the
disease in their patients.
9. References
Agarwal P, Griffith A. (2008) Restless legs syndrome: a unique case and essentials of
diagnosis and treatment. Medscape J Med. 2008;10(12):296.
Allen RP, Earley CJ. (1996) Augmentation of the restless legs syndrome with
carbidopa/levodopa. Sleep. 1996 Apr;19(3):205-13.
Allen RP, Earley CJ. (2000) Defining the phenotype of the restless legs syndrome (RLS)
using age-of-symptom-onset. Sleep Med 2000; 1: 11–9.
Allen RP, Picchietti D, Hening W, Trenkwalder C, Walters A, Montplaisi J. (2003) Restless
legs syndrome: diagnostic criteria, special considerations, and epidemiology. A
report from the restless legs syndrome diagnosis and epidemiology workshop at
the National Institutes of Health. Sleep Med. 2003 Mar;4(2):101-19.
Allen RP, Ritchie SY. (2008) Clinical efficacy of ropinirole for restless legs syndrome is not
affected by age at symptom onset. Sleep Med. 2008 Dec;9(8):899-902.
Auger C, Montplaisir J, Duquette P. (2005) Increased frequency of restless legs syndrome in
a French-Canadian population with multiple sclerosis. Neurology 2005;65:1652-53.
Arunthari V, Kaplan J, Fredrickson PA, Lin SC, Castillo PR, Heckman MG. (2010)
Prevalence of Restless Legs Syndrome in Blood Donors. Mov Disord. 2010 Jul
30;25(10):1451-5.
Bachmann CG, Rolke R, Scheidt U, Stadelmann C, Sommer M, Pavlakovic G, Happe S,
Treede RD, Paulus W. (2010) Thermal hypoesthesia differentiates secondary
restless legs syndrome associated with small fiber neuropathy from primary
restless legs syndrome. Brain. 2010 Mar;133(Pt 3):762-70.
Balendran J, Champion D, Jaaniste T, Welsh A. (2011). A common sleep disorder in
pregnancy: Restless legs syndrome and its predictors. Aust N Z J Obstet Gynaecol.
2011 Jun;51
Benes H, Mattern W, Peglau I, Dreykluft T, Bergmann L, Hansen C, Kohnen R, Banik N,
Schoen SW, Hornyak M. (2011) Ropinirole improves depressive symptoms and
restless legs syndrome severity in RLS patients: a multicentre, randomized,
placebo- controlled study. J Neurol. 2011 Jun;258(6):1046-54.
Benediktsdottir B, Janson C, Lindberg E, Arnardóttir E, Olafsson I, Cook E, Thorarinsdottir
EH, Gislason T. (2010) Prevalence of restless legs syndrome among adults in
Iceland and Sweden: Lung function, comorbidity, ferritin, biomarkers and quality
of life. Sleep Med. 2010 Dec;11(10):1043-8.
Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. (2004) Sex and the risk of restless
legs syndrome in the general population. Arch Intern Med. 2004 Jan 26;164(2):196-202.
www.intechopen.com
Risk Factors and Treatment of Restless Legs Syndrome in Adults
175
Bhowmik D, Bhatia M, Tiwari S, Mahajan S, Gupta S, Agarwal SK, Dash SC. (2004) Low
prevalence of restless legs syndrome in advanced chronic renal failure in the
Indian population: a case-control study. Ren Fail. 2004 Jan;26(1):69-72.
Boentert M, Dziewas R, Heidbreder A, Happe S, Kleffner I, Evers S, Young P. (2010) Fatigue,
reduced sleep quality and restless legs syndrome in Charcot-Marie-Tooth disease:
a web-based survey. J Neurol. 2010 Apr;257(4):646-52.
Bogan RK, Fry JM, Schmidt MH, Carson SW, Ritchie SY; TREAT RLS US Study Group.
(2006) Ropinirole in the treatment of patients with restless legs syndrome: a USbased
randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc.
2006 Jan;81(1):17- 27.
Calzetti S, Negrotti A, Bonavina G, Angelini M, Marchesi E. (2009) Absence of co-morbidity
of Parkinson’s Disease and restless legs syndrome: a case-control study of patients
attending a movement disorder clinic. Neurol Sci. 2009 Apr;30(2):119-22.
Cesnik E, Casetta I, Turri M, Govoni V, Granieri E, Strambi LF, Manconi M. (2010) Transient
RLS during pregnancy is a risk factor for the chronic idiopathic form. Neurology
2010; 75(23):2117-20.
Chen NH, Chuang LP, Yang CT, Kushida CA, Hsu SC, Wang PC, Lin SW, Chou YT, Chen
RS, Li HY, Lai SC. (2010) The prevalence of restless legs syndrome in Taiwanese
adults. Psychiatry Clin Neurosci. 2010 Apr;64(2):170-8.
Connor, JR; Boyer, PJ; Menzies, SL, Dellinger B, Allen RP, Ondo WG, Earley CJ. (2003)
Neuropathological examination suggests impaired brain iron acquisition in restless
legs syndrome. Neurology 2003;61(3): 304–9.
Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT, Earley CJ. (2009) Altered
dopaminergic profile in the putamen and substantia nigra in restless leg syndrome.
Brain 2009 Sep;132(Pt 9):2403-12.
Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ. (2011) Profile of altered
brain iron acquisition in restless legs syndrome. Brain. 2011 Apr;134(Pt 4):959-68.
Cui Y, Wang Y, Liu Z. (2008) Acupuncture for restless legs syndrome. Cochrane Database Syst
Rev. 2008 Oct 8;(4):CD006457.
de Mello MT, Lauro FA, Silva AC, Tufik S. (1996) Incidence of periodic leg movements and
of the restless legs syndrome during sleep following acute physical activity in
spinal cord injury subjects. Spinal Cord (1996) 34:294-296.
Deriu M, Cossu G, Molari A, Murgia D, Mereu A, Ferrigno P, Manca D, Contu P, Melis M.
(2009) Restless legs syndrome in multiple sclerosis: a case control study. Mov
Disord. 2009 Apr 15;24(5):697- 701.
Domínguez RO, Michref A, Tanus E, Amartino H. (2007) Restless legs syndrome in Fabry
disease: clinical feature associated to neuropathic pain is overlooked. Rev Neurol.
2007 Oct 16- 31;45(8):474-8.
Douay X, Waucquier N, Hautecoeur P, Vermersch P; G-SEP (Groupe Septentrional d’Etudes
et de Recherche sur la Sclérose en Plaques). (2009) High prevalence of restless legs
syndrome in multiple sclerosis. Rev Neurol (Paris) 2009 Feb;165(2):194-6.
Dzaja A, Wehrle R, Lancel M, Pollmächer T. (2009) Elevated estradiol plasma levels in
women with restless legs during pregnancy. Sleep. 2009 Feb;32(2):169-74.
Earley CJ, Kuwabara H, Wong DF, Gamaldo C, Salas R, Brasic J, Ravert HT, Dannals RF,
Allen RP. (2011) The dopamine transporter is decreased in the striatum of subjects
with restless legs syndrome. Sleep 2011 Mar 1;34(3):341-7.
www.intechopen.com
Sleep Disorders
176
Ekbom K. (1945) Restless legs: a clinical study. Acta Med Scand Suppl 1945;158:1–123.
Facco FL, Kramer J, Ho KH, Zee PC, Grobman WA. (2010) Sleep disturbances in pregnancy.
Obstet Gynecol. 2010;115(1):77-83.
Gao X, Schwarzschild MA, O’Reilly EJ, Wang H, Ascherio A. (2010) Restless legs syndrome
and Parkinson’s Disease in men. Mov Disord. 2010 Nov 15;25(15):2654-7.
Gemignani F, Marbini A, Di Giovanni G, Salih S, Margarito FP, Pavesi G, Terzano
MG.(1997) Cryoglobulinaemic neuropathy manifesting with restless legs
syndrome. J Neurol Sci. 1997 Nov 25;152(2):218- 23.
Gemignani F, Brindani F, Vitetta F, Marbini A, Calzetti S. (2007) Restless legs syndrome in
diabetic neuropathy: a frequent manifestation of small fiber neuropathy. J Peripher
Nerv Syst. 2007 Mar;12(1):50-3.
Ghorayeb I, Bioulac B, Scribans C, Tison F. (2008) Perceived severity of restless legs
syndrome across the female life cycle. Sleep Med. 2008 Oct;9(7):799-802.
Goffredo Filho GS, Gorini CC, Purysko AS, Silva HC, Elias IE. (2003) Restless legs
syndrome in patients on chronic hemodialysis in a Brazilian city: frequency,
biochemical findings and co-morbidities. Arq Neuropsiquiatr. 2003 Sep;61(3B):723-7.
Hansen RA, Song L, Moore CG, Gilsenan AW, Kim MM, Calloway MO, Murray MD. (2009)
Effect of ropinirole on sleep outcomes in patients with restless legs syndrome:
meta-analysis of pooled individual patient data from randomized controlled trials.
Pharmacotherapy. 2009 Mar;29(3):255-62.
Hassan N, Pineau CA, Clarke AE, Vinet E, Ng R, Bernatsky S. (2011) Systemic lupus and
risk of restless legs syndrome. J Rheumatol 2011; 38(5):874-6.
Hattan E, Chalk C, Postuma RB. (2009) Is there a higher risk of restless legs syndrome in
peripheral neuropathy? Neurology 2009 Mar 17;72(11):955-60.
Hayes CA, Kingsley JR, Hamby KR, Carlow J. (2008) The effect of endovenous laser
ablation on restless legs syndrome. Phlebology 2008;23:112–117.
Hening WA, Walters A, Kavey N, Gidro-Frank S, Côté L, Fahn S. (1986) Dyskinesias while
awake and periodic movements in sleep in restless legs syndrome: treatment with
opioids. Neurology. 1986 Oct;36(10):1363-6.
Hening WA, Allen RP, Ondo WG, Walters AS, Winkelman JW, Becker P, Bogan R, Fry JM,
Kudrow DB, Lesh KW, Fichtner A, Schollmayer E; SP792 Study Group. (2010)
Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind,
placebo- controlled trial in the United States. Mov Disord. 2010 Aug 15;25(11):1675-83.
Högl B, Garcia-Borreguero D, Trenkwalder C, Ferini-Strambi L, Hening W, Poewe W,
Brenner SS, Fraessdorf M, Busse M, Albrecht S, Allen RP. (2011) Efficacy and
augmentation during 6 months of double- blind pramipexole for restless legs
syndrome. Sleep Med. 2011 Apr;12(4):351-60.
Inoue Y, Kuroda K, Hirata K, Uchimura N, Kagimura T, Shimizu T. (2010) Long-term openlabel
study of pramipexole in patients with primary restless legs syndrome. J
Neurol Sci. 2010 Jul 15;294(1- 2):62-6.
Italian REMS Study Group, Manconi M, Ferini-Strambi L, Filippi M, Bonanni E, Iudice A,
Murri L. (2008) Multicenter case-control study on restless legs syndrome in
multiple sclerosis: the REMS study. Sleep. 2008 Jul;31(7):944-52.
Kaplan PW, Allen RP, Buchholz DW, Walters JK. (1993) A double-blind, placebo-controlled
study of the treatment of periodic limb movements in sleep using
carbidopa/levodopa and propoxyphene. Sleep. 1993 Dec;16(8):717-23.
www.intechopen.com
Risk Factors and Treatment of Restless Legs Syndrome in Adults
177
Kanter AH. (1995) The effect of sclerotherapy on restless legs syndrome. Dermatol Surg. 1995
Apr;21(4):328-32.
Kilfoyle DH, Dyck PJ, Wu Y, Litchy WJ, Klein DM, Dyck PJ, Kumar N, Cunningham JM,
Klein CJ. (2006) Myelin protein zero mutation His39Pro: hereditary motor and
sensory neuropathy with variable onset, hearing loss, restless legs and multiple
sclerosis. J Neurol Neurosurg Psychiatry. 2006 Aug;77(8):963-6.
Kushida C, Martin M, Nikam P, Blaisdell B, Wallenstein G, Ferini-Strambi L, Ware JE Jr.
(2007) Burden of restless legs syndrome on health-related quality of life. Qual Life
Res. 2007;16:617-624.
LaRochelle JS, Karp BI. (2004) Restless legs syndrome due to interferon- alpha. Mov Disord.
2004 Jun;19(6):730-1.
Lettau LA, Gudas CJ, Kaelin TD. (2010) Remission of restless legs syndrome and periodic
limb movements in sleep after bilateral excision of multiple foot neuromas: a case
report. J Med Case Reports. 2010 Sep 17;4:306.
Lettieri CJ, Eliasson AH. (2009) Pneumatic compression devices are an effective therapy for
restless legs syndrome: a prospective, randomized, double-blinded, shamcontrolled
trial. Chest. 2009 Jan;135(1):74-80.
Lin SC, Kaplan J, Burger CD, Fredrickson PA. (1998) Effect of pramipexole in treatment of
resistant restless legs syndrome. Mayo Clin Proc. 1998 Jun;73(6):497-500.
Lo Coco D, Cannizzaro E, Lopez G. (2009) Restless legs syndrome in a patient with
multifocal motor neuropathy. Neurol Sci. 2009 Oct;30(5):401-3.
Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Casetta I, Mollica G, Ferini-
Strambi L, Granieri E. (2004) Restless legs syndrome and pregnancy. Neurology.
2004 Sep 28;63(6):1065-9.
Manconi M, Fabbrini M, Bonanni E, Filippi M, Rocca M, Murri L, Ferini- Strambi L. (2007)
High prevalence of restless legs syndrome in multiple sclerosis. Eur J Neurol. 2007
May;14(5):534-9.
Manconi M, Rocca MA, Ferini-Strambi L, Tortorella P, Agosta F, Comi G, Filippi M. (2008)
Restless legs syndrome is a common finding in multiple sclerosis and correlates
with cervical cord damage. Mult Scler. 2008 Jan;14(1):86-93.
Manconi M, Ferri R, Zucconi M, Oldani A, Giarolli L, Bottasini V, Ferini- Strambi L. (2011).
Pramipexole versus ropinirole: polysomnographic acute effects in restless legs
syndrome. Mov Disord. 2011 Apr;26(5):892-5.
Manconi M, Ferri R, Zucconi M, Clemens S, Giarolli L, Bottasini V, Ferini- Strambi L. (2011)
Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome.
Neurology. 2011 12;77(2):110-7.
Marin LF, dos Santos WA, Pedroso JL, Ferraz HB, de Carvalho LB, do Prado GF. (2010)
Restless legs syndrome associated with Guillain- Barré syndrome: a report of two
cases. Parkinsonism Relat Disord. 2010 Jul;16(6):418-9.
Merlino G, Lorenzut S, Gigli GL, Romano G, Montanaro D, Moro A, Valente M. (2010) A
case-control study on restless legs syndrome in nondialyzed patients with chronic
renal failure. Mov Disord. 2010 Jun 15;25(8):1019-25.
Michaud M, Soucy JP, Chabli A, Lavigne G, Montplaisir J. (2002) SPECT imaging of striatal
pre- and postsynaptic dopaminergic status in restless legs syndrome with periodic
leg movements in sleep. J Neurol. 2002;249:164–70.
www.intechopen.com
Sleep Disorders
178
Moccia M, Pellecchia MT, Erro R, Zingone F, Marelli S, Barone DG, Ciacci C, Strambi LF,
Barone P. (2010) Restless legs syndrome is a common feature of adult celiac
disease. Mov Disord. 2010 May 15;25(7):877-81.
Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, Lesperance P. (1997)
Clinical,vpolysomnographic, and genetic characteristics of restless legs syndrome:
a study of 133 patients diagnosed with new standard criteria. Mov Disord
1997;12(1):61–5.
Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B. (1999) Restless legs syndrome
improved by pramipexole: a double-blind randomized trial. Neurology. 1999 Mar
23;52(5):938-43.
Montplaisir J, Karrasch J, Haan J, Volc D. (2006) Ropinirole is effective in the long-term
management of restless legs syndrome: a randomized controlled trial. Mov Disord.
2006 Oct;21(10):1627-35.
Moreira NC, Damasceno RS, Medeiros CA, Bruin PF, Teixeira CA, Horta WG, Bruin VM.
(2008) Restless legs syndrome, sleep quality and fatigue in multiple sclerosis
patients. Braz J Med Biol Res. 2008 Oct;41(10):932-937.
Neau JP, Porcheron A, Mathis S, Julian A, Meurice JC, Paquereau J, Godeneche G, Ciron J,
Bouche G. (2010) Restless legs syndrome and pregnancy: a questionnaire study in
the Poitiers district, France. Eur Neurol. 2010; 64(5):268-74.
Neau JP, Marion P, Mathis S, Julian A, Godeneche G, Larrieu D, Meurice JC, Paquereau J,
Ingrand P. (2010) Restless legs syndrome and pregnancy: follow-up of pregnant
women before and after delivery. Eur Neurol. 2010;64(6):361-6.
Oertel WH, Benes H, Bodenschatz R, Peglau I, Warmuth R, Happe S, Geisler P, Cassel W,
Leroux M, Kohnen R, Stiasny-Kolster K. (2006) Efficacy of cabergoline in restless
legs syndrome: a placebo- controlled study with polysomnography (CATOR).
Neurology. 2006 Sep 26;67(6):1040-6.
Oertel WH, Benes H, Garcia-Borreguero D, Högl B, Poewe W, Montagna P, Ferini-Strambi
L, Sixel-Döring F, Trenkwalder C, Partinen M, Saletu B, Polo O, Fichtner A,
Schollmayer E, Kohnen R, Cassel W, Penzel T, Stiasny-Kolster K. (2010) Rotigotine
transdermal patch in moderate to severe idiopathic restless legs syndrome: a
randomized, placebo-controlled polysomnographic study. Sleep Med. 2010
Oct;11(9):848-56.
Oertel W, Trenkwalder C, Beneš H, Ferini-Strambi L, Högl B, Poewe W, Stiasny-Kolster K,
Fichtner A, Schollmayer E, Kohnen R, García- Borreguero D; on behalf of the SP710
study group. (2011) Long- term safety and efficacy of rotigotine transdermal patch
for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label
extension study. Lancet Neurol. 2011 Jun 24. [Epub ahead of print]
O’Keeffe ST, Gavin K, Lavan JN. (1994) Iron status and restless legs syndrome in the
elderly. Age Ageing 1994;23(3):200–3.
Ondo W. (1999) Ropinirole for restless legs syndrome. Mov Disord. 1999 Jan;14(1):138-40.
Ohayon MM, Roth, T. (2002) Prevalence of restless legs syndrome and periodic limb
movement disorder in the general population. J Psychosom Res 2002 Jul;53(1):547–554.
Phillips B, Young T, Finn L, Asher K, Hening W, Purvis C. (2000), Epidemiology of Restless
Legs Symptoms in Adults. Arch Intern Med. 2000;160:2137-2141
Pantaleo NP, Hening WA, Allen RP, Earley CJ. (2009) Pregnancy accounts for most of the
gender difference in prevalence of familial RLS. Sleep Med. 2010 Mar;11(3):310-3.
www.intechopen.com
Risk Factors and Treatment of Restless Legs Syndrome in Adults
179
Partinen M, Hirvonen K, Jama L, Alakuijala A, Hublin C, Tamminen I, Koester J, Reess J.
(2006) Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a
polysomnographic dose- finding study–the PRELUDE study. Sleep Med. 2006
Aug;7(5):407-17.
Paulus W, Trenkwalder C. (2006) Less is more: pathophysiology of dopaminergic-therapyrelated
augmentation in restless legs syndrome. Lancet Neurol. 2006 Oct;5(10):878-86.
Quinn C, Uzbeck M, Saleem I, Cotter P, Ali J, O’Malley G, Gilmartin JJ, O’Keeffe ST. (2011)
Iron status and chronic kidney disease predict restless legs syndrome in an older
hospital population. Sleep Med. 2011 Mar;12(3):295-301.
Quiroz C, Pearson V, Gulyani S, Allen R, Earley C, Ferré S. (2010) Up-regulation of striatal
adenosine A(2A) receptors with iron deficiency in rats: effects on locomotion and
cortico-striatal neurotransmission. Exp Neurol. 2010 Jul;224(1):292-8.
Reynolds G, Blake DR, Pall HS, Williams A. (1986) Restless leg syndrome and rheumatoid
arthritis. BMJ 1986;292:659-60.
Rijsman RM, de Weerd AW, Stam CJ, Kerkhof GA, Rosman JB. (2004) Periodic limb
movement disorder and restless legs in dialysis patients. Nephrology (Carlton). 2004
Dec;9(6):353-61.
Russell, M. (2007) Massage therapy and restless legs syndrome. J Bodywork Movement Ther
2007 11(2):146–150.
Salih AM, Gray RES, Mills KR, Webley M. (1994) A clinical, serological and
neurophysiological study of restless legs syndrome in rheumatoid arthritis. Br. J
Rheumatol 1994;33:60-3.
Sikandar R, Khealani BA, Wasay M. (2009) Predictors of restless legs syndrome in
pregnancy: a hospital based cross sectional survey from Pakistan. Sleep Med. 2009
Jun;10(6):676-8.
Snyder AM, Wang X, Patton SM, Arosio P, Levi S, Earley CJ, Allen RP, Connor JR. (2009)
Mitochondrial ferritin in the substantia nigra in restless legs syndrome. J
Neuropathol Exp Neurol. 2009 Nov;68(11):1193-9.
Sperfeld AD, Unrath A, Kassubek J. (2007) Restless legs syndrome in hereditary spastic
paraparesis. Eur Neurol. 2007;57(1):31-5.
Stiasny K, Röbbecke J, Schüler P, Oertel WH. (2000) Treatment of idiopathic restless legs
syndrome (RLS) with the D2-agonist cabergoline–an open clinical trial. Sleep. 2000
May 1;23(3):349-54.
Stiasny-Kolster K, Kohnen R, Schollmayer E, Möller JC, Oertel WH; Rotigotine Sp 666 Study
Group. (2004) Patch application of the dopamine agonist rotigotine to patients with
moderate to advanced stages of restless legs syndrome: a double-blind, placebocontrolled
pilot study. Mov Disord. 2004 19(12):1432-8.
Synofzik M, Godau J, Lindig T, Schöls L, Berg D. (2011) Restless legs and substantia nigra
hypoechogenicity are common features in Friedreich’s ataxia. Cerebellum. 2011
Mar;10(1):9-13.
Takaki J, Nishi T, Nangaku M, Shimoyama H, Inada T, Matsuyama N, Kumano H, Kuboki
T. (2003) Clinical and psychological aspects of restless legs syndrome in uremic
patients on hemodialysis. Am J Kidney Dis. 2003 Apr;41(4):833-9.
Taylor-Gjevre RM, Gjevre JA, Skomro R, Nair B. (2009) Restless legs syndrome in a
rheumatoid arthritis patient cohort. J Clin Rheumatol 2009;15:12-15.
www.intechopen.com
Sleep Disorders
180
Taylor-Gjevre RM, Gjevre JA, Skomro RP, Nair BV. (2011) Assessment of sleep health in
patients with rheumatic disease. International Journal of Clinical Rheumatology 2011;
6(2):207-218.
Trenkwalder C, Collado Seidel V, Kazenwadel J, Wetter TC, Oertel W, Selzer R, Kohnen R.
(2003) One-year treatment with standard and sustained-release levodopa:
appropriate long-term treatment of restless legs syndrome? Mov Disord. 2003
Oct;18(10):1184-9.
Trenkwalder C, Hundemer HP, Lledo A, Swieca J, Polo O, Wetter TC, Ferini-Strambi L, de
Groen H, Quail D, Brandenburg U; PEARLS Study Group. (2004) Efficacy of
pergolide in treatment of restless legs syndrome: the PEARLS Study. Neurology.
2004 Apr 27;62(8):1391-7.
Trenkwalder C, Garcia-Borreguero D, Montagna P, Lainey E, de Weerd AW, Tidswell P,
Saletu-Zyhlarz G, Telstad W, Ferini-Strambi L; Therapy with Ropiunirole; Efficacy
and Tolerability in RLS 1 Study Group. (2004) Ropinirole in the treatment of
restless legs syndrome: results from the TREAT RLS 1 study, a 12 week,
randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg
Psychiatry. 2004 Jan;75(1):92-7.
Tunç T, Karadağ YS, Doğulu F, Inan LE. (2007) Predisposing factors of restless legs
syndrome in pregnancy. Mov Disord. 2007 Apr 15;22(5):627-31.
Ulfberg J, Nyström B. (2004) Restless legs syndrome in blood donors. Sleep Med
2004;5(2):115-8.
Unruh ML, Levey AS, D’Ambrosio C, Fink NE, Powe NR, Meyer KB; Choices for Healthy
Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study. (2004) Restless
legs symptoms among incident dialysis patients: association with lower quality of
life and shorter survival. Am J Kidney Dis. 2004 May;43(5):900-9
Verbaan D, van Rooden SM, van Hilten JJ, Rijsman RM. (2010) Prevalence and clinical
profile of restless legs syndrome in Parkinson’s Disease. Mov Disord. 2010 Oct
15;25(13):2142-7.
Walters AS, Hening WA, Kavey N, Chokroverty S, Gidro-Frank S. (1988) A double-blind
randomized crossover trial of bromocriptine and placebo in restless legs
syndrome. Ann Neurol. 1988 24(3):455-8.
Walters AS, Hening W. (1987) Clinical presentation and neuropharmacology of restless legs
syndrome. Clin Neuropharmacol. 1987 Jun;10(3):225-237.
Walters AS. The International Restless Legs Syndrome Study Group. (1995) Toward a better
definition of the restless legs syndrome. Mov Disord 1995;10:634–42.
Walters AS and the International Restless Legs Syndrome Study Group. (2003) Validation of
the International Restless Legs Syndrome Study Group rating scale for restless legs
syndrome. Sleep Med 2003; 4: 121–32.
Wang J, O’Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A. (2009) Efficacy of oral iron
in patients with restless legs syndrome and a low-normal ferritin: A randomized,
double-blind, placebo- controlled study. Sleep Med. 2009 Oct;10(9):973-5.
Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G. (2007) Valvular heart disease
and the use of dopamine agonists for Parkinson’s disease. N Engl J Med. 2007 Jan
4;356(1):39-46.
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Sleep Disorders
Edited by Dr. Chris Idzikowski
ISBN 978-953-51-0293-9
Hard cover, 190 pages
Publisher InTech
Published online 14, March, 2012
Published in print edition March, 2012
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individuals with a valuable insight into the latest diverse developments within the study of sleep disorders. This
book is a collection of chapters, which can be viewed as independent units dealing with different aspects and
issues connected to sleep disorders, having in common that they reflect leading edge ideas, reflections and
observations. The authors take into account the medical and social aspects of sleep-related disorders,
concentrating on different focus groups, from adults to pregnant women, adolescents, children and
professional workers.
How to reference
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John A. Gjevre and Regina M. Taylor-Gjevre (2012). Risk Factors and Treatment of Restless Legs Syndrome
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