Restless legs syndrome is a nervous disorder where patients have an irresistible urge to move their legs. Great advances in understanding the condition have been made. Ongoing research offers hope for successful new treatments.
Restless legs syndrome (RLS) has been known for centuries. In 1672, Sir Thomas Willis, an English physician wrote of “leapings and contractions“ so intense that sufferers “are not more able to sleep than if they were in a place of the greatest torture.“ RLS is characterised by four criteria, as defined by the International Restless Legs Syndrome Study Group: (i) the desire to move the limbs associated with numbness of the legs; (ii) a motor restlessness; (iii) an intensification of symptoms at rest with relief by activity; and (iv) a worsening of symptoms in the evening or at night.
RLS patients have an irresistible urge to move their legs, often accompanied by creeping, twitching feelings. These sensations commonly intensify in the evening or at night, leading to sleep disturbances and insomnia. Patients with RLS have a characteristic difficulty in trying to describe their symptoms; they may report sensations such as an almost irresistible urge to move their legs, which are not painful but are distinctly bothersome. The severity of symptoms ranges from mild to intolerable.
RLS, which is also known as Ekbom Syndrome, was originally classified as a peripheral nerve dysfunction. In the mid-1940s, Swedish neurologist Karl A. Ekbom described a disorder characterised by sensory symptoms and motor disturbance of the limbs, mainly during rest. He named the condition “restless legs syndrome”. Today it is generally accepted that the problem originates in the central nervous system. Alternations in the complex integration between structures of the peripheral and central nervous system may play a role in its onset.
The diagnosis of the condition is based on the four criteria mentioned above and the measurement of periodic limb movements during sleep (PLMS) which can wake patients up several times and seriously disturb sleep. In general, night-time leg movements are recorded by a nocturnal polysomnogram to compare change in PLMS before and after specific treatment.
Patients with RLS report significantly lower quality-of-life scores than subjects without the syndrome. Patient surveys have evaluated the impact of the disease on sufferers. Results revealed that nearly half of patients polled believe that their symptoms have negatively affected their relationship with their partner. Ten per cent claim that they can no longer sleep in the same bed as their partner. Forty per cent of respondents agree that the symptoms of RLS make them anxious, and 50 per cent report a general feeling of fatigue.
RLS is a common disease in the general population. Although the syndrome affects about ten per cent of the European and US adult population, it is often unrecognized and misdiagnosed. In 2004, the RLS patient group for Germany reported that 870,000 people were suffering from the condition in that country alone.
Population-based studies are rare, and risk factors in the general population are not known. Between 50 and 90 per cent of patients with RLS report a positive family history. An autosomal dominant inheritance is suggested. Symptoms progress over time in about two-thirds of patients. Some patients with uraemia, diabetes mellitus, anaemia, or pregnancy become very symptomatic with this entity.
RLS may begin at any age, even as early as infancy, but most patients who are severely affected are middle-aged or older. Prevalence has been found to increase with age, and women are affected twice as often as men. While the prevalence in women who have never had children is similar to those among men up to age 64 years, the risk of RLS increases gradually for women with one or more children. Apparently, having had children is the major factor in explaining the sex differences.
Until recently, there were no approved treatments for RLS. There was a general perception that RLS is trivial. Research into the syndrome finally suggested that RLS is a sensory-motor condition rather than a psychological one, improving the prospects for effective medical treatment. Dopaminergic medicines have been used to treat some patients as the syndrome was generating increasing interest in the scientific community.
For people with RLS and mild symptoms, lifestyle changes were and still are suggested to produce relief, including: (i) stopping use of caffeine, alcohol, and tobacco products; (ii) taking supplements to increase iron, folic acid, and magnesium in the body; (iii) keeping a regular sleep schedule; and (iv) getting moderate exercise.
Since June 2004, a medicine which has been shown to significantly reduce PLMS in RLS has been available in Europe. The compound – a dopamine agonist that was originally developed to treat Parkinson’s disease – has changed clinical practice for this hitherto overlooked condition by improving motor symptoms, sleep and health-related quality of life. Today, the US National Heart, Lung and Blood Institute guidelines on RLS already say that dopaminergic agents are first-line medicines for most RLS patients.
Comparative trials are underway to investigate the efficacy and safety of different transdermal doses and immediate-release tablets of established dopamine agonist medicine. Further dopamine agonists are being actively developed by different research groups, the most advanced of which is a D3 agonist. It is currently in clinical trials phase 2/3 and, according to its manufacturer, will be available in Europe by 2006.
Another compound under investigation is a combined D2 and D3 agonist which completed phase 2 trials in Europe in 2004 and is now in phase 3.
An experimental approach is a preclinical project by another research group looking into nitric oxide donors for RLS, among other indications.
Research to determine the cause of the syndrome has shown that dopamine-producing cells in the central area of the brain, also known as substantia nigra, are deficient in an iron transport receptor, although there are no unique pathological changes in the cells. This firmly establishes RLS as a sensory-motor rather than psychological disorder, meaning there is a good chance that further treatments can be developed.
Next steps could be to pinpoint other potential breakdowns in the iron packaging and transport system to the centre of the brain, including the genes that regulate the iron transport proteins. This research could lead to diagnostic tests and novel targets for the therapy of RLS.
Additionally, clinical studies have shown that centrally-acting dopamine receptor antagonists reactivate symptoms when given to patients with the syndrome. Results of single-photon emission computed tomography (SPECT) suggest deficiency of D2.
Sympathetic hyperactivity also has been implicated on the basis of observations that sympathetic nerve blockade relieves periodic limb movements during sleep and that alpha-adrenergic blockers improve symptoms of RLS. Studies also have suggested possible underactivity of the serotonin and gamma-aminobutyric acid (GABA) neurotransmitter systems.
Further recommended ways to advance and encourage research in the field of RLS include: (i) the development of an animal model; (ii) additional genetic and epidemiologic investigations of RLS; (iii) efforts to define genetic and non-genetic forms of RLS; and (iv) establishment of a brain tissue bank to aid investigators.