Restless legs syndrome
What is Restless Legs Syndrome?
Restless Legs Syndrome (RLS) is a neurological disorder characterized by the presence of sensory and motor symptoms in the legs, associated with an urgent need to move the legs, which appear late in the day, during rest, and improve with movement. It was first described by Thomas Willis in 1672, although the complete description of the syndrome was made by Karl Eckbom in 1945.
– Is Restless Legs Syndrome a rare disease?
No, on the contrary, RLS is a common disease, affecting 5-10% of the population. Despite its high prevalence, it is not usually diagnosed until many years after its onset, as the symptoms can be misinterpreted, being attributed to an anxiety or psychiatric problem, which delays its identification, diagnosis, and treatment.
-Causes of Restless Legs Syndrome
Although much research has been done on this syndrome, it is still not well known why it originates. What is clear is that Restless Legs Syndrome has a complex multifactorial origin, that is to say, there are several factors that favor its appearance.
In these individuals, genetically predisposed to RLS, there are other conditions that also favor RLS, the main one being iron deficiency (iron deficiency). The presence of iron deficiency anemia (due to iron deficiency) multiplies the risk of developing RLS sixfold. However, patients with RLS usually do not have anemia, although they do have iron deficiency (iron deficiency). This is determined by analyzing the levels of ferritin in the blood, a protein responsible for storing iron in various tissues. Some studies suggest that the lower the ferritin levels, the greater the intensity of RLS symptoms. However, in recent years, research in this regard has increased, and ferritin seems not to be such a reliable marker of iron stores, as it can be elevated in other situations, linked to inflammatory diseases. Therefore, new, more reliable markers of iron metabolism are currently being sought in patients with RLS. Hepcidin, a hormone regulating iron absorption, is a promising marker.
According to recent research, the fundamental alteration in RLS consists in the presence of a difficulty in the transport of iron from the blood to the central nervous system. Iron shows in these patients a difficulty in crossing the blood-brain barrier, and therefore its levels in certain deep brain structures, such as substantia nigra, thalamus, globus pallidus, caudate and dentate, are reduced. However, cases have been described of patients with RLS whose brain iron is normal, or even elevated, so that the disorder of iron metabolism in RLS is much more complex, and is currently under investigation.
These alterations in the access and distribution of iron to the brain cause an alteration of transmission in several nerve pathways, mainly affecting the dopaminergic and glutamatergic systems. Basic research studies have shown that iron deficiency causes an increase in the release of dopamine in the synaptic cleft, and a reduction in the number of receptors where dopamine exerts its function. This alteration would cause sensory symptoms (need to move the legs, restlessness, pain or discomfort in the legs), and motor symptoms (periodic leg movements, which are kicks that occur during sleep).
Similarly, iron deficiency causes increased levels of glutamate, an excitatory brain neurotransmitter, which would cause sleep fragmentation, due to the presence of multiple awakenings throughout the night.
In recent years, research studies suggest that the dopaminergic and glutamatergic pathways are interrelated, since another neurotransmitter, adenosine, influences both pathways. Therefore, three neural circuits are affected in RLS (those using dopamine, glutamate, and adenosine), and these, in turn, are interrelated.
In summary, the causes of RLS are complex, since it is caused by a sum of several factors, so that a series of factors act on individuals with genetic variants at risk for presenting RLS, mainly iron deficiency (iron deficiency), so that iron has difficulty accessing the brain. This alters the transmission in the pathways that use dopamine, glutamate and adenosine, which finally leads to the appearance of the symptoms: restlessness in the legs, with an imperious need to move them, discomfort or pain in the legs, which improves with movement, and the presence of involuntary movements, similar to kicking, during sleep.
– Who is most at risk for Restless Legs Syndrome?
RLS is more frequent in women. RLS is also more frequent in the elderly than in the general population. Patients with renal insufficiency, especially in advanced stages, are more at risk of presenting RLS.
Those who have a family member with RLS are at increased risk for RLS, due to the genetic factors mentioned above. In these cases, RLS symptoms may begin in childhood.
RLS is also very common during pregnancy, especially in the third trimester.
– Can Restless Legs Syndrome appear as a side effect of any drug?
Indeed, many drugs can provoke the appearance of RLS symptoms. Especially those that alter dopaminergic transmission such as neuroleptics, antivertiginants (sulpiride), antiemetics (metoclopramide, levogastrol); but it can also appear after treatment with antihistamines, CNS stimulants (methylphenidate), antidepressants (except bupropion, reboxetine, agomelatine, and tianeptine), calcium antagonists of the dihydropyridine group (nifedipine, amlodipine, nicardipine…), and beta-blockers (beta-blockers).), and beta-blockers (propanolol, atenolol, bisoprolol…).
-Symptoms of Restless Legs Syndrome
Patients with RLS have an urgent need to move their legs, which appears when they are at rest (sitting or lying down), in the late afternoon and at night, and improves with movement. This forces them to move their legs, walk or change position continuously to alleviate these symptoms. In many cases, they also present with leg discomfort, which may be felt as tingling, pain, “restlessness”, or “discomfort”, although these are often difficult to verbalize.
Symptoms often affect the daily life of patients, since from 20-21h it is very difficult for them to remain seated, which has a negative impact on daily and social activities, which are usually performed at that time, such as going to the movies, theater, or dinner. If rest is prolonged, symptoms may also appear during the day, so patients with RLS often find it difficult to make long journeys.
Given the time of onset of symptoms, it is also very common that they prevent the reconciliation of sleep, given the need to remain in motion, often needing to walk around the room to relieve symptoms. Sleep maintenance is also frequently affected, as the symptoms generally persist until the early morning, improving later, until they generally disappear when waking up.
Approximately 80% of patients with RLS have involuntary leg movements, called Periodic Leg Movements. These are present during wakefulness, and during sleep, in the late afternoon and at night. They consist of a flexion of the foot, knee and hip, in a sequential manner, as if it were a kick, which appears in one and the other leg, alternately.
It is considered pathological when 15 or more of these movements occur per hour of sleep. Each one is accompanied by a brief awakening, which causes the sleep to be very fragmented. It can even affect the sleep of the bed partner, since the kicks can become vigorous, reaching him or her, or causing awakenings due to the frequent movements.
– Restless Legs Syndrome Prevention
Since this disease has a high genetic component, there is no real strategy that can prevent its onset. Those individuals genetically predisposed to present RLS are at high risk of developing it, especially if they are women, and present iron deficiency.
In those patients with iron deficiency, the causes of iron loss, such as digestive bleeding and heavy menstruation, should be studied. By correcting these, iron stores will increase, and this will help the symptoms of RLS to improve.
Another way to prevent the onset or worsening of RLS symptoms is to avoid drugs that can cause it. Let us remember that there are many drugs that can cause RLS: neuroleptics, antivertiginants (sulpiride), antiemetics (metoclopramide, levogastrol), antihistamines, CNS stimulants (methylphenidate), antidepressants (except bupropion, reboxetine, agomelatine, and tianeptine), calcium antagonists of the dihydropyridine group (nifedipine, amlodipine, nicardipine, etc.), and beta-blockers (nifedipine, amlodipine, nicardipine, etc.), and beta-blockers (beta-blockers).), and beta-blockers (propanolol, atenolol, bisoprolol…).
– Types of Restless Legs Syndrome
According to their origin, they can be differentiated:
- Idiopathic RLS: without other associated disease. These cases have a high genetic component.
- Secondary or comorbid RLS: those cases associated with iron deficiency, or occurring in the context of chronic kidney disease. In the context of chronic kidney disease or other pathologies, such as Parkinson’s disease or Multiple Sclerosis for example.
According to its evolution, RLS can be defined as:
- Chronic: when symptoms occur two or more times/week, for at least one year.
- Intermittent: if symptoms appear less than twice/week in the last year, having presented at least five symptomatic periods in a lifetime.
This last type is very frequent, it is patients who alternate periods with RLS symptoms, and others free of symptoms. Very often the summer is a period in which symptoms are more frequent and intense.
However, the underlying causes and alterations are similar in all cases of RLS. There is no clinical, analytical or polysomnographic marker that can differentiate idiopathic RLS from secondary RLS, nor chronic from intermittent RLS.
– Prognosis of Restless Legs Syndrome
RLS can run as a chronic disease, so that once symptoms begin they remain, and persist throughout the patient’s life. Even in these cases, it is common for patients to have no symptoms on a daily basis, or for the intensity of symptoms to vary from day to day.
In cases of intermittent RLS, patients alternate between symptomatic and symptom-free periods. These periods may last several weeks or months, the duration varying from one individual to another. Generally in summer, with the heat, patients describe an aggravation of symptoms.
– Diagnosis of Restless Legs Syndrome
The diagnosis of RLS is clinical, i.e. it is made on the basis of the symptoms reported by the patient during the consultation. The neurologist will ask the patient about the symptoms he/she perceives in the legs, during rest, and the maneuvers he/she performs to relieve them. It is also of interest to collect information from the bed partner, who can report the involuntary movements that the patient presents during sleep, which are usually described as kicks.
A diagnosis of RLS will be established if the five main diagnostic criteria, as defined in the RLS Diagnostic Criteria, are met:
- Presence of urgency to move the legs usually (but not always) accompanied by unpleasant sensations and discomfort in the legs.
- Symptoms appear or worsen during rest, such as lying down or sitting.
- Symptoms are partially or totally relieved by movement.
- Symptoms occur exclusively or worsen in the afternoon/evening (or this was noted at the onset of the disease).
- The symptoms are not due to other diseases or habits, such as: muscle pain, venous stasis, edema of the lower limbs, arthritis, cramps, postural discomfort, habit of moving the feet when at rest (foot-tapping).
The symptoms of RLS can be confused with those of other diseases, mainly:
- Venous insufficiency: this also causes discomfort in the legs late in the day, but, unlike RLS, these symptoms improve with rest. In addition, these patients do not feel the need to move them; on the contrary, they improve by keeping their legs at rest and elevated.
- Cramps: consist of a painful contraction of the muscles of the posterior compartment of the leg. They usually occur at night, and at rest, but are not associated with the restlessness characteristic of RLS.
- Painful polyneuropathy and neuropathic pain: these are entities that cause intense, burning, burning pain that worsens at night. However, this pain does not worsen with rest, and is not associated with the restlessness typical of RLS. On the other hand, patients with RLS do not usually present with severe pain, as in the case of neuropathies. They usually describe the symptoms as leg discomfort rather than pain.
- Postural discomfort: keeping the legs in the same posture can cause discomfort, especially in the case of osteoarthritis of the knees or hips. In this case, the discomfort will not only appear at night, nor will there be the restlessness characteristic of RLS.
These will be the symptoms of RLS, which will allow us to differentiate it from other diseases.
Nocturnal polysomnography
Although not essential for diagnosis, a nocturnal polysomnogram (PSG) is often requested. This consists of a sleep study, performed in the hospital, during which the patient’s brain, eye, respiratory and muscular activity is recorded. Performing the PSG will allow us to evaluate the impact of RLS symptoms on the reconciliation and maintenance of sleep, so that we will objectively quantify how long it takes the patient to fall asleep, due to RLS symptoms, and how many times the patient wakes up or becomes briefly alert during the night, due to the fragmentation of sleep that accompanies RLS. The PSG also measures the number of leg movements per hour of sleep. Eighty percent of patients with RLS have associated Periodic Leg Movements during sleep, and in this case they will have more than 15 movements/hour of sleep, sometimes these can be very numerous, even more than 100 movements/hour. With all these PSG data, we will have a clearer idea of the repercussions of RLS on the patient’s sleep.
In addition, the PSG can help us to rule out the presence of other sleep disorders, such as Obstructive Sleep Apnea-Hypopnea Syndrome (OSAS), which consists of the presence of respiratory events during sleep, in which the airway collapses, interrupting airflow. Many patients with RLS have associated OSAHS, and identifying it will allow us to treat it properly.
- Blood analysis
Once the diagnosis of RLS has been established, a blood test will be performed, in which the hemogram and the biochemical profile of iron-related parameters (iron, ferritin, transferrin, transferrin saturation index) will be analyzed. In this way we will know if there is anemia or iron deficiency associated with RLS.
- Brain neuroimaging
Since, as we have seen, in RLS the brain iron content is altered, in recent years the study of the same is being promoted by means of imaging tests. In this sense, it is possible to study the iron in the substantia nigra by performing a transcranial Doppler. This is a simple technique, but very dependent on the explorer, i.e., it must be performed by an expert for its results to be reliable. Magnetic resonance imaging (MRI) of the brain can also be performed, preferably with a high field (3 Teslas). The advantage of MRI is that it allows us to study iron in all brain structures, not only in the substantia nigra. In the coming years, when the alterations in the distribution of brain iron are better known, the use of brain MRI will probably be extended in the study of RLS.
– Restless Legs Syndrome Treatment
First, we will begin by recommending non-pharmacological, lifestyle modification measures that can improve the symptoms of RLS:
- Sleep hygiene: maintaining a stable sleep schedule, every day of the week, both for going to bed and getting up. Specifically, in patients with RLS, it is recommended that they go to bed somewhat later than usual, and reserve some tasks that require movement for the last hours of the day, so that, by not being at rest, they will delay the onset of symptoms. Therefore, they should also get up a little later than usual.
- Physical exercise: aerobic physical exercise is recommended, at least 3 times/week.
- Avoid consumption of stimulants and intoxicants: patients with RLS should not consume stimulants such as caffeine, theine, or tobacco, as these will worsen the symptoms of RLS. Alcohol fragments sleep, so its consumption should also be avoided.
- Avoid drugs that can aggravate or provoke RLS: all the patient’s medication should be reviewed, and all drugs that can worsen RLS symptoms should be withdrawn and replaced by others that do not have this side effect.
If, despite all these measures, RLS symptoms persist and negatively affect the patient’s sleep and quality of life, pharmacological treatment is indicated. This happens in cases of moderate or severe RLS, which constitute 25% of RLS patients. Various treatments are available:
- Side effects of dopaminergic agonists:
In general, these drugs are well tolerated. Their most frequent side effects are: nausea, headache, dizziness, leg edema, visual hallucinations, drowsiness, and impulse control disorder. When using low doses, these side effects are rare in patients with RLS.
- Dopamine agonist-induced augmentation phenomenon.
This is the major problem associated with treatment with these drugs, which favor the development of a clinical worsening, known as “augmentation phenomenon”. It consists of symptoms becoming more intense, appearing earlier and earlier in the afternoon, and even affecting the arms. Symptoms will improve as drug doses are reduced. This occurs in 8% of patients each year, so that after 10 years, 80% of patients treated with dopamine agonists will worsen as a result of the treatment. Therefore, these drugs are no longer considered the first choice for the treatment of RLS, being reserved for the most severe cases, and trying to use the minimum doses, and discontinue treatment as soon as possible.
- Side effects of antiepileptic drugs
Its most frequent side effects are dizziness, drowsiness and weight gain, although, since very low doses are used, they are infrequent and quickly reverse when the dose is reduced or the treatment is suspended.
- Risks associated with opioid use
Its use is limited by the high risk of addiction and dependence. In addition, tramadol used chronically, can also provoke the appearance of the phenomenon of augmentation, and worsen the symptoms.
- Oral iron
Classically, oral iron (oral ferrous sulfate) has been used, although this mode of administration has several limitations. Its absorption is very low, so that the treatment must be very long, generally at least 2-3 months, and it is not possible to increase ferritin levels very much.
- Side effects of oral iron
Oral formulations frequently present digestive tolerance problems, causing both diarrhea and constipation, which makes compliance with treatment difficult.
- Intravenous iron
In order to favor therapeutic compliance and avoid the digestive problems of oral iron, intravenous iron formulations have begun to be used. In this way, ferritin levels can be raised rapidly, and it is easier for the iron to reach the brain in sufficient quantity to replace the deficit that sometimes exists in some brain structures. Several formulations of intravenous iron are available:
- Iron sucrose (200 mg × 5 doses or 500 mg × 2 doses)
- Low molecular weight iron dextran (975 mg in a single dose)
- Carboxymaltose iron (1 g in a single dose or 500 mg in two separate doses of 5 to 7 days): it is the most commonly used.
- Side effects of intravenous iron
The big problem with intravenous iron is that our body cannot discard the free iron. When administering a large amount of iron, once the brain captures the iron it needs, much of the free iron will remain circulating in the blood, and will end up being deposited, mainly in the liver and heart muscle, which can lead to cirrhosis and heart failure. Moreover, as we have seen, not all patients with RLS have a cerebral iron deficit, so intravenous iron may not be effective in all cases, and may even be harmful in those cases described that show increased cerebral iron.
- Perampanel: is an antiepileptic that regulates glutamate release. In doses of 2-4mg it has been shown to be effective in patients with RLS, being well tolerated.
- Dipyridamole: is an antiplatelet, which increases adenosine levels, and therefore can improve RLS symptoms. It is used at doses of 100-400mg, and has been effective in some small studies, although it is not clear what is the most recommended regimen in RLS.
– Restless Legs Syndrome and Cardiovascular Risk
For years, some studies have suggested that patients with RLS may be at increased risk of cardiovascular disease, such as coronary infarction and stroke. It has been proposed that the numerous awakenings during sleep cause an increase in blood pressure levels repeatedly throughout the night, which would eventually damage the cardiovascular system. However, it has not been demonstrated that there is a causal relationship between RLS and cardiovascular risk. It seems more likely that this association is explained by the fact that patients with RLS have more cardiovascular risk factors than the general population, since they more frequently have hypertension, hypercholesterolemia, or obesity. Therefore, they are people with several factors that favor cardiovascular disease, and it has not been demonstrated that RLS itself directly increases cardiovascular risk.
-Infantile Restless Legs Syndrome and ADHD
RLS can coexist with Attention Deficit Hyperactivity Disorder. But caution should be exercised, and symptoms of RLS should not be misinterpreted as attention deficit.
In children, the circadian pattern is not as strict as in adults, so they do not only have symptoms at night, but at any time of the day. In addition, the time of day when they spend most hours sitting is at school, so children with RLS often have to move their legs while sitting in class, or even get up and walk or run, to alleviate symptoms. Based on this behavior, they may be misdiagnosed with Attention Deficit Hyperactivity Disorder (ADHD).
If they are also started on stimulant treatment for ADHD, such as amphetamine derivatives (methylphenidate), which worsen the symptoms of RLS, treatment failure and poor school performance are more than likely.
Therefore, in all children with hyperactive behaviors, it is always necessary to question carefully, in relation to sleep habits, and possible pathologies associated with sleep, since any child deprived of sleep, that is, who sleeps less than he/she needs, will show a tendency to hyperactive behavior.
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