Transcript RLS - Home - Dr Nin Bajaj, MA, FRCP, FRCPE, PhD

Restless Leg Syndrome
Nin Bajaj
Consultant Neurologist
Historical Context
• ‘Instructions for curing the Watching evil “in
London practice of Physick” published in 1685:
‘…..Wherefore to some, when being in bed
they betake themselves to sleep, presently in
the arms and legs. Leaping and contractions of
the tendons and so great a restlessness and
tossing of the members ensure, that the
diseased are no more able to sleep, than if
they were in the place of the greatest
torture!…..’
Glaxo denies pushing 'lifestyle' treatments
· 'Restless leg syndrome can ruin people's lives'
· British drug firms' figures outstrip expectations
Fiona Walsh
Friday April 28, 2006
Guardian
GlaxoSmithKline, Europe's biggest drugs manufacturer, yesterday defended
itself against accusations that it is turning healthy people into patients by
"disease mongering" and pushing "lifestyle" treatments for little-known
ailments.
Studies published in a respected medical journal, the Public Library of Science
Medicine, this month accused the big pharmaceutical companies of
"medicalising" problems such as high cholesterol and sexual dysfunction. The
authors of the report highlighted the "restless legs" syndrome, described by
GSK as "common yet unrecognised" when it launched its Ropinirole treatment
last year.
David Stout, head of GSK's pharmaceutical operations, yesterday denied the
accusations, saying: "You need to talk to the patients. Things like restless leg
syndrome can ruin people's lives. It is easy to trivialise things when you don't
have them. If people did not want the treatments, they would not seek them."
Sleep Disturbance
• Nine out of 10 people with RLS either
cannot get to or stay asleep, or their
sleep is disturbed during the night
[Hening et al, 2004a], and people with
moderate to severe RLS average less
than five hours sleep per night [Allen et
al, 2003].
Description of Sensation
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Like an electric current
The heeby-jeebies
Crazy legs
Like Coca-Cola bubbling through my veins
The gotta-moves
Aching in my bones
Pulling
Elvis Legs
Description of Sensation
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Tearing
Throbbing
Creepy Crawly
Pain
Like a tooth ache in the legs
Growing pains
Itching bones
Like maggots crawling through my veins
Supportive Features
1. Dopaminergic responsiveness
2. Periodic limb movements during sleep
(PLMS) (in individuals under 50 years of
age).
• Periodic limb movements are clonic type
movements (or uncontrollable 'jerks') usually of the lower extremities.
3. Family history- 60% of patients with RLS
especially early onset
Associated Features
1.
Usually progressive, most patients middle to
older age. May occur de novo during or be
exacerbated by pregnancy.
2. Neurological examination usually normal but
can be an associated
neuropathy/radiculopathy
3. Sleep disturbance that can be associated
Prevalence
• 5-10% of the population experiencing
symptoms at some time in their lives
[reviewed in detail in Allen & Earley, 2001].
• In the recent RLS Epidemiology, Symptoms
and Treatment (REST) Primary Care Study,
3.4% of the sample of 23,052 patients
reported RLS symptoms twice a week which
were judged to have a moderate or severe
impact on their quality of life [Hening et al,
2004a].
Familial History
• 24% of young onset RLS patients (< age
45) have a first degree relative with
RLS
• Up to 60% may have a family history
Genetics
• Desautels et al. genome-wide scan in a
large French-Canadian family
• significant linkage chromosome 12q for
RLS with a significant LOD score of
3.59 (RLS 1)
• autosomal recessive
Genetics
• Desautels et al. 2005
• another study which supported the
previously reported chromosome 12q
linkage results
• 276 individuals from 19 families
Genetics
• Bonati et al. (2003) reported (RLS 2)
• locus on chromosome 14q13-21 region in
a 30-member, three-generation Italian
family affected by RLS and PLMS
• autosomal dominant inheritance pattern
Genetics
• Chen et al. (2004) 15 large and
extended multiplex pedigrees consisting
of 453 subjects, 134 were affected
with restless legs syndrome
• novel significant RLS susceptibility locus
on 9p24-p22 with a multipoint
nonparametric linkage (NPL) score of
3.22 (RLS 3).
Neurochemical Basis
• Iron, dopamine, opiates
Iron hypothesis
• conditions that cause secondary RLS – iron deficiency
anaemia, pregnancy and end stage renal failure – are
all linked to iron deficiency [Philipps 2004 Neurology
62:S9-S16]
• Serum iron levels exhibits circadian variation with up
to a 50% drop in iron concentration at night
• Iron is needed for the conversion of tyrosine to dopa
by tyrosine hydroxylase, so a lack of iron could affect
dopaminergic function
• MRI studies have shown depleted iron levels in the
substantia nigra of RLS patients [Allen et al, 2001],
and
Iron hypothesis
• autopsy studies have confirmed depleted iron
and altered iron protein levels [Connor et al,
2003]
• iron-deprived rats, reduced central iron
concentrations have resulted in striatal
changes, including D2R and dopamine
transporter levels, and increased
extracellular dopamine – a pattern of
dopamine abnormalities similar to RLS
patients [Allen and Earley, 2001]
Iron hypothesis
• Intravenous iron supplementation has
been shown to have beneficial effects
on RLS symptoms [Allen and Earley,
2001], but the same has not been shown
for oral iron treatment [Davis et al,
2000]
• In the absence of a peripheral iron
deficiency, the GI tract may not be able
to absorb sufficient iron to affect
central stores in the brain.
Dopamine and RLS
• chance finding that low doses of l-dopa
provided almost complete relief from
RLS [Akpinar, 1982].
• dysfunction of the central dopaminergic
system due to cellular loss in the
mesocorticolimbic dopamine systems
have been implicated
Dopamine and RLS
• positron emission tomographic (PET) and
single photon emission computed
tomographic (SPECT) studies in RLS
patients have found small decreases in
dopaminergic measures in the striatum,
compared with controls [Allen and
Earley, 2001
Dopamine and RLS
• Binding studies showed a decrease for
dopamine D2 receptor in the striatum
• methodology issues make it difficult to
be sure that observed differences were
not due to sleep loss, age differences
between patients and controls, or to
changes in extracellular dopamine [Allen
and Earley, 2001].
Dopamine and RLS
• RLS may originate from disinhibition of
the spinal reflexes as a result of
abnormalities of the dopaminergic and
dopamine-linked systems
• final common pathway may be influenced
by supraspinal opioid and monoamine
pathways
Opiates/Dopamine and RLS
• RLS patients have been shown to have
disturbed supraspinal pain modulation
involving the basal ganglia and/or the
descending dopaminergic pathways [StiasnyKolster et al, 2004]
• Endogenous opioids may play a secondary role
possibly via their effects on the dopaminergic
system
• High doses of opiates can relieve RLS
symptoms, and their beneficial effects can be
blocked by the dopamine antagonist, pimozide
[Montplaisir et al, 1991].
Secondary RLS
• One in five pregnant women get RLS
[Hening et al, 1999], usually during the
later stages of pregnancy or after
childbirth [Allen and Earley, 2001].
• ?associated with reduced serum
ferritin/folate
• Self resolving on parturition
Secondary RLS
• Iron deficiency anaemia
• Diabetes mellitus
• End stage renal disease (ESRD)
(particularly patients receiving
haemodialysis or peritoneal dialysis
• Vitamin B12 /Folate deficiency
• Parkinson's disease
Secondary RLS
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Peripheral neuropathy
Fibromyalgia
Rheumatoid arthritis
Spinocerebellar ataxia
Charcot-Marie-Tooth disease (type 2)
Differential Diagnosis
• Nocturnal leg cramps
• Peripheral neuropathy (not usually
associated with motor restlessness or
helped by movement)
• Vascular disease (such as varicose veins
or deep vein thrombosis)
Differential Diagnosis
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Painful legs and moving toes
Intermittent claudication
Neuroleptic induced akathisia
Attention Deficit Hyperactivity
Disorder in children "growing pains"
• Anxiety or generalised anxiety disorder
Making the Diagnosis
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Clinical symptoms
Normal neurological and vascular exam
Exclude secondary causes with blood tests
Full blood count
Iron studies
Serum ferritin
Serum Vitamin B12 /Folate
Thyroid function tests
Urea & Electrolytes
Serum glucose
Making the Diagnosis
• Sometimes polysomnography to exclude
PLM, Nocturnal awakenings, Sleep
architecture related problems
Treatment- conservative
• Mild RLS may not require medical
treatment
• reassurance should be offered and
lifestyle changes may be useful (e.g.
stopping smoking, relaxation, better
sleep hygiene)
Treatment- conservative
• Some drugs may worsen RLS e.g.
antidepressants, calcium blocker drugs
(used to treat high blood pressure),
anti-nausea medications except
domperidone, high intake of caffeine
and some anti-allergy medications.
Treatment- sleep hygiene
• Walking and stretching
• Hot or cold bath
• Relaxation exercises (biofeedback or
yoga)
• Having an engaging discussion or activity
during sitting to distract mind
• Massaging affected limbs
Treatment- sleep hygiene
• Quiet, comfortable and cool sleeping
environment
• Regular hour for going to bed at night
• Waking at the same time in morning
• Avoiding tea/coffee before bed
• Avoiding water tablets before bedtime
• Some people find sleeping late and rising
late may be beneficial
Drug trials- Levodopa
• A review of 18 studies of levodopa in RLS,
including eight double blind trials, showed
that treatment consistently reduced RLS and
PLMS
• But levels of daytime augmentation up to 82%
(Allen and Earley 1996) and early morning
rebound of 20-35%, especially at high doses
[Standards of Practice Committee of the
American Academy of Sleep Medicine, 1999].
Drug Trials-Levodopa
• combination of regular and slow release
levodopa prolonged the duration of
response compared to conventional
levodopa
Drug Trials-Dopamine Agonists
• number of dopamine agonists, with
activity mainly at D2 receptors, have
been used
• includes the ergot derivatives,
pergolide, cabergoline and alphadihydroergocryptine (DHEC), and the
non-ergot derivatives, pramipexole,
ropinirole, piribedil and talipexole
Dopamine Agonists- Pergolide
• pergolide improves RLS, PLMS and sleep, both
in the short and long term [Hening et al,
2004b].
• nausea was reported in 41%, congestion also in
41%, and augmentation in 27% (Staisny K et al
2001)
• 78.6% of patients remained on long term
treatment
• reports of serious pergolide complications,
typical of ergot agents, including
pleuropulmonary fibrosis or cardiac
valvulopathy [Hening et al, 2004b].
Dopamine Agonists- Cabergoline
• double-blind, placebo controlled, multi-centre dose
finding trial followed by an open-label extension of 47
weeks carried out on 85 patients with cabergoline
(Stiasny-Kolster Neurology 2004)
• Severity of RLS as assessed by the RLS-6 rating
scale and International RLS Study group rating scale,
was markedly improved with a mean cabergoline dose
of 2.2 mg/daily
• Augmentation occurred in 9%
• There were 11 withdrawals over the course of a year
due to drug related side-effects including nausea and
dizziness and one incident of hallucinatory psychosis.
Dopamine Agonists- Requip
• ropinirole assessed in four double blind, placebo
controlled studies with a total of 818 RLS patients
[Trenkwalder et al, 2004; Walters et al, 2004; Allen
et al, 2004; Montplaisir, 2004]
• associated with significant improvements in RLS and
PLMS, quality of life and sleep, which were maintained
over a 36 week period.
• In one study, in which change in PMLS was a primary
endpoint, 54% of patients achieved levels of periodic
limb movements in sleep that were similar to those of
people without RLS/PLMS – defined as five or fewer –
by the 12th week of the study [Allen et al, 2004].
Dopamine Agonists- Mirapexin
• pramipexole in patients with moderate to severe
restless legs syndrome (RLS)
• 12-week, double-blind, randomized, placebo-controlled
trial of fixed doses of pramipexole (0.25, 0.50, and
0.75 mg/day)(N = 344)
• primary efficacy endpoints were patient ratings of
symptom severity on the International RLS Study
Group Rating Scale (IRLS) and clinician ratings of
improvement on the Clinical Global ImpressionsImprovement (CGI-I) scale. Secondary efficacy
endpoints included quality of life (QOL)
Winkelman JW et al. Neurology (2006)
Dopamine Agonists- Mirapexin
• pramipexole was superior to placebo for IRLS in a
dose dependent manner
• pramipexole increased the percentage of patients
with a CGI-I rating of "very much improved" or "much
improved" at the end of the trial
• well tolerated: most frequent adverse events with
higher occurrence in the pramipexole group were
nausea (19.0% vs 4.7%) and somnolence (10.1% vs
4.7%)
Treatment
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2 licensed drugs: ropinerole and
pramipexole
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Start dopmaine agonist of choice
Treatment- Algorithm
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If patients are intolerant to dopamine
agonists then levodopa (Sinemet or
Madopar) should be given at night-time
before bed
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80-82% of patients taking levodopa
may develop augmentation or rebound
Treatment
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If levodopa is no longer effective or if
symptoms start appearing in the early
morning (rebound phenomenon) or
evening/daytime with spread to upper limb
(augmentation), then dopamine agonists may
be reintroduced
cabergoline may be particularly useful as
this drug works given once daily. Dopamine
agonists with shorter half-life may need to
be given up to 3 times a day.
Treatment
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If symptoms are resistant then
carbamazepine or gabapentin may be tried
inhibit the hyperactivity of the nervous
system that may be related to the
symptoms
Gabapentin may be particularly useful for
haemodialysis patients because it is
dialyzable and has a long half-life, and for
'painful' RLS
Treatment
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Severe unremitting painful RLS may
need to be treated by strong
painkillers such as Codeine, Tramadol,
Oxycodone or Propoxyphene under
specialist guidance
Treatment
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Bedtime sedatives such as clonazepam
or zopiclone may be useful in some
cases with severe insomnia
may also exert a beneficial effect by
reducing nervous activity and by
increasing muscle relaxation
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Levodopa 100-600 mg/daily
Bromocroptine 7.5 mg nocte
Pergolide ).75 mg nocte or bd
Ropinerole 0.5-4.0 mg nocte
Pramipexole 1.5 mg nocte/bd
Cabergoline 0.5-4mg nocte
Clonzepam 0.5-2 mg nocte