Download Treatments of Restless Legs Syndrome

IN THE NAME OF GOD
Treatments of Restless
Legs Syndrome
Dr. maryam Dehghan
Case Scenario
A 46 years old woman with discomfort in the legs that occurs
only at rest and is immediately relieved by movement. Terms
that patients use to describe the symptoms include crawling,
itching and stretching, all localized to deep structures rather
than the skin. Symptoms typically worsen towards the end of
the day and are maximal at night. Which one of the treatments
is more benefit for reduce this symptoms ?
•
PICO
Patient or Problem
• A 46 years old woman with restless legs syndrome
Intervention
Treatment with:
• Acupuncture
• Levodopa
• Dopamine agonists
• Iron
Comparison
• Drugs with placebo
Outcomes
• Symptom improvement of RLS
Key words
• Restless legs syndrome
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•
•
•
Acupuncture
Levodopa
Dopamine agonists
Iron
• INTRODUCTION — Restless legs syndrome (RLS) refers to symptoms
of spontaneous, continuous leg movements associated with
unpleasant paresthesias .These sensations occur only at rest and are
relieved by movement. Sleep disturbance and a frequent association
with involuntary, jerking movements of the legs during sleep, known
as periodic leg movements of sleep (PLMS), are common.
• EPIDEMIOLOGY — Mild symptoms of RLS occur in 5 to 15 percent of
the population.
• PATHOGENESIS — In most cases RLS is a primary idiopathic disorder,
but it also can be associated with a variety of underlying medical
disorders.
• Primary RLS — The cause of primary (or idiopathic) RLS is unknown.
However, a family history consistent with dominant inheritance is
present in more than 40 percent of patients with idiopathic RLS .
• Secondary RLS — RLS can occur secondary to a number of
disorders including iron deficiency, uremia, diabetes mellitus,
rheumatic disease, and venous insufficiency, among others.
• CLINICAL MANIFESTATIONS — The hallmark of RLS is a
marked discomfort in the legs that occurs only at rest and is
immediately relieved by movement. The abnormal feelings are
typically deep seated and localized below the knees.
Distribution is usually bilateral, but some asymmetry may
occur and the arms can be affected in more severe cases.
• DIAGNOSIS —The International Restless Legs Study Group proposed
the following four features as essential criteria for the diagnosis of
RLS:
• 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.
• The urge to move or unpleasant sensations begin or worsen during
periods of rest or inactivity such as lying or sitting.
• 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.
• 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 severe, the worsening at night may not be
noticeable but must have been previously present.
13
Acupuncture for
restless legs syndrome
Cui Y, Wang Y, Liu Z
• Department of Acupuncture and Moxibustion, Guang An Men
Hospital, The China Academy of Chinese Medicine Science,
Beijing, China
• Editorial group: Cochrane Movement Disorders Group.
• Publication status and date: Edited (no change to
conclusions), published in Issue 8, 2012.
• Review content assessed as up-to-date: 30 May 2008.
• Citation: Cui Y, Wang Y, Liu Z. Acupuncture for restless legs
syndrome. Cochrane Database of Systematic Reviews 2008,
Issue 4.
• Art.No.: CD006457. DOI: 10.1002/14651858.CD006457.pub 2.
• Copy right © 2012 The Cochrane Collaboration. Published by
John Wiley & Sons, Ltd.
Background
Restless legs syndrome (RLS ) is a common
movement disorder for which patients may
seek treatment with acupuncture .
However, the benefits of acupuncture in the
treatment of RLS are unclear and have not
been evaluated in a systematic review until
now.
Objectives
To evaluate the efficacy and safety of
acupuncture therapy in patients with RLS .
Search methods
We searched :
• Cochrane Central Register of Controlled Trials (CENTRAL, The
Cochrane Library, Issue 1, 2007)
• MEDLINE( January 1950 to February 2007)
• EMBASE ( January 1980 to 2007 Week 8)
• Chinese Biomedical Database (CBM) (1978 to February 2007)
• China National Knowledge Infrastructure (CNKI) (1979 to February
2007)
• VIP Database (1989 to February 2007)
• Japana Centra Revuo Medicina (1983 to 2007)
• Korean Medical Database (1986 to 2007)
• Four Chinese journals, relevant academic conference proceedings
and reference lists of articles were handsearched.
Selection criteria
Randomized control led trials and quasirandomized trials comparing acupuncture with
no intervention, placebo acupuncture, sham
acupuncture, pharmacological treatments, or
other non-acupuncture interventions for
primary RLS were included. Trials comparing
acupuncture plus non-acupuncture treatment
with the same non-acupuncture treatment
were also included. Trials that only compared
different forms of acupuncture or different
acupoints were excluded.
Data collection and analysis
Two authors independently identified
potential articles, assessed methodological
quality and extracted data. Relative risk (RR)
was used for binary outcomes and weighted
mean difference for continuous variables.
Results were combined only in the absence
of clinical heterogeneity.
Main results
Fourteen potentially relevant trials were identified
initially, but twelve of them did not meet the selection
criteria and were excluded.
Only two trials with 170 patients met the inclusion
criteria. No data could be combined due to clinical
heterogeneity between trials.
Both trials had methodological and/or reporting
shortcomings. No significant difference was detected in
remission of overall symptoms between acupuncture
and medications in one trial (RR 0. 97, 95% CI 0. 76 to
1. 24).
Another trial found that dermal needle therapy
used in combination with medications and
massage was more effective than medications and
massage alone, in terms of remission of
unpleasant sensations in the legs (RR 1.36, 95% CI
1.06 to 1.75; WMD-0.61, 95% CI-0.96 to -0.26) and
reduction of RLS frequency (WMD-3.44, 95% CI5.15 to -1.73).
Authors’ conclusions
There is insufficient evidence to determine
whether acupuncture is an efficacious and
safe treatment for RLS. Further well-designed,
large-scale clinical trials are needed.
27
Levodopa for the treatment
of restless legs syndrome
Scholz H, Trenkwalder C, Kohnen R,
Kriston L, Riemann D, Hornyak M
• Interdisciplinary Pain Canter,UniversityMedical Center,
Freiburg, Freiburg, Germany
• Editorial group: Cochrane Movement Disorders Group.
• Publication status and date: Edited (no change to
conclusions), published in Issue 5, 2011.
• Review content assessed as up-to-date: 18 January 2011.
• Citation: Scholz H, Trenkwalder C, Kohnen R, Kriston L,
Riemann D, Hornyak M. Levodopa for the treatment of
restless legs syndrome. Cochrane Database of Systematic
Reviews 2011, Issue 2.
• Art.No.: CD005504. DOI: 10.1002/14651858.CD005504.pub2.
• Copyright © 2011 The Cochrane Collaboration. Published by
JohnWiley & Sons, Ltd.
Background
Levodopa plus dopamine decarboxylase
inhibitor is a common treatment for restless
legs syndrome (RLS).
Objectives
To evaluate efficacy and safety of levodopa
for RLS compared to placebo and other
active agents.
Search methods
We searched CENTRAL ( The Cochrane
Library 2008, Issue 4), MEDLINE, EMBASE,
PsycINFO and CINAHL, from January 1985
to December 2008, reference lists of
articles, and contacted pharmaceutical
companies.
Selection criteria
We included double -blind randomised
controlled trial s (RCT) investigating levodopa
treatment versus placebo or other treatment
for at least seven day s in patients with RLS
(age ≥ 18 years). Outcomes included
symptom severity, CGI-I, objective as well as
self rated sleep parameters, quality of life ,
and safety parameters.
Data collection and analysis
Two authors extracted data, assessed risk
of bias, and contacted pharmaceutical
companies and authors for additional
information. We collected dropouts due to
adverse events and patients experiencing
adverse events.
Main results
Six placebo controlled and three active controlled RCTs
were included (521 participants). Symptom severity (11
point rating scale, 0 points indicating no symptoms, 10
points indicating maximally severe symptoms) was more
reduced with levodopa than placebo in two studies (me an
difference (MD) -1.34, 95% confidence interval (CI-2.18 to 0.5, P=0.002). Periodic limb movements in sleep per hour
of sleep (PLMS-Index; PLMSI) improved by -26.28/h
compared to placebo (95% CI-30.53 to -22.02, P<0.00001).
The CGI-I changed more with levodopa than placebo in
two studies (MD-1.25, 95% CI-1.89 to -0.62, P=0.0001).
In two studies, sleep quality (sleep questionnaire, visual
analogue scale) showed a large effect (standardised mean
difference (S MD) 0.92, 95% CI 0.52 to 1.33, P<0.00001)
where as quality of life (50 mm Visual Analogue Scales)
improved by 3.23 compared to placebo (95% CI 1.64 to 4.82,
P<0. 0001).
Few patients dropped out of treatment (3 of 218 patients)
but more levodopa treated patients experienced adverse
events than with placebo (odds ratio 2.61, 95% CI 1.35 to
5.04, P=0.004).
Two dopamine agonist controlled studies showed smaller
effects with levodopa than cabergoline and pramipexole on
the IRLS (MD 5.25, 95% CI 2.10 to 8.40, P=0.001), CGI-I (MD
0.62, 95% CI 0.37 to 0.87, P<0.00001), and quality of life
(MD 5.54, 95% CI 2.65 to 8.43, P=0.0002).
Authors’ conclusions
Levodopa is efficacious for the short-term
treatment of RLS. Augmentation, the
clinically most relevant adverse event, was
not investigated sufficiently.
Dopamine agonists for
the treatment of restless
legs syndrome
Scholz H, Trenkwalder C, Kohnen R, Kriston L,
Riemann D, Hornyak M
• Magdolna Hornyak, Interdisciplinary Pain Canter,
University Medical Center.
• Editorial group: Cochrane Movement Disorders Group.
• Publication status and date: Edited (no change to
conclusions), published in Issue 5, 2011.
• Review content assessed as up-to-date: 18 January 2011.
• Citation: Scholz H, Trenkwalder C, Kohnen R, Kriston L,
Riemann D, Hornyak M. Dopamine agonists for the
treatment of restless legs syndrome . Cochrane Database
of Systematic Reviews 2011, Issue 3.
• Art. No. : CD006009. DO I: 10. 1002/ 14651858 . CD0 06 00
9. pub 2.
• Copy right © 2011 The Cochrane Collaboration. Published
by John Wiley & Sons, Ltd
Background
According to clinical guidelines, dopamine
agonists are the first-line treatment of
restless legs syndrome (RLS ).
Objectives
To evaluate efficacy and safety of dopamine
agonists for RLS .
Search methods
We searched the Cochrane Central Register
of Controlled Trials (The Cochrane Library
2008, Issue 4), MEDLINE, EMBASE, PsycINFO
and CINAHL, from January 1985 to
December 2008, plus reference lists of
articles. We contacted pharmaceutical
companies.
Selection criteria
We included double -blind randomized
controlled trials (RCTs) of dopamine agonist
treatment versus placebo or other
treatment for a period of at least seven days
in patients with RLS ( ≥ 18 years). Outcomes
included the International RLS Severity
Rating Scale (IRLS ), Clinical Global
Impressions (CGI-I), poly somnography and
self rated sleep quality, quality of life , day
time functioning, and safety parameters.
Data collection and analysis
Two reviewers extracted data separately ;
assessed risk of bias; and contacted
pharmaceutical companies and authors for
additional information. We collected
dropout rates due to adverse events and
experience of adverse events.
Main results
We included 35 placebo controlled and three active controlled
RCTs (N=7365). The mean reduction on the IRLS was −5.7
points lower in dopamine agonist treatment compared to
placebo (95% confidence interval (CI)−6.7 to −4.7). Periodic
limb movements in sleep per hour of sleep (PLMS -Index;
PLMSI) were −22.4/ h lower than in placebo (95% CI −27.8 to
−16.9).
Self rated quality of sleep and disease specific quality of life
were improved by a standardized mean difference (SMD) of
0.40 (95% CI 0.33 to 0.47) and 0.34 -95% CI 0.23 to 0. 44),
respectively. Patients were more likely to drop out (odds ratio
(OR) 1.82, 95% CI 1.35 to 2.45) and experienced more adverse
events under dopamine agonist treatment than with placebo
(OR 1.82, 95% CI 1.59 to 2.08).
Authors’ conclusions
The meta-analyses show the superiority of
dopamine agonists over placebo. Cabergoline
and pramipexole showed larger efficacy
compared to levodopa in some but not all
outcomes.
Forest plot of
comparison: 1
Dopamine agonists
versus placebo,
outcome: 1.2
Medication
subgroups: change on
IRLS.
Forest plot of
comparison: 1
Dopamine agonists
versus placebo,
outcome: 1.4
Medication
subgroups: change in
periodic limb
movements in sleep.
64
Iron for restless legs
syndrome
Trotti LM, Bhadriraju S, Becker LA
• Department of Neurology, Emory University School of
Medicine, Atlanta, USA.
• Editorial group: Cochrane Movement Disorders Group.
• Publication status and date: New, published in Issue 5, 2012.
• Review content assessed as up-to-date: 25 April 2011.
• Citation: Trotti LM, Bhadriraju S, Becker LA. Iron for restless
legs syndrome. Cochrane Database of Systematic Reviews
2012, Issue 5.
• Art. No.: CD007834. DOI: 10.1002/14651858.CD007834.pub2.
• Copyright © 2012 The Cochrane Collaboration. Published by
JohnWiley & Sons, Ltd.
Background
Restless legs syndrome (RLS) is a common
neurologic syndrome and is associated with
iron deficiency in many patients. It is
unclear whether iron therapy is effective
treatment for RLS.
Objectives
The objective of this review was to assess
the effects of iron supplementation (oral or
intravenous) for patients with RLS.
Search methods
We searched the Cochrane Central Register of
Controlled Trials (CENTRAL), MEDLINE (Jan
1995 to April 2011); EMBASE (Jan 1995 to
April 2011); PsycINFO (Jan 1995 to April 2011);
and CINAHL (Jan 1995 to April 2011).
Corresponding authors of included trials and
additional members of the International
Restless Legs Syndrome Study Group were
contacted to locate additional published
or unpublished trials.
Selection criteria
Controlled trials comparing any formulation
of iron with placebo, other medications, or
no treatment in adults diagnosed with RLS
according to expert clinical interview or
explicit diagnostic criteria.
Data collection and analysis
Two review authors extracted data and at
least two authors assessed trial quality. We
contacted trial authors for missing data.
Main results
Six studies (192 total subjects) were identified and included in
this analysis. The quality of trials was variable.
Our primary outcome was restlessness or uncomfortable leg
sensations, which was quantified using the IRLS severity scale in
four trials and another RLS symptom scale in a fifth trial.
Combining data from the four trials using the IRLS severity
scale, there was no clear benefit from iron therapy (mean
difference in IRLS severity scores of -3.79, 95% CI: -7.68 to 0.10,
p = 0.06).
However, the fifth trial did find iron therapy to be beneficial
(median decrease of 3 points in the iron group and no change in
the placebo group on a 10 point scale of RLS symptoms,
p=0.01). Quality of life was improved in the iron group relative
to placebo in some studies but not others.
Changes in periodic limb movements were not different
between groups (measured in two studies).
Objective sleep quality, subjective sleep quality and daytime
functioning were not different between treatment groups in
the studies that assessed them.
The single study of subjects with end stage renal disease did
show a benefit of therapy.The single study that was limited
to iron deficient subjects did not show clear benefit of iron
supplementation on RLS symptoms. There was no clear
superiority of oral or intravenous delivery of iron. Iron
therapy did not result in significantly more side effects than
placebo (RR 1.39, 95% CI 0.85 to 2.27).
Authors’ conclusions
There is insufficient evidence to determine
whether iron therapy is beneficial for the
treatment of RLS. Further research to
determine whether some or all types of RLS
patients may benefit from iron therapy, as
well as the best route of iron administration,
is needed.
SUMMARY
Article 1
There is insufficient evidence to support the use of acupuncture for the
symptomatic treatment of restless legs syndrome.
This review investigated the efficacy and adverse effects of
acupuncture in treating RLS . There view did not find consistent
evidence to determine whether acupuncture is effective and safe in
the treatment of RLS , based on the two trials identified.
Article 2
Levodopa is recommended for the treatment of RLS .
We could include nine trials in the meta-analysis which compared
levodopa treatment to placebo or to other active treatments in RLS.
Levodopa reduced symptom severity to a larger extent than
placebo. Periodic limb movements in sleep, monitored during
polysomnography, were reduced more in levodopa treatment
compared to placebo; however, total sleep time was not changed.
quality of sleep and quality of life were markedly improved. Only a
very low number of patients discontinued treatment due to
adverse events but a larger number of patients on levodopa
treatment reported adverse events compared to placebo. Evidence
of three active controlled trials comparing levodopa to cabergoline,
pergolide, and pramipexole was in favour of dopamine agonists
regarding reduction of RLS severity, symptom improvement, and
quality of life .
Article 3
Dopamine agonists are recommended as first-line treatment for RLS .
We could include 38 trials in the meta-analyses which investigated the
efficacy and safety of dopamine agonist treatment compared to placebo
or to other treatments for RLS. Treatment durations varied from one week
to seven months, but most treatments had durations of one to 12 weeks.
Patients suffered from moderate to severe RLS and were treated with the
dopamine agonists cabergoline, lisuride, pergolide, pramipexole,
ropinirole, rotigotine, and sumanirole .
Dopamine agonists lead to a larger improvement on the
International RLS Severity Rating Scale (IRLS) compared to placebo.
Also periodic limb movements in sleep were significantly reduced
by dopamine agonists compared to placebo. Sleep efficiency was
also slightly improved. Patients rated their quality of sleep and
quality of life as markedly improved. Patients were, however, more
likely to discontinue dopamine agonist
treatment and experienced more adverse events when treated with
dopamine agonists compared to placebo. All dopamine agonists
were superior to placebo except sumanirole. Indirect descriptive
comparisons revealed the highest efficacy for the ergoline
dopamine agonists cabergoline and pergolide. The non-ergoline
dopamine agonists lisuride, pramipexole, rotigotine, and ropinirole
showed adequate efficacy.
Article 4
Low blood levels of iron are frequently seen in people who have RLS and
the lack of iron may be part of the cause of RLS. Iron can be
supplemented either in pill form or through injections into the
bloodstream.
This review was performed to see if iron supplements are effective in
reducing the symptoms of RLS. Six studies of iron were included, which
together involved only 192 subjects. Results from the studies were
conflicting, with some studies showing that iron was not effective but
others showing some help for patients’ feelings of restlessness or
discomfort.
News
• IgG4-related disease — Multiple names have been used for an
increasingly recognized syndrome comprised of disorders
previously thought to be unrelated (eg, type I autoimmune
pancreatitis; many of the patients with inflammatory orbital
pseudotumor; and salivary and/or lacrimal gland disorders,
including Mikulicz’s disease, that may be mistaken for
Sjögren’s syndrome). These conditions share pathologic,
serologic, and clinical features, including tissue infiltration
with immunoglobulin G4 (IgG4)-positive cells. A multinational,
multidisciplinary group of experts has reached consensus on
the term “IgG4-related disease” for the overall condition and
on nomenclature for its individual organ system
manifestations .The group also agreed upon guidelines for
diagnosis, including the critical histopathologic finding
Questionnaire for the diagnosis of SLE
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Have you ever had arthritis or rheumatism for more than 3 months?
Do your fingers become pale, numb, or uncomfortable in the cold?
Have you had any sores in your mouth for more than 2 weeks?
Have you been told that you have low blood counts (anemia, low WBC count, or low platelet
count)?
Have you ever had a prominent rash on your cheeks for more than 1 month?
Does your skin break out after you have been in the sun (not sunburn)?
Has it ever been painful to take a deep breath for more than a few days (pleurisy)?
Have you ever been told that you have protein in your urine?
Have you ever had rapid loss of lots of hair?
Have you ever had a seizure, convulsion, or fit?
• High reprint orders in medical journals and pharmaceutical industry
funding: case-control study
• Objectives To assess the extent to which funding and study design are
associated with high reprint orders.
• Design Case-control study.
• Setting Top articles by size of reprint orders in seven journals, 2002-09.
• Participants Lancet, Lancet Neurology, Lancet Oncology (Lancet
Group), BMJ, Gut,Heart, and Journal of Neurology, Neurosurgery &
Psychiatry (BMJ Group) matched to contemporaneous articles not in the list
of high reprint orders.
• Main outcome measures Funding and design of randomised controlled
trials or other study designs.
• Results Median reprint orders for the seven journals ranged from 3000 to
126 350. Papers with high reprint orders were more likely to be funded by
the pharmaceutical industry than were control papers (industry funding
versus other or none: odds ratio 8.64, 95% confidence interval 5.09 to 14.68,
and mixed funding versus other or none: 3.72, 2.43 to 5.70).
• Conclusions Funding by the pharmaceutical industry is associated with high
numbers of reprint orders.