5 - SLEEP DISORDERS
Restless Legs Syndrome/Periodic Limb Movement
Restless Legs Syndrome
(RLS) is a sensorimotor disorder characterized by periodic irresistible
urges to move the legs, usually associated with unpleasant and
uncomfortable sensations in the legs. These symptoms occur during
wakefulness, but are exacerbated or engendered by rest/inactivity
and partially relieved by movement. The diurnal pattern of symptoms
likely reflects modulation by the circadian system. RLS is reported
to profoundly disturb sleep, yet the extent of nocturnal sleep
disturbance and of daytime sleepiness has not been established.
Estimates of RLS in various populations range from 2 to 15%,
but incidence and prevalence have not been precisely defined,
particularly as a function of gender and ethnicity. Several
reports indicate a higher prevalence of RLS among women than
men, and in individuals of Northern European ancestry. The etiology
and pathogenesis of RLS are thought to involve alterations in
efficiency of central dopamine neurotransmission, based largely
on the clinical observation that dopaminergic drugs relieve
symptoms. The inheritance pattern of RLS suggests an autosomal
dominant mode of transmittance, but the genes accounting for
this observation are not known. RLS is also associated with
iron deficiency, and is quite common in end-stage-renal disease
and during pregnancy.
About 85-90% of patients
with RLS also exhibit periodic limb movements (PLMs) during
sleep. Unlike RLS, which is diagnosed on the basis of history
and symptoms, periodic limb movement disorder (PLMD) relies
upon quantification of repetitive stereotypic leg movements
associated with a brief arousal during sleep monitoring. Patients
manifesting PLMD have complaints of daytime fatigue and sleepiness
or insomnia. Similar to RLS, PLMD may involve altered central
dopamine mechanisms since dopaminergic agents or other drugs
that interact with dopamine mechanisms, e.g., opiates, are equally
effective treatments for most patients. The incidence of PLMD,
like RLS, is higher in the elderly. Without better understanding
of the etiology, pathogenesis, and neurophysiology of these
disorders, treatment strategies are limited, and can be unsatisfactory.
Both disorders have profound negative impact on quality of life
including daytime functioning, work performance, and social
and family life.
about the clinical significance of PLMs during sleep in the
absence of sensory complaints consistent with RLS. PLMs can
occur without associated EEG micro-arousals and in the absence
of sleep complaints or of daytime symptoms. If associated with
micro-arousals, the frequency of PLMs does not correlate with
objective measures of daytime sleepiness or with indices of
disrupted sleep. This lack of a correlation may reflect insensitivity
in the methods used for scoring EEG micro-arousals and sleep
fragmentation. Abnormal limb movements during sleep have been
associated with physiological correlates of arousal in autonomic
or cortical functioning suggesting that PLMs are part of an
underlying arousal disorder. It is possible that abnormal limb
movements during sleep may be associated with an unidentified
neurophysiological alteration in micro-structure of the EEG
In The Last 5 Years
- Several potential
animal models of RLS and PLMD have been developed based upon
interruption of normal dopaminergic responsivity.
- Imaging studies
suggest reduced central dopamine receptor binding with age,
but only small and inconsistent decreases in dopaminergic transmission
have been reported in traditional nigrostriatal dopaminergic
pathways in patients with RLS. This finding suggests that alterations
might exist in extrastriatal dopaminergic pathways.
- RLS and PLMD are
more common in children with attention deficit hyperactivity
disorder providing an opportunity to address developmental aspects
of these disorders and responsivity to dopaminergic interventions.
studies in humans suggest that RLS is associated with inefficiencies
of spinal cord inhibition that may be brainstem mediated and
- RLS shows high
familial aggregation. A recent study of genes involved in central
dopaminergic transmission and metabolism showed no evidence
of involvement in RLS. However, other recent studies have identified
a susceptibility locus for RLS on chromosome 12q in a large
French-Canadian family and a polymorphism in a gene involved
in catecholamine (monoamine oxidase A) metabolism in women with
- Central Nervous
System (CNS) imaging studies have shown reduced iron concentrations
in some brain regions. These reductions correlate with RLS severity
and low cerebral spinal fluid (CSF) ferritin combined with high
serum and CSF transferrin levels.
- The RLS case definition
was updated and revised in 2002. This provides a basis for the
development of specific questionnaires to advance clinical recognition
and to clarify RLS prevalence.
- EEG patterns of
cortical activation precede PLMs and indices of autonomic arousal,
suggesting that PLMD are associated with an underlying arousal
- Determine the role
of altered central dopaminergic mechanisms, iron metabolism,
and other possible mediators in the pathogenesis of RLS and
PLMD through animal and human studies. The development, refinement,
and validation of animal models for RLS and PLMD are needed.
Modern techniques of neuropathology in the evaluation of brains
and spinal cords from patients with RLS and PLMD should be used
to identify potential abnormalities underlying these disorders.
- Identify and further
characterize genes involved in RLS and PLMD.
- Determine the extent
of nocturnal sleep disturbance and daytime sleepiness in children
and adults with RLS and PLMs.
- Develop and validate
questionnaires based on the new RLS case definition and determine
the population-based incidence, prevalence, and morbidity, particularly
in children and as a function of gender, race, and ethnic distribution.
- Establish the developmental
changes in adults explaining the higher incidence of RLS and
PLMD in the elderly.
- Pregnancy and uremia
provide reversible models to study the development and remission
of RLS and the role of altered iron metabolism. Conduct clinical
trials of iron supplementation in RLS patients with low ferritin
- Improve available
treatment strategies for RLS and PLMD. Dopamine agonists, opioids,
and anticonvulsants are used most frequently and are effective
in reducing RLS symptoms and PLMs, but the necessary large multi-center
trials and long-term studies have not been conducted. These
studies should include assessment of quality of life and assess
the sensitivity of existing questionnaires to treatment changes.