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Pathophysiology
Clinical features
Diagnosis
Management
Severe or
refractory cases
Case study
the authorS
Dr Omar Ahmad
neurologist, Macquarie Neurology
and Macquarie University,
Macquarie, NSW.
Restless legs
syndrome
Dr Kate Ahmad
neurogenetics and neuromuscular
fellow, Royal North Shore Hospital,
St Leonards, NSW.
Background
RESTLESS legs syndrome (RLS)
is a common sleep–wake disorder
and is characterised by an urge to
move. The symptoms are often difficult to describe or painful and display a circadian pattern. Two forms
are described (primary or secondary)
based on the presence or absence of
an underlying cause. The syndrome
was first described by the physician
Sir Thomas Willis (who, incidentally,
is the eponym for the ‘Circle of Wil-
lis’) in 1682.1 His eloquent observations continue to be relevant:
Wherefore to some, when being
“
abed they betake themselves to
sleep, presently in the arms and
legs, leapings and contractions on
the tendons, and so great a restlessness and tossings of other members
ensue, that the diseased are no more
able to sleep, than if they were in a
place of the greatest torture.”
The syndrome was described
occasionally after this but it was not
until the thesis of Karl-Axel Ekbom
in 1945, that it was characterised
comprehensively.2
Up to 10% of the adult population
is affected with minor RLS symptoms and 2.7% are affected more
severely with symptoms at least twice
a week.3,4 It is most often diagnosed
in middle to late life and the prevalence increases with age until the age
of 79. In practice, it is unusual for the
primary form of RLS to present late
in life; elderly patients are more likely
to have a secondary form. It has been
reported in children with an incidence
of 2% and affects women twice as
often as men.5 While most epidemiological data comes from Caucasian
populations in Europe and America,
RLS has also been described at a similar incidence in other racial groups.
cont’d next page
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23
How To Treat – Restless legs syndrome
Pathophysiology
Figure 1: Normal
MRI brain
(susceptibility
weighted
imaging) at
the level of
the midbrain
showing iron
content of deep
nuclei.
MANY regions and processes
within the nervous system are
involved in RLS. Importantly,
abnormalities of brain iron metabolism, dopaminergic transmission
and genetics all play a role in the
pathophysiology.
The genetics of RLS is not fully
understood but a family history is
present in at least 40% of patients.
Linkage studies have identified
eight loci that are associated with
RLS but they are not causally
related. Genome-wide association studies have found four gene
variants that convey an increased
risk.6-8 One of these genes is
a marker of body iron stores
whereas the mechanism by which
the others are associated with the
pathogenesis of RLS is unknown.6
Image courtesy
Professor John
Magnussen,
Macquarie Medical
Imaging.
Iron deficiency
Iron deficiency is implicated in the
pathogenesis and is supported by
multiple lines of evidence. Firstly,
RLS patients have significantly
lower ferritin levels compared with
controls. Low CSF ferritin levels
are also observed in RLS patients.9
Recent insights suggest that there
is dysregulation of iron entry via
the endothelial cells of the blood–
brain barrier.10 These cells serve
as a reservoir for brain iron and
have significantly altered expression of iron management proteins.
In addition, autopsy, MRI (figure
1) and sonographic studies have
shown reduced iron levels within
neuromelanin cells of the substantia
nigra.11 Iron also plays an important role in dopamine production
through tyrosine hydroxylase and is
involved in noradrenaline and serotonin transmission.
Reduced dopaminergic activity
Dopaminergic signalling also
plays an important role as highlighted by the efficacy of dopaminergic drugs. Autopsy studies
have shown reduced dopamine
D2 receptor binding in the basal
ganglia. Functional imaging studies have shown conflicting results,
with some showing reduced dopamine D2 receptor binding in the
basal ganglia while others have
shown increased or unchanged
binding.12-14 Spinal dopaminergic
pathways may also be important
and several animal studies have
focused on this pathway.
Clinical features
RLS is characterised by the urge to
move the legs and its features can
be conveniently remembered by
the acronym URGE (Urge to move,
Rest induces symptoms, Getting
active brings relief, Evening and
night worsens).15 The clinical features are similar for both primary
and secondary forms of RLS.
The motor symptoms are preceded by an uncomfortable sensation in the legs that is poorly
localised and poorly described. It
can be characterised as creeping,
pulling, crawling or pain. This
symptom is relieved by movement
and brought on by rest. The symptoms peak at night and are often
worst between midnight and 2am.
Patients not uncommonly need to
climb out of bed to relieve their
symptoms.
With increasing disease severity, the circadian pattern becomes
less pronounced and symptoms
become noticeable earlier in the
evening or throughout the day.
This daytime encroachment of
symptoms is often first noted in
situations where prolonged sitting
is required (eg, in the cinema, day
trips, or on public transport).
Sleep disruption is an associated
feature of RLS and significantly
impacts quality of life and general health. Impaired sleep may be
due to a combination of an initial
difficulty in falling asleep and the
frequent need to relieve symptoms
with activity, which then necessitates leaving the bed.
Physical examination is usually
Figure 2:
Polysomnography
findings in periodic
limb movements in
sleep, a condition
associated with, but
diagnostically distinct
from RLS. Boxed
areas show periodic
muscle discharges
from left leg tibialis
anterior.
Image courtesy
Dr Jonathan Williamson,
Macquarie Respiratory and
Sleep.
With increasing
disease severity, the
circadian pattern
becomes less
pronounced and
symptoms become
noticeable earlier
in the evening or
throughout the day.
normal unless a secondary cause is
responsible.
Periodic limb movements of
sleep
About 85% of RLS sufferers also
have periodic limb movements in
sleep. These are brief stereotyped
jerking movement of the lower
limbs that occur in sleep. They can
cause arousal from sleep and are
an additional cause of insomnia
and daytime drowsiness in RLS.
Periodic limb movements in sleep
have separate diagnostic criteria
and can be diagnosed on polysomnography (figure 2). However, this
condition is not specific to RLS
and can be seen in degenerative
neurological conditions and with
ageing.
Diagnosis
THE diagnosis of RLS rests on
meeting the essential and supportive
criteria developed by the International RLS Study Group (IRLSSG),
as illustrated in the box on the next
page.16 These criteria were developed in 1995 and revised in 2002
and 2011. The specificity of having the first four essential features is
84% for a diagnosis of RLS.17
Although they are not part of the
most recent criteria, associated features further improve the diagnostic accuracy. There is no biological
marker specific for RLS and often
24
| Australian Doctor | 2 August 2013
the most useful test is the response
to dopaminergic therapy. The
use of a levodopa challenge is one
approach and involves using a single
dose of 100/25mg at the usual onset
time. Another approach is to start
a low-dose dopamine agonist and
assess treatment response in a week.
Adverse effects are unlikely and a
lack of clear response may warrant
further investigation for mimics or
specialist referral. Of note, the circadian pattern of RLS is the most useful at differentiating it from other
mimics.
Primary vs secondary RLS
Primary RLS is typically associated with an earlier onset and
young onset (<30 years) when
compared with secondary forms.
It is associated with a positive
family history in 60-90% of cases
and is very slowly progressive over
many years.18
The three classical causes of secondary RLS are iron deficiency,
pregnancy and renal failure. RLS
is also commonly described in a
variety of neurological and autoimmune conditions (table 1). Iron
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deficiency and/or anaemia are
highly associated and feature in
the pathophysiology of the disorder.19 Pregnancy can be associated
with severe RLS symptoms, which
tend to be worse in the third trimester.20 The association may
relate to the induction of relative
iron deficiency during pregnancy,
or be due to hormonal influences.
RLS is frequently seen in
patients with end-stage renal failure and occurs in 21% of dialysis patients.21, 22 Interestingly, in
this clinical setting it is associated
with increased mortality but is not
clearly related to iron levels or
anaemia. It may be that it relates
to associated neuropathy, which
is found in a high proportion of
patients with end-stage renal failure. Neuropathy as the aetiological culprit may also be true for the
connective tissue disease and coeliac associations.23-26
Conditions associated with RLS
Several recent trials have reported
an increased prevalence of RLS in
patients with Parkinson’s disease,
though this co-pathology is perhaps less pronounced than would
be expected, given there is dopaminergic dysfunction in both conditions.27,28
Conversely, the evidence for
a link with multiple sclerosis is
mounting. This relationship has
been explored recently in a metaanalysis of 24 studies showing
fourfold-increased odds for RLS
in MS patients.29 There are several possible explanations for this,
with corticospinal tract pathology
seemingly most likely to cause
RLS symptoms. A similar explanation may account for other associations with spinal cord disease
and spinocerebellar ataxia.
A review of the patient’s medications is always warranted as
drugs are another association that
should not be overlooked. The
most common offenders are antidepressants and metoclopramide.
Drugs may also exacerbate primary RLS, and should be reviewed
whenever a patient’s symptoms
become more severe.
Screening for secondary
causes
If RLS is suspected, a basic screen
for secondary causes should be
performed. This would include
iron studies, vitamin B12 and renal
function. Selected patients may
warrant further investigation with
an autoimmune panel (ANA, RF,
ENA, SS-A/SS-B), coeliac serology
and nerve-conduction studies.
Polysomnography is not necessary for making a diagnosis of
RLS and is used mainly for treatment-resistant cases and for judging treatment response in clinical
trials.
Differential diagnoses
Differential diagnoses, or mimics,
of RLS are relatively easy to differentiate as they tend to lack the cardinal RLS features of worsening at
night and relief with movement.
The most common mimics are
painful neuropathy, leg cramps,
akathisia, and pressure-related
sensory symptoms (table 2). Pain-
Table 1: Secondary causes of RLS
Patient
Prevalence in patient population
General population
7%
Pregnancy
13.5%
Iron deficiency anaemia
31%
Renal failure
21%
Polyneuropathies
20%
Parkinson’s disease
20%
Rheumatoid arthritis/systemic
sclerosis
25%
Coeliac disease
31%
Multiple sclerosis
29%
Spinocerebellar ataxia (SCA3)
45%
Medications such as SSRIs,
TCAs, lithium, anticonvulsants,
metoclopramide, antipsychotics
-
Table 2: Mimics
Restless legs syndrome diagnostic criteria from the international
RLS Study Group (2011)
Essential
An urge to move legs usually but not always accompanied by or felt to be
caused by uncomfortable sensations in the legs
The urge to move the legs and any accompanying unpleasant sensations
begin or worsen during periods of rest or inactivity such as lying or sitting
The urge to move the legs and any accompanying unpleasant sensations are
partially or totally relieved by movement, such as walking or stretching, as
long as that activity continues
The urge to move the legs and any accompanying unpleasant sensations
during rest or inactivity only occur or are worse in the evening or night than
during the day
The occurrence of the above features are not solely accounted for as
symptoms primary to another medical or a behavioural condition (eg, myalgia,
venous stasis, leg oedema, arthritis, leg cramps, positional discomfort,
habitual foot tapping)
Associated features
Condition
Distinguishing features
Nocturnal leg cramps
Calves only, painful. Urge to move legs is
confined to stretching out the cramp. More
sudden in onset and brief duration
Radiculopathy
One-sided, positional not just with rest,
radiation from back
Painful neuropathy
Can be nocturnal, sensory symptoms or
numbness. Neurological signs include loss
of vibration and ankle jerks
Akathisia
Motor restlessness. Related to neuroleptic
exposure, absence of pain, affects whole
body and present throughout day
Vascular/neurogenic
claudication
Opposite pattern, worse with walking/
standing. Nil circadian pattern
Venous insufficiency
Evidence of venous hypertension —
discolouration, varicose veins, oedema.
Present throughout day and preference for
leg elevation
Pressure-related symptoms
Short duration, relief with change in
position. Affects arms as well as legs.
Often unilateral. Normal phenomenon
Others: Inflammatory arthritis,
erythromelalgia, complex
regional pain syndrome
Difficult to confuse with RLS. Continuous
in nature
Dopaminergic responsiveness
Presence of periodic limb movements in sleep or in wakefulness
Positive family history
Usually progressive clinical course
Normal neurological examination in the idiopathic form
Sleep disturbance
ful neuropathies are the most
difficult to exclude as symptoms
often overlap with RLS. In addition, early neuropathies may not
initially result in abnormal investigations. Some chronic pain syn-
dromes can present in the legs and
lower back without a clear structural basis. These are often associated with psychological features
and are typically not responsive to
dopaminergic therapy.
Management
MILD symptoms of RLS (IRLS
score <10) can be managed with
simple measures such as increased
activity in the evening or a trial of
magnesium supplements (powdered
or tablet form at night). Good sleep
hygiene should be encouraged, as
should the avoidance of stimulants
at night. Treatment with an oral
iron replacement can be useful if the
ferritin is less than 50μg/L.30,31 While
IV iron therapy is an option, the risk
of iron overload and anaphylaxis
needs to be taken into account.
Treatment in the setting of normal
levels is not proven to be of benefit.
Choice of pharmacotherapy
The common drugs used for the
treatment of RLS are listed in table
3. The usual approach is to treat
with the lowest possible dose and
to use one agent at a time. In primary RLS, dopaminergic agents
are considered first line followed by
anticonvulsants. Opioids are used
in more severe cases and after other
approaches have failed. Combina-
tion therapy is required in up to
20% of cases.
Longer-acting agents are in theory
better at achieving a good response
and less likely to be associated with
rebound of symptoms in the middle of the night. Timing of treatment should be directed towards
the evening about two hours before
symptom onset. The decision to
begin pharmacotherapy should be
based on symptom severity. This
can be gauged by applying the IRLS
rating scale (see Online resources,
page 30). This is used primarily in
a research setting, however it is still
relatively simple and its components
are a useful guide for initiating treatment.
Dopamine agonists
Dopamine agonists, the first-line
agents for primary RLS, have had
their efficacy confirmed in 18 randomised controlled trials. The
proportion of responders (>50%
reduction in IRLS score) is in the
order of 61% with a number needed
to treat of 4-9.32 Dopamine agonist
therapy is also shown to improve
sleep quality parameters and periodic limb movements in sleep.
Studies comparing the various dopamine agonists are lacking. Dopamine agonists have been
studied in patients with moderate
to severe RLS symptoms. Ergotderived dopamine agonists, despite
having good evidence (eg, cabergoline and pergolide) are no longer
used for prolonged periods because
of the risk of fibrotic complications. The three non-ergot dopamine agonists used are pramipexole,
ropinirole and rotigotine. There is
no known cross-tolerance among
agents, and lack of response to
one may not influence response to
another agent.
Pramipexole
Pramipexole can be started at a
dose of 0.125-0.25mg two hours
before symptom onset. Doses
up to 0.75mg a day can be used
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Table 3: Drug therapies
Half-life
(hours)
Initial dose
Maximum
Levodopa
1-2
50/12.5mg
400/100mg
Pramipexole
8-12
0.125mg
1.5mg
Pramipexole extended
release
20
0.375mg
2.25mg
Ropinirole
6
0.5mg
4mg
Rotigotine
5 — constant
2mg/24 hrs
4g/24 hrs
Gabapentin
5-7
300mg
1200mg
Gabapentin enacarbil*
6
600mg
2700mg
Pregabalin
10
25mg
300mg
Oxycodone
6.5
5mg
25mg
Tramadol
5-7
50mg
150mg
Clonazepam
39
0.25mg
2mg
Clonidine
12
0.05mg
0.4mg
Dopaminergic agents
Anticonvulsants
Opioids
Others
*not currently marketed in Australia
2 August 2013 | Australian Doctor |
25
How To Treat – Restless legs syndrome
from previous page
although some patients may
require even higher doses. Splitting the dose by using a small dose
early in the evening and a higher
dose before bed is a good approach
for patients with more prolonged
symptoms. An extended release
formulation is approved for Parkinson’s disease (Sifrol ER) and
has anecdotal evidence as a therapeutic option for RLS (although it
has not been formally studied in
this condition).
Features and treatment of
augmentation
Features
Increasing symptom severity
without known trigger
Earlier onset of symptoms
Shorter latency to symptoms when
at rest
Extension of symptoms to other
body parts
Decreased duration of medication
benefit
Paradoxical response to
medication
Ropinirole
Ropinirole can be started at a dose
of 0.5mg a day. It can be gradually
increased as required and the usual
maintenance dose is in the order of
2mg daily. Doses up to 4mg daily
can be used. The extended-release
formulation of ropinirole is not
available in Australia.
Rotigotine
Rotigotine is available as a transdermal patch for once-daily dosing. It is available in doses from
2-8mg every 24 hours. It is particularly useful for moderate to
severe RLS with daytime symptoms. Skin reactions occur in 17%
of patients. It has recently been
approved for Parkinson’s disease
in Australia and its cost is the main
drawback for use in RLS.
Levodopa
Levodopa has the longest history
of use in RLS. It has a short halflife (1-2 hours) and can therefore
be associated with rebound symptoms later in the night. It also has
a high rate of augmentation over
time (60% — see below) and is
generally avoided in patients with
moderate to severe symptoms.33
Levodopa may have a role in
patients with very mild or occasional symptoms and can be used
intermittently rather than regularly
in this setting. A dose of 50/12.5mg100/25mg of regular-release preparation is used initially. Because of its
rapid action, levodopa can be used
as a diagnostic test and a partial or
complete response to a single dose is
suggestive.
If levodopa therapy is to be used
in more severe disease, longeracting preparations are preferred
to avoid rebound symptoms
and often in combination with
a short-acting formulation (eg,
Sinemet CR 100/25mg + Sinemet
100/25mg). Levodopa in combination with a catechol O-methyl
transferase (COMT) inhibitor
(Stalevo) is another option for
increasing half-life.
Treatment
Lowest possible dose of
dopaminergic agent for as long as
possible
Exclude or treat iron deficiency
Increase daytime activity (eg,
encourage walking)
Split dose of dopaminergic
medication or add additional dose
Switch to another dopamine
agonist – nil cross-tolerance
Switch to anticonvulsant or opioid
Combination therapy
Drug holidays
Attacks of sudden
onset of sleep and
excessive daytime
sleepiness are
associated with
dopamine agonist
therapy ... patients
need to be cautioned
about driving and
operating heavy
machinery.
Table 4: Incidence of augmentation
Dopaminergic agonist
% of cases with augmentation
Levodopa
27-82%
Pramipexole
9.2-30%
Ropinirole
7%
Rotigotine
9.7%
Tramadol
reports
in Parkinson’s and with night-time
dosing this complication is less
commonly encountered.
Dopamine agonist side effects
Impulse-control disorders
Impulse-control disorders have been
well reported and characterised in
Parkinson’s and were thought to
be rare in RLS. Recent data have
reported rates of 7-17%, similar
to rates in Parkinson’s disease.34
Impulse-control disorders are a
complex of disinhibitory psychomotor behaviours and include excess
gambling, hypersexuality, excess
shopping and dopamine addiction.
These can be devastating for patients
and cause financial ruin. Screening
for these disorders should be routine
during follow-up. Impulse-control
disorders are reversible upon cessation of dopamine agonist therapy
or lowering of dose. The common
occurrence of impulse-control disorders in the RLS-treated population may be an argument against
their current use as first-line agents.
Levodopa therapy does not seem to
carry this risk.
Dopamine agonists are associated
with unique side effects that have
come to light in more recent times
and these need to be discussed with
patients before starting therapy.
The common side effects include
nausea, headache, dizziness and
oedema.
Attacks of sudden onset of sleep
and excessive daytime sleepiness
are associated with dopamine agonist therapy in Parkinson’s disease.
Its prevalence in RLS is slightly
higher than controls and patients
need to be cautioned about driving
and operating heavy machinery
in the early stages of treatment.
Doses used in RLS are lower than
Augmentation
Augmentation is a significant complication of dopaminergic therapy
for RLS. It is an intensification
of RLS symptoms above baseline
associated with prolonged dopaminergic stimulation.
Some factors favour the development of augmentation. These
include high medication doses,
use of short half-life medications,
longer duration of therapy and
positive family history of RLS.
It is therefore most commonly
seen with levodopa therapy (table
4) and can be seen within 2-4
months. Dopamine agonists are
26
| Australian Doctor | 2 August 2013
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also associated with augmentation
at lower rates. The presentation is
that of quite severe RLS symptoms
and may involve more pain and
paraesthesia.
Diagnosis. Clues to the development of augmentation include
earlier onset of symptoms in the
evening, a shorter latency during
inactivity and extension of symptoms to other body parts (see box
above right). In its most severe
form, it may resemble akathisia,
with a feeling of inner restlessness
and inability to sit or stand still.
The circadian pattern may also be
lost and walking may not relieve
symptoms. It is likely related
to overstimulation of dopamine receptors with subsequent
decreased receptor sensitivity.
Management. The major goal is
prevention and using the lowest effective dose of dopaminergic medication is recommended.
Severity of symptoms should also
be taken into account and mild
augmentation may not require
change in medication. Exacerbating factors should be addressed; in
particular iron deficiency (ferritin
<50μg/L) should be sought and
treated. With moderate symptoms,
dopaminergic medication can be
split into two with an earlier dose
given in the afternoon.
Alternatively, a changeover to
a longer-acting formulation can
be trialled. Another strategy is to
change to a different dopamine
agonist, as there is no cross-tolerance. With severe symptoms, it
may be necessary to stop dopaminergic therapy altogether while
overlapping therapy with a dif-
ferent class of agent. Another
approach that can be used is rotation of dopaminergic therapy at
three-monthly intervals.
Anticonvulsants
The most widely used anticonvulsants in RLS are gabapentin and
pregabalin. Gabapentin enacarbil,
a prodrug of gabapentin, has also
been well studied in RLS. It has the
advantage of more prolonged action
compared with gabapentin, but it is
not currently available in Australia.
Anticonvulsants are effective
agents for moderate to severe symptoms and are not reported to produce augmentation as a side effect.
Their efficacy has been confirmed
in seven trials with a responder rate
of 61% (>50% reduction in IRLS
score) and a number needed to treat
of 4.1.32
They have also been shown to
improve sleep parameters. They
are a good choice in patients with
secondary forms of RLS such as
coexisting neuropathy or in haemodialysis patients. Anticonvulsants
are also a good choice in patients
with prominent pain.
Often they are used in combination with other RLS agents to treat
severe symptoms. Their side-effect
profile is also favourable although
elderly patients may develop dizziness, somnolence and oedema.
Although they have not been
directly compared with dopaminergic agents, they are seen as being
less effective for the primary form
of RLS.
Valproate, carbamazepine and
topiramate have also been evaluated in RLS with mixed results.
These drugs’ side-effect profile is less
favourable, which also limits their
widespread use.
Gabapentin is initiated as a
night-time dose of 200-300mg and
increased as required. Doses up to
1200mg at night can be used. A
regular daytime dose is often given
when symptoms progress. Pregabalin is utilised in a similar fashion and
is started at 25-50mg at night.
cont’d page 29
How To Treat – Restless legs syndrome
Severe or refractory RLS
Opioids
THE opioids have traditionally
played an important role in the
management of RLS. They have
been less well studied in comparison
with dopamine agonists or anticonvulsants. Despite this, they can be
highly effective even at low doses.
The two agents most commonly
used are oxycodone and tramadol.
The single oxycodone trial showed
a 52% improvement in RLS symptoms along with improvement in
periodic limb movements in sleep.35
These agents should be used with
caution, given the risk for abuse and
addiction. However, in severe cases
there is often little choice but to
recommend these agents. The main
side effects are constipation, respiratory depression and dependence.
Respiratory depression requires
special mention, as there is a higher
prevalence of sleep apnoea in RLS
patients. These agents are often
used in combination with dopaminergic agents to control symptoms
completely. Augmentation has been
reported with tramadol and it is not
yet clear whether this extends to
other opioids.
Oxycodone is started at a dose
shown benefit in two trials and is
used at doses of 0.05mg a day up
to a maximum of 0.4mg a day.38,39
The main side effects are sedation,
dry mouth and hypotension.
When to refer
of 5mg at night and used at mean
doses of 15mg daily. The extended
release formulation is typically used.
Tramadol is started at 50mg and is
available in a sustained-release formulation.
in two small trials with mixed
results.36,37 It is less effective than
other therapies and is used primarily for insomnia associated
with RLS. Clonazepam has a long
half-life and may cause daytime
somnolence. It is also prone to
cause respiratory depression and
dependence.
Despite these drawbacks, it is
Other drugs
Clonazepam
This agent
has
been
studied
useful in combination with other
therapies to improve sleep. Clonazepam is started at doses of
0.25mg at night and can be used
at doses up to 2mg.
Clonidine
Clonidine is associated with significant side effects and has a minor
role in RLS therapeutics. It has
It is not unreasonable for GPs to
initiate therapy for mild to moderate RLS. Referral may be sought
after an adequate trial of one
or two agents, when symptoms
become more severe or if there is
a lack of response. The development of augmentation is another
indication for referral.
Referral should also be considered in secondary forms of RLS
to assist with management. All
general neurologists are capable
of managing RLS, although more
advanced aspects of therapy may
require input from a movement
disorder specialist.
Research and other measures
Pneumatic compression devices have
shown promise in a single controlled
trial and are still investigational.40
Little data is available on other nonpharmacological therapies, as these
studies use very small numbers.
Recommended approach
A PRACTICAL approach is to use
dopaminergic agents as first-line
therapy for primary RLS in the
younger population. With RLS that
starts later in life, is secondary in
nature or has prominent pain, anticonvulsants often make the best
first-line therapy (figure 3). In those
with addictive personality traits,
dopamine agonists are best avoided
as first-line agents. In general, opioids should be avoided initially
and only used in combination with
other agents for moderate to severe
disease. Anecdotally, while clonazepam can be useful as an adjunct to
therapy it does not provide complete
control of symptoms when used as
monotherapy.
Special populations
Certain situations require an alteration of approach and this is especially true of pregnancy.
Pregnancy
In pregnancy, RLS is severe in
40% of cases and treatment cannot
always be avoided.
Iron replacement should be used
first line, followed by opioids, as
there are fewer safety concerns with
these agents. Dopaminergic agents
such as pramipexole can also be
used in severe cases, as there is reasonable evidence of safety from
other populations; however, they are
considered as a last resort.
End-stage renal failure
In patients with end-stage renal failure or on dialysis, gabapentin is used
first line and requires dose adjustment. In this setting, iron infusion
may also be successful. Clonidine
is an alternative option that may be
considered. RLS will often subside
following renal transplantation.
Parkinson’s disease
In patients with Parkinson’s, the
Figure 3: Management guideline.
Restless legs syndrome
Mild
symptoms
• Sleep hygiene
• Exercise
• Iron
replacement
if ferritin low
• Low-dose
levodopa prn
Secondary RLS
Primary RLS
Moderate to severe
symptoms
• Pramipexole
• Ropinirole
• Gabapentin or
pregabalin
• Long-acting dopamine
agonist
• Dopamine agonist and
opioid/clonazepam
• Dopamine agonist and
gabapentin
Moderate to severe
symptoms
• Gabapentin or
pregabalin
• Gabapentin and
pramipexole
• Gabapentin and opioid
• Other anticonvulsants
• Clonidine
Summary of treatment
Mild RLS
Augmentation
— Exercise, magnesium. Low-dose levodopa as prn therapy
— Treat iron deficiency
Moderate RLS
• Split dosing of dopamine agonist
• Change to longer-acting dopamine agonist
• Change to another dopamine agonist
• Change to gabapentin or opioid
• Dopamine agonist rotation
— Pramipexole or ropinirole initially
— Gabapentin in certain populations
— With increasing duration of symptoms
• Split dose of dopamine agonist or extra dose earlier in evening
• Change to extended release formulation
— With increasing intensity of symptoms
In those with
addictive personality
traits, dopamine
agonists are best
avoided as first-line
agents.
evening dose of levodopa may
be increased. Rotigotine and
extended release pramipexole may
also be considered.
Neuropathy
First-line agents for patients with
neuropathy are gabapentin or pregabalin. Difficult-to-treat cases
may require the addition of an opioid or a dopamine agonist. Other
anticonvulsants such as valproate
and carbamazepine are also effective alternative treatment options.
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• Add gabapentin at night
• Add tramadol/oxycodone
• Change dopamine agonist
Severe RLS
— Dopamine agonist plus opioid or clonazepam
— Gabapentin/pregabalin plus opioid
— Dopamine agonist washout and replacement with another class
— Clonidine
— Drug holidays
— Rotation of dopamine agonist every three months
cont’d next page
2 August 2013 | Australian Doctor |
29
How To Treat – Restless legs syndrome
Case study
Online resources
ALBERT is an 87-year-old man who presented
with persistent restless legs. He has had this problem for the past 30 years and had sought medical
advice from GPs and neurologists on numerous
occasions.
He complains of legs that recurrently involuntarily twitch or jerk suddenly when he is trying to
get to sleep, and occasionally is woken up by these
movements, although he does have a disjointed
sleep broken by nocturia. He blames the restless
legs on his past history of polio as a child, which
had affected his right leg. However, he still has full
use of his legs and mobilises without aid or assistance.
In the past he has trialled various medications
including pramipexole, levodopa and carbidopa,
clonazepam and carbamazepine. He also frequently requests temazepam to help him overcome
the restless legs and get to sleep. He is currently on
pramipexole 0.75mg daily and attributes his constipation to this. As a result, he is taking increasing
doses of Coloxyl, Movicol and Senakot to manage
this.
International Restless Legs
Syndrome Study Group
Includes rating scale (IRLS)
irlssg.org
Because of treatment resistance, he proceeded to
have sleep studies, which confirmed the presence of
periodic limb movements in sleep and myoclonus.
The pramipexole was tapered over a week and
at the same time he was started on gabapentin at
200mg each night. This was increased to a maintenance dose of 400mg a night. At this dose, his limb
movements subsided and he was far less troubled
by limb jerking. He did not tolerate a low dose of
clonazepam (0.25mg) in combination with this.
Polio and in particular post-polio syndrome is a
rarely described secondary cause of RLS.41 It frequently begins when other symptoms of post-polio
syndrome begin and is often associated with new
muscle pain. Sleep studies in these patients demonstrate a variety of movements including periodic
limb movements in sleep, myoclonus and more
ballistic movements. Interruption of spinal cord
pathways from past polio is a likely mechanism
for RLS in this disorder. Treatment is usually the
same, however the nocturnal movements are more
likely to respond to anticonvulsants and benzodiazepines.
References
Available from howtotreat
@cirrusmedia.com.au
Further reading
•Walters AS, et al. Validation of
the International Restless Legs
Syndrome Study Group rating
scale for restless legs syndrome.
Sleep Medicine 2003; 4:121-32.
• Aurora R, et al. The treatment
of restless legs syndrome and
periodic limb movement disorder
in adults — an update for 2012:
practice parameters with an
evidence-based systematic review
and meta-analyses. Sleep 2012;
35:1039-62.
• Wilt T, et al. Pharmacologic
therapy for primary restless legs
syndrome: a systematic review
and meta-analysis. JAMA Internal
Medicine 2013; 173:496-505.
Conclusion
RLS is a very common sleep–wake
disorder with a complex pathophysiology. The recent insights into iron
metabolism and deficiency within
the nervous system are a key to
understanding its pathogenesis and
its likely secondary effects on other
neurotransmitters.
It is important to recognise that
there are primary and secondary
forms of RLS and that management
will vary according to this. The diagnosis is relatively simple and almost
entirely clinically based. An important clue to this is the response to
dopaminergic medication.
Several treatment-related issues
can complicate long-term management. The most important are
those associated with dopaminergic
therapy and include impulse-control disorders and augmentation.
The former has emerged as a significant risk in the RLS population
Instructions
How to Treat Quiz
Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points.
We no longer accept quizzes by post or fax.
The mark required to obtain points is 80%. Please note that some questions have more than one correct answer.
Restless legs syndrome
— 2 August 2013
1. Which TWO statements are correct
regarding epidemiology of restless legs
syndrome (RLS)?
a) RLS is most commonly diagnosed from midlife to later life
b) RLS is rare, affecting less than 0.1% of the
population
c) RLS is very rare in children, affecting less than
0.02% of the paediatric population
d) RLS affects women twice as often as men
2. Which TWO statements are correct
regarding the epidemiology and
pathophysiology of RLS?
a) Excessive stimulation of the dopaminergic
pathways is not implicated in the
pathophysiology of RLS
b) Genetics is not a factor in the pathogenesis
of RLS
c) Iron deficiency may be a contributing factor
of RLS
d) RLS may be secondary to systemic
conditions such as renal failure
3. Which TWO statements are correct
regarding the clinical features of RLS?
a) There is an urge to move the legs that is
relieved by activity
b) Patients often complain of sleep disruption
and requires careful discussion with
patients before initiation of therapy.
Despite this, dopamine agonists
remain first-line agents in most
cases. With increasing disease severity, more complicated regimes are
employed and combination therapy
is often required.
GO ONLINE TO COMPLETE THE QUIZ
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and insomnia impacting on quality of life and
general health
c) RLS is never present during the day
d) RLS symptoms are typically worst in the late
afternoon
4. Which TWO statements are correct
regarding the diagnosis of RLS?
a) Diagnosis may be made with a 100/25mg
levodopa challenge
b) The circadian pattern of RLS is the most
useful at differentiating it from other diagnoses
c) A genetic blood test confirms the diagnosis
d) Polysomnography is the first-line investigation
for the diagnosis of RLS
5. Which THREE of the following conditions
are causes of secondary RLS?
a) Coeliac disease
b) Rheumatoid arthritis
c) Polycythaemia
d) Multiple sclerosis
6. Which THREE of the following are mimics
of RLS?
a) Akathisia
b) Parkinson’s disease
c) Painful neuropathy
d) Leg cramps
7. Which TWO statements are correct
regarding the medications used to treat
RLS?
a) More than 60% of patients treated with a
dopamine agonist respond with a >50%
reduction in the International Restless Legs
Syndrome Study Group rating scale (IRLS)
score
b) Ergot-derived dopamine agonists such as
cabergoline are the first-line drugs of choice
for RLS
c) Low-dose opioids may be used with close
monitoring in refractory RLS
d) Levodopa is a drug of choice when the RLS
is moderate to severe
8. Arthur, an 82-year-old man, presents
with frequent insomnia because of an
urge to move his legs that is relieved only
when he moves his legs. Which TWO
statements are correct?
a) RLS can be clinically diagnosed with 84%
specificity if Arthur has the first four essential
features of the 2011 revised IRLS criteria
b) Elderly patients presenting with first-onset
RLS are more likely to have a secondary
form
c) Arthur should be screened for co-occurring
multiple sclerosis
d) Arthur should be referred to a sleep
physician for further review
9. Which TWO statements are correct
regarding investigation and diagnosis of
Arthur’s presentation?
a) Blood tests should be ordered, including
iron studies, vitamin B12, renal function,
and possibly an autoimmune panel, coeliac
serology and nerve conduction studies
b) The presence of periodic limb movements in
sleep is diagnostic of RLS
c) RLS is excluded if Arthur also experiences
symptoms during the day
d) A review of Arthur’s medications, including
antidepressants, is essential
10. Which TWO statements are
correct in the management of Arthur’s
condition?
a) Arthur may be advised that dopamine
agonists are hormone mimics and therefore
have no significant side effects
b) For mild symptoms, sleep hygiene, iron
replacement and exercise may be sufficient
c) Arthur should be started on a dopaminergic
agent as the first-line therapy
d) Augmentation may occur within 2-4 months
of dopamine agonist therapy
CPD QUIZ UPDATE
The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2011-13 triennium.
You can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept
the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.
how to treat Editor: Dr Steve Liang
Email: [email protected]
Next week The prevalence of chronic disease and comorbidity increases significantly with age. Therapeutic guidelines give little consideration to age or comorbidity. The next How to Treat looks at the
complexities of pharmacological therapy for the older patient, as this population is vulnerable to prescribing complications. The authors are Associate Professor Sarah Hilmer and Associate Professor
Susan Ogle, both senior staff specialists, Royal North Shore Hospital, St Leonards, and associate professors, Sydney Medical School, University of Sydney, NSW.
30
| Australian Doctor | 2 August 2013
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