Restless Legs Syndrome (RLS), also known as Willis-Ekbom disease, is a frequent neurological disorder whose recognition among neurologists is still low, despite the typical symptoms reported by patients. This condition was first described in 1685 by Sir Thomas Willis, a British anatomist and physician, but it was in 1944 that Karl Axel Ekbom, a Swedish physician, reported all the clinical features and coined the term RLS. Restless Legs Syndrome is a common, chronic, multifactorial movement disorder of the limbs in which patients have an irresistible urge to move their legs. This is often associated with abnormal, painless sensations that begin at rest and are enhanced by activities.
There is a daytime pattern of symptoms worsening overnight. There is a sleep disorder as well as an association with involuntary jerking leg movements during sleep known as periodic sleep leg movements. There are more than three million cases per year in the United States. Restless Legs Syndrome is underdiagnosed and there is a significant delay in diagnosis. The disorder may begin in childhood, but the diagnosis is often not made until the 3rd decade of life. Symptoms of restless legs syndrome worsen at rest and in sleep. Today the condition can be treated with medication.
Between 5% and 15% of the population may have restless legs syndrome. Familial RLS tends to occur under the age of 45. Age can range from infancy to over 90 years old. Women are more affected than men. African Americans are less frequently affected than whites. 11 to 29% of pregnant women suffer from it. It is three times more common in pregnant women than in non-pregnant women and has a higher prevalence in the third trimester. 25% to 50% of patients with end-stage renal disease have restless legs syndrome with symptoms, particularly during hemodialysis. Restless Legs Syndrome affects nearly 1/3 of pregnant patients, but luckily the symptoms disappear after delivery.
Genetics and environment
Although the symptoms of RLS had already been described as early as the 3rd century BC, it was first classified as a neuromuscular disease by a Swedish neurologist Ekbom in 1945. Despite recent advances, many individuals remain undiagnosed and untreated for a significant portion of their life. their lives as many health care professionals doubt its validity as a disease. While most of the articles describe RLS as a secondary disease or symptoms of other diseases, a breakthrough came in 2007 when a team of scientists discovered the genetic basis of RLS through genomic association studies (GWAS) and discovered three genes. polymorphic. MEIS1, BTBD9 and MAP2K5 / SKOR1 were directly associated with RLS and were located in the non-coding part of the genome. With further research, secondary variants were also found, which included the alcohol dehydrogenase 1B gene (ADH1B), the vitamin D3 receptor gene (VDR), and the nitric oxide synthase (NOS1) genes.
A study conducted in 2007 by Winkelmann et al. was the first large-scale genome-wide association (GWAS) that identified three genomic associations with RLS. The study included the MEIS1, BTBD9 and MAP2K5 / SKOR1 genes located within these loci and their association with RLS which was subsequently confirmed in several follow-up studies. In 2011, Catoire et al. reported that there is an association between MEIS1 and RLS. In 2012, DeAndrade et al. examined the BTBD9 gene on mutant mice. The study revealed that BTBD9 was associated with RLS and altered serum iron levels and monoamine neurotransmitters. In 2018, a GWAS study was conducted on 646 patients with chronic insomnia disorder (DIC) with or without RLS. It was one of the first studies on the direct role of the role of the MEIS1 gene as a root cause of RLS. Patients were profiled for the three MEIS1 variants and were grouped as CID without RLS and CID + RLS. The study revealed a strong association of MEIS1 as the main cause of RLS in all patients.
There are two types of restless legs syndrome. A primary and secondary form. The secondary form of rest can occur secondary to some disorders, including: iron, magnesium or folic acid deficiency; celiac disease and fibromyalgia, diabetic neuropathy, end stage renal disease, pre-diabetic state, some forms of migraine and venous insufficiency. Medicines are known to cause or exacerbate the symptoms of restless legs syndrome. They include anti-dopaminergic drugs (e.g. neuroleptics), diphenhydramine, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs).
The RLS-IBS connection
The mechanism underlying the comorbidity between RLS and IBS is still unclear; A number of hypotheses have been proposed, including bacterial overgrowth syndrome (SIBO), mast cell activation, pain sensory abnormalities, iron deficiency, and vitamin D metabolism. SIBO has been considered a potential etiological factor in ‘IBS. A recent meta-analysis based on a large dataset of case-control studies suggested a higher prevalence of SIBO in patients with IBS compared to healthy controls. A higher prevalence of SIBO was also found in the RLS studies. Interestingly, rifaximin, which is an antibiotic for SIBO, has been found to improve both IBS symptoms and RLS symptoms. Low-grade mucosal inflammation, particularly mast cell activation, may be a contributing factor to the pathogenesis of IBS. A study showed that mast cell activation syndrome (MCAS) is common in patients with overlapping symptoms of IBS / functional diarrhea.
Another recent cross-sectional study indicated that RLS is associated with MCAS. These studies reveal that the potential links between RLS and IBS could be inflammation and immune alterations. Sensory pain abnormalities are common in both RLS and IBS, which may be the mechanism for their comorbidity. Static mechanical hyperalgesia, reflecting central sensitization, has been confirmed in patients with primary and secondary RLS. Patients with primary RLS exhibited blunt pressure hyperalgesia, pinprick, and vibration. Patients with secondary RLS associated with small fiber neuropathy exhibited thermal hyperalgesia in cold (fiber A mediated), heat (fiber C mediated), and pinprick. Visceral hypersensitivity may explain the typical symptoms of IBS, such as sudden / urgent bowel movements, abdominal pain or bloating, in a subset of patients (30-40%). The hyper-excitability of the central nervous system, in fact, plays an important role in the pathophysiology of the irritable bowel.
In idiopathic restless legs syndrome, a dysfunction of the dopaminergic system and iron stores in specific regions of the brain decrease. There may be an autosomal dominant inheritance; there have been reports of several large relatives with different susceptibility loci with restless legs syndrome. This suggests a genetic basis for the disease. Calcium / phosphate imbalance, anemia, iron deficiency and subclinical peripheral nerve abnormalities may be involved in the pathophysiology of restless legs uremic syndrome. Vitamin D deficiency and calcium metabolism, preeclampsia, a strong family history, low serum iron and ferritin levels, high estrogen levels can also play a role in pregnancy. The pathophysiology of iron in RLS has been extensively studied. It is based on the observation that peripheral iron decrease and iron deficiency anemia are strongly associated with RLS.
In addition, conditions that alter iron status, such as pregnancy and kidney failure, are risk factors for RLS, the symptoms of which are relieved by treatment of iron deficiency.However, normal serum ferritin is found in most of patients with RLS, suggesting the presence of possible different pathophysiological mechanisms involving iron metabolism. Studies in patients with normal peripheral iron stores have led to the hypothesis that central nervous system iron status may be more important in RLS. Indeed, reduced cerebrospinal fluid (CSF) ferritin and decreased brain iron have been reported in RLS patients with normal serum ferritin. Brain iron deficiency has been demonstrated in neuropathological and magnetic resonance imaging (MRI) samples involving, primarily, the substantia nigra and, to a lesser extent, the putamen, the caudate and the thalamus.
This regional brain iron deficiency is linked to reduced activity of the iron-1 regulatory protein on microvessels, a protein involved in the transport and storage of iron in the brain, particularly in cells of the substantia nigra. Therefore, even in the presence of a normal peripheral iron state, a decrease in the supply and accumulation of iron in specific brain regions can occur with a reduction of the transferrin receptor on the endothelial cells of the blood brain barrier. The main consequences of iron deficiency in the brain are hypoxia and myelin loss. In turn, this myelin deficiency of specific deep brain areas could contribute to RLS symptoms by impairing sensorimotor integration. There is an integrated view with iron homeostasis and the dopamine network. The dopaminergic pathophysiology of RLS finds its foundations in the discovery of the dramatic response to dopaminergic agents (first Levodopa, in the early 1980s, then dopamine agonists), which implies a probable brain dopaminergic deficiency.
However, some studies have shed light on a more complex and partly surprising set of pathophysiological mechanisms involving dopamine metabolism in the brain. The level of the homovanillic acid (HVA) dopamine metabolite in cerebrospinal fluid was increased in patients with RLS, suggesting increased dopamine production. Furthermore, the pathophysiological mechanisms of iron and dopamine appear to be interrelated, since the hypoxic pathway, activated by the brain iron imbalance, interferes with dopamine metabolism, activating the enzymatic cascade producing greater dopamine synthesis. It follows that distinguishing primary from secondary RLS on the basis of iron deficiency may be questionable, as iron is involved in pathophysiology even when iron deficiency is not evident. On the other hand, some authors include iron deficiency in the definition of primary RLS due to its essential role in the genesis of the disease.
Furthermore, it has been shown that, in addition to dopamine, adenosine and other neurotransmitters such as glutamate are involved in the pathophysiology of RLS and this would lead to new treatments that act on these systems. For example, perampanel (a selective AMPA glutamate receptor antagonist) has shown efficacy in some series of patients with RLS.
RLS is a sensorimotor disorder characterized by typical symptoms with a peculiar circadian way of presentation. Patients complain of a strong, irresistible urge to move their legs, often accompanied by feelings of discomfort deep in the legs. The urge typically begins or worsens during periods of inactivity (for example, lying down or sitting) and is relieved by movement, such as walking or stretching. Symptoms occur in the evening or at night and may progressively worsen during the night, but tend to resolve spontaneously in the early morning hours. Terms patients use to describe symptoms include crawling, pulling, itching, drawing, or stretching, all of which are localized to deep structures rather than to the skin. Pain and tingling paraesthesia of the type that occurs in painful peripheral neuropathy is usually absent and there is no sensitivity to skin contact. Symptoms can range from some patients who have very mild problems to others who have severe sleep disturbances and quality of life disturbances.
Symptoms typically worsen towards the end of the day and peak at night, when they appear within 15 to 30 minutes of lying down in bed. In severe cases, symptoms may occur early in the day while the patient is seated, thus interfering with meeting attendance, cinema sitting and similar activities. In milder cases, patients fidget, move in bed, and kick or massage their legs to find relief. Occasionally, the arms can be affected. Patients with more severe symptoms feel compelled to get out of bed and walk on the floor to relieve symptoms. Periodic leg movements during sleep are characterized by forced and involuntary dorsiflexion of the foot that lasts from 0.5 to five seconds and occurs every 20 to 40 seconds during sleep. You may experience twitching in the limbs during sleep. These occur in 80% of patients with RLS.
Physical examination is usually normal in patients with restless legs syndrome. It is performed to identify secondary causes.
Essential diagnostic criteria (all must be met):
- There is an uncontrollable need to move the lower limbs and it can be accompanied by unpleasant and unpleasant sensations.
- The urge to move the extremities is less during the day but progressively worsens in the evening and at night. Symptoms also appear at rest or during periods of sleep and inactivity.
- The urge to move the lower limbs can be partially or completely relieved by walking or stretching the legs. As long as activity is continued, symptoms are mild or absent.
- The urge to move the lower limbs worsens during the evening and makes it impossible to sleep. Therefore, the patient is often fatigued during the day.
- The presence of these symptoms should not be attributed to other behavioral conditions, such as tardive dyskinesia, leg cramps, muscle spasms or discomfort from the position.
Leg movements are usually involuntary and can involve sudden dorsiflexion movements that can last 1-5 seconds and recur every 30-40 seconds during sleep. Positive family history is common in children. Physical examination is usually normal. However, the patient should be examined to rule out a neurological disorder, radiculopathy, or Parkinson’s disease.
There are no specific tests except those to rule out secondary causes. Blood work is done to rule out other causes as well. Electromyography (EMG) and nerve conduction studies are done if radiculopathy or neuropathy is suspected. Polysomnography is often performed to quantify the frequency of leg movements and characterize the sleep pattern. A nocturnal polysomnogram can be useful for quantifying sleep periodic leg movements (PLMS), which are stereotyped leg movements, which occur in approximately 90% of patients with RLS. They are characterized by the extension of the big toe with partial flexion of the ankle, knee and sometimes the hip, usually bilaterally but not always synchronously.
The upper limbs may occasionally be involved. PLMS can be used as an ancillary diagnostic criterion, along with response to dopaminergic treatment, especially in patients with difficult-to-diagnose RLS. They can provide insight into the severity of RLS and the amount of sleep instability and fragmentation, as PLMS are typically associated with increased heart rate and blood pressure, and often arousal as well. This could explain the mechanism by which RLS can increase the risk of developing cardiovascular disease, although there is no clear-cut evidence for an association between RLS and cardiovascular risk.
Avoid excess caffeine, antidepressants, antipsychotics, dopamine blocking antiemetics, and centrally acting antihistamines. Short daily dialysis in patients with kidney failure, iron replacement, exercise, massage, and heat can relieve symptoms. Dopamine agonists including pramipexole, ropinirole, rotigotine, and cabergoline lead to reduced symptoms, improved sleep quality and quality of life. The rotigotine transdermal patch may also be used. It is well tolerated and has a relatively low risk of clinically significant increase in restless legs syndrome. In a large meta-analysis involving 3286 participants, pramipexole was shown to improve symptoms of patients with moderate to severe primary RLS and possibly better than ropinirole. In a small study, rotigotine improved periodic limb movements and symptoms of short-term restless legs syndrome among dialysis patients.
The use of Gabapentin or Pregabalin should be considered for the initial treatment of those patients who have severe sleep disturbances, comorbid insomnia, anxiety or chronic pain. The drugs are effective anywhere from 1-5 years, but they also have adverse effects that reduce their compliance. today, first-line treatment is a delta alpha2 calcium channel ligand or dopamine receptor agonist. Benzodiazepines (clonazepam) are commonly used, although without a specific pharmacodynamic rationale, other than relief from associated anxiety. Benzodiazepines (clonazepam) can be safely used during the second and third trimester of pregnancy at low doses (0.25-1 mg once daily).
Considering the pathophysiology of the disease, systemic iron deficiency must always be sought because iron supplementation alone can alleviate the symptoms of RLS. This also applies to worsening symptoms in patients on stable therapy, who may show low peripheral iron levels as a cause of decompensation of previously stable disease control. The patient should be informed that the response to iron administration is usually gradual, unlike other drugs used in the treatment of the disorder. Intravenous iron is also needed when serum ferritin is not very low, because iron absorption from the intestinal tract is not effective unless there is systemic iron deficiency. In fact, there is an endogenous regulation system for the absorption of oral iron, in physiological conditions, which prevents the patient from an excessive serum concentration of iron.
In about 70% of patients, symptoms progress and become moderate to severe. In addition to the legs, some patients may begin to experience the same symptoms in the arms. Overall, symptoms are less severe in the morning and worsen during the evening and night. In some patients, the symptoms are so severe that they invalidate, interrupt sleep, and cause daytime fatigue. Studies show that patients with restless legs are prone to hypertension, headaches and sleep difficulties. The quality of life for most patients is poor.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Dott. Gianfrancesco Cormaci
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