Restless Legs Syndrome (RLS, Wittmaack-Ekbom's syndrome) is a condition that is characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can also affect the arms or torso. Moving the affected body part modulates the sensations, providing temporary relief. RLS causes a sensation in the legs or arms that can most closely be compared to a burning, itching, or tickling sensation in the muscles. Some controversy surrounds the marketing of drug treatments for RLS.
RLS may start at any age, including early childhood, and is a progressive disease for a certain portion of those afflicted, although the symptoms have disappeared permanently in some sufferers.
OMIM RESTLESS LEGS SYNDROME, SUSCEPTIBILITY TO, 1; RLS1
Linkage Analysis Identifies a Novel Locus for Restless Legs Syndrome on Chromosome 2q in a South Tyrolean Population Isolate, 2006
EPIDEMIOLOGY
RLS affects an estimated 7% to 10% of the general population in North America and Europe. Only a minority of sufferers (around 2.7% of the population) experience daily or severe symptoms. RLS is twice as common in women as in men, and whites are more prone to RLS than African Americans. RLS occurs in 3% of individuals from the Mediterranean or Middle Eastern region, and in 1-5% of those from the Far East, indicating that different genetic or environmental factors, including diet, may play a role in the prevalence of this syndrome. With age, RLS becomes more common, and RLS diagnosed at an older age runs a more severe course.
RLS is even more common in individuals with iron deficiency, pregnancy and end-stage renal disease. Neurologic conditions linked to RLS include Parkinson disease, spinal cerebellar atrophy, spinal stenosis, lumbar sacral radiculopathy and Charcot-Marie-Tooth disease type 2.
DIAGNOSIS
The diagnosis of RLS relies essentially on a good medical history and physical examination. Sleep registration in a laboratory (polysomnography) is not necessary for the diagnosis. Peripheral neuropathy, radiculopathy and leg cramps should be considered in the differential diagnosis; in these conditions, pain is often more pronounced than the urge to move. Akathisia, a side effect of several antipsychotics or antidepressants, is a more constant form of leg restlessness without discomfort.
PATHOGENESIS
Dopamine
Most research on the disease mechanism of restless legs syndrome has focused on the dopamine and iron sistem(iron metabolism ) as a cofactor in dopamine production. These hypotheses are based on the observation that levodopa and iron can be used to treat RLS, but also on findings from functional brain imaging (such as positron emission tomography and functional magnetic resonance imaging), autopsy series and animal experiments (evidence of iron involvement). Late-onset restless legs syndrome is associated with low iron content of the basal ganglia and increased activity of the dorsolateral prefrontal cortex (T2 relaxometry and fMRI of the brain in late-onset restless legs sindrome )
L-dopa
Topographic scalp amplitude mappings from the distracter and target stimuli. Each participant in the 3 groups (7 per group), controls, patients with restless legs syndrome, and patients with Parkinson's disease, performed the same task. The patients were matched for age, sex, and education. The P3a amplitudes illustrate increasing dopaminergic deficits from left to right; the P3b amplitudes differed little between the control group and the patients with restless legs syndrome; patients with Parkinson's disease had appreciably smaller amplitudes overall.
Differences in dopamine- and iron-related markers have also been demonstrated in the cerebrospinal fluid of individuals with RLS. A connection between these two systems is demonstrated by the finding of low iron levels in the substantia nigra of RLS patients, although other areas may also be involved.Therefore reflecting a basic disturbance of iron metabolism RLS patients have transferrin receptor
TfR
and DMT1 levels in lymphocytes significantly higher than for controls. No significant differences in ferritin subtypes or transferrin levels were found.(Altered iron metabolism in lymphocytes from subjects with restless legs syndrome )
Ferritin
RISK FACTORS
The most commonly associated medical condition is iron deficiency (specifically blood ferritin below 50µg/L), which accounts for just over 20% of all cases of RLS. Other conditions associated with RLS include pregnancy, varicose vein or venous reflux, folate deficiency, sleep apnea, uremia, diabetes, thyroid disease, peripheral neuropathy, Parkinson's disease and certain auto-immune disorders such as Sjögren's syndrome, celiac disease, and rheumatoid arthritis.
More than 60% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.(Young JE etc) particularly in those who develop it before age 40.
No one knows the exact cause of RLS at present. Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the substantia nigra (study published in Neurology, 2003). Iron is an essential cofactor for the formation of L-dopa, the precursor of dopamine.
Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to RLS. Their role in RLS pathogenesis is still unclear.
There is also some evidence that periodic limb movements in sleep (PLMS) are associated with BTBD9 on chromosome 6p21.2.
TREATMENT
According to some guidelines, all people with RLS should have their ferritin levels tested; ferritin levels should be at least 50 µg for those with RLS. Oral iron supplements can increase ferritin levels. For some people, increasing ferritin will eliminate or reduce RLS symptoms. A ferritin level of 50 µg is not sufficient for some sufferers and increasing the level to 80 µg may greatly reduce symptoms.
Dopamine agonists, such as ropinirole, pramipexole, carbidopa / levodopa or pergolide, can be used to treat RLS but may cause augmentation. This is characterised by a severely increased dopamine concentration in the CNS; overstimulation of the dopamine D1 receptors compared with D2 receptors in the spinal cord may lead to D1-related pain and generate periodic limb movements. Dopamine agonists may also cause rebound, when symptoms increase as the drug wears off. Also, a recent study indicated that dopamine agonists used in restless leg patients can lead to an increase in compulsive gambling and iron deficiency may be a main predisposing factor of augmentation, probably caused by a reduced function of the dopamine transporter.
