Ferini_EU Neurology 09/03/2010 11:51 Page 84
Restless Legs Syndrome
moderately or severely distressing by 2.7%. These subjects were compared with the D
2
and D
3
receptors, predominantly at the spinal
defined as RLS sufferers and probably required treatment. level.
23
It has recently been shown that iron deficiency and sleep
deprivation may increase the risk of augmentation.
23
Prevalence rates
Primary or secondary forms may be recognised in RLS.
3
In the primary of augmentation in open-label trials with levodopa range from 18.6 to
forms, there is substantial evidence of a genetic contribution to RLS. 82%.
24
A recent study showed augmentation in 36 of 60 patients (60%)
Familial aggregation has been well documented, with about 50% of treated for six months with levodopa (median daily dose 300mg).
25
idiopathic cases reporting a positive family history of RLS: in most Increased severity of RLS and higher dosage of levodopa are
pedigrees, it segregates in an autosomal dominant fashion, with a high associated with higher risk of developing augmentation: maximum
penetrance rate (90–100%).
12
dosages of 300–400mg should not be exceeded.
20
Linkage studies in RLS families have revealed eight loci, but no causally Several double-blind controlled studies have shown that both ergoline
related sequence variant has been identified using this approach.
12
A (cabergoline, pergolide) and non-ergoline (ropinirole, pramipexole,
recent genome-wide association study of RLS identified common rotigotine) dopamine agonists are able to control RLS symptomatology.
12
variants in three genomic regions: MEIS1, BTBD9 and MAP2K5 on In a short-term follow-up study, the D
2
receptor agonist bromocriptine
chromosomes 2p, 6p and 15q, respectively.
13
Each genetic variant was was found to be effective in treating RLS and PLMS.
26
However,
associated with a greater than 50% increase in the risk of RLS. MEIS1 has bromocriptine is frequently associated with severe adverse effects,
been implicated in limb development, raising the possibility that RLS has especially nausea.
27
Pergolide, another D
2
receptor agonist, has been
components of a developmental disorder.
13
A genome-wide significant more extensively studied and its efficacy has been well-documented in
association with a common variant in an intron of BTBD9 on short- and long-term follow-up studies.
28,29
An open follow-up of a
chromosome 6p was found independently in the Icelandic population.
14
controlled study in 28 RLS patients showed that the beneficial effect of
An association between this variant and PLMS without RLS (and the pergolide persisted for at least one year in 22 patients (79%): five
absence of such an association for RLS without PLMS) suggests that it is subjects (18%) discontinued medication, predominantly because of
a genetic determinant of PLMS.
14
nausea, and six (21%) developed augmentation.
29
Cabergoline, a long-
acting D
2
receptor agonist, was also used successfully to treat RLS, and
The most common causes of secondary RLS are iron deficiency, the beneficial effects of a low dose of drug (mean dosage 2.2mg) on
end-stage renal disease and pregnancy.
1–3
Peripheral neuropathies of symptoms has been demonstrated to persist for up to one year.
30
A
different origin, diabetes and multiple sclerosis have been seen at higher recent controlled study with cabergoline showed a frequency of
than expected frequencies in RLS patients.
15–17
Moreover, RLS has been augmentation of 4%.
31
reported as an adverse event resulting from treatment with several
drugs.
18
The majority of published papers focusing on this issue are case Retroperitoneal, pericardial and pleuropulmonary fibrosis are well
reports, but in a recent prospective study that addressed this problem known but rare complications of treatment with ergolinic dopamine
for the class of second-generation antidepressants, RLS was observed in agonists.
32
Recently, two studies also showed that pergolide and
9% of patients.
19
cabergoline were associated with an increased risk of cardiac-valve
regurgitation compared with non-ergot-derived dopamine agonists.
33,34
Pharmacological Treatment of
Restless Legs Syndrome In the last few years two non-ergoline-derivative agonists, pramipexole
Pharmacological treatment should be limited to those patients who and ropinirole,
12,20
have been extensively studied for RLS treatment. A
suffer from clinically relevant RLS symptoms, including intermittent RLS recent double-blind, placebo-controlled study confirmed the efficacy of
with impaired sleep quality or quality of life.
12,20
Dopaminergic agents are pramipexole, a full agonist with high affinity for the D
3
receptor subtype,
considered first-line treatment.
3,20
at a median dose of 0.35mg/day.
35
In a long-term follow-up study, of
78% of patients who took pramipexole for more than a year, 96%
Several open-label studies have documented the short-term efficacy showed sustained improvement in their RLS symptom severity after a
of levodopa given with a dopa-decarboxylase inhibitor.
3
Dosages of mean 30 months of treatment.
36
Augmentation with pramipexole was
standard levodopa of between 100 and 200mg improve RLS symptoms reported in open trials, ranging from 8.3 to 39%.
37–39
Some randomised,
as measured on a visual analogue scale.
21
Levodopa is a short-acting placebo-controlled trials have shown that ropinirole is also effective for
medication, and the immediate response without a long titration the treatment of RLS.
27
A long-term open-label study over 52 weeks
period is appreciated by patients.
3
However, a possible side effect of showed that ropinirole (mean dose 1.90mg/day) maintained
levodopa is morning rebound, characterised by the presence of RLS therapeutic efficacy in 83% of RLS patients as measured by the clinical
symptoms occurring de novo as a consequence of evening or night- global impression (CGI) scale.
40
There have been no reports of
time treatment.
3
With levodopa, it is also possible to observe a augmentation in the published studies, but the phenomenon has not
rebound of PLMS in the later part of the night, if levodopa is been systematically assessed.
20
administered only at bedtime.
3
However, the most relevant clinical side
effect of levodopa therapy is augmentation.
22
Augmentation is a Sleepiness associated with sudden onset of sleep was reported in
phenomenon characterised by an earlier onset of symptoms by at patients with Parkinson’s disease (PD) treated with pramipexole and
least four hours, or an earlier onset by between two and four hours ropinirole.
41
In RLS patients, sleepiness might be seen during treatment
plus at least one of the following compared with symptom status with dopamine agonists, but is much less problematic;
3
moreover, the
before treatment: shorter latency to symptoms when at rest; extension use of these compounds in RLS may, in contrast to PD, reduce the risk
of symptoms to other body parts; greater intensity of symptoms; and of sudden onset of sleep, probably due to their beneficial effect on
shorter duration of relief from treatment.
22
Augmentation is probably sleep.
42
Striatal and limbic dysregulation have been suggested in PD as
triggered by intense dopaminergic stimulation of the D
1
receptor putative factors in compulsive behaviours arising from dopamine
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