Restless Legs Syndrome

Epidemiology and Pathology

Epidemiology

• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency:
  • Approximately 2% of the population are affected by a severe form of restless legs Restless legs A disorder characterized by aching or burning sensations in the lower and rarely the upper extremities that occur prior to sleep or may awaken the patient from sleep. Polyneuropathy syndrome (RLS).
  • Approximately 20% experience a milder form of RLS at some point in their lives.
  • Highest prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: Northern Europe and North America
  • Lowest prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: Africa
• More common in women than men (attributed to pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care as risk factor)
• Positive family history Family History Adult Health Maintenance in 40%–60% of cases
• Age of onset:
  • RLS has been described in all age groups.
  • Most common and most severe in the middle-aged and elderly populations

Pathophysiology

The exact pathophysiology of RLS is still under investigation. Although more frequent in advanced age, neurodegenerative processes are not shown to play a role in RLS. Studies have shown some factors causative for or associated with the condition:

• Central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification:
  • Reduced central iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements stores
  • Abnormalities in dopaminergic systems 
  • Thalamic dysfunction 
  • Impaired neurotransmitter metabolism ( glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids, glutamine Glutamine A non-essential amino acid present abundantly throughout the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. Synthesis of Nonessential Amino Acids, GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS, endogenous opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics) 
• Peripheral nervous system Peripheral nervous system The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. Nervous System: Anatomy, Structure, and Classification:
  • A-delta fiber sensitization (transmits signals of hyperalgesic, neuropathic pain Neuropathic pain Caused by lesion or disease affecting the nervous system (PNS or CNS). Pain: Types and Pathways)
  • Altered, intramuscular blood flow Blood flow Blood flow refers to the movement of a certain volume of blood through the vasculature over a given unit of time (e.g., mL per minute). Vascular Resistance, Flow, and Mean Arterial Pressure of the leg Leg The lower leg, or just “leg” in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg: Anatomy
  • Peripheral hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage 
  • Altered endothelial function
• Other:
  • Family history Family History Adult Health Maintenance and genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics
  • Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deficiency anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types and low iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements stores
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care (especially in the 3rd trimester) 
  • Chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease ( uremia Uremia A clinical syndrome associated with the retention of renal waste products or uremic toxins in the blood. It is usually the result of renal insufficiency. Most uremic toxins are end products of protein or nitrogen catabolism, such as urea or creatinine. Severe uremia can lead to multiple organ dysfunctions with a constellation of symptoms. Acute Kidney Injury)
  • Parkinson’s disease
  • Multiple sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor
  • Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus
  • Thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy disorders
  • Venous insufficiency
  • Drugs:
    • Antidepressants
    • Antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
    • Dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors antagonists 
    • Caffeine Caffeine A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine’s most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. Stimulants
    • Alcohol
    • Tobacco

Clinical Presentation and Diagnosis

Clinical presentation

• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship complain of a constant, intense urge to move their legs or arms (rarely other body parts):
  • Worsened with inactivity
  • Relieved with movement
  • Worse at night than during the day
• The sensations triggering the urge to move may be described as:
  • Unpleasant, but not necessarily painful 
  • Deep
  • Tingling Tingling Posterior Cord Syndrome
  • Burning
  • Itching
  • Creeping
  • Cramping
  • Tension 
• Symptoms are unexplained by other medical or behavioral disorders.
• Symptoms in arms: described mostly in severe, persistent RLS 
• Secondary symptoms: insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia, depression, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder

Diagnostic criteria

The diagnosis of RLS is made clinically. The following are the International Restless Legs Restless legs A disorder characterized by aching or burning sensations in the lower and rarely the upper extremities that occur prior to sleep or may awaken the patient from sleep. Polyneuropathy Syndrome Study Group (IRLSSG) diagnostic criteria for RLS (all 5 symptom are required for diagnosis):

• The urge to move the legs (not always related to discomfort or unpleasant sensations)
• Symptoms start or worsen during inactivity or rest.
• Symptoms are at least partially improved with movement (e.g., stretching, walking), for as long as the movement continues.
• Symptoms are worse or occur only in the evening/night.
• Symptoms cannot be solely a result of another medical or behavioral condition.

Additional evaluation

Testing is not required for diagnosis; however, additional studies may be used to rule out other medical conditions.

• Laboratory studies to exclude secondary causes may include:
  • Iron studies Iron Studies Iron Deficiency Anemia (low iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements stores, testing recommended in all individuals with suspected RLS)
  • BUN and creatinine ( uremia Uremia A clinical syndrome associated with the retention of renal waste products or uremic toxins in the blood. It is usually the result of renal insufficiency. Most uremic toxins are end products of protein or nitrogen catabolism, such as urea or creatinine. Severe uremia can lead to multiple organ dysfunctions with a constellation of symptoms. Acute Kidney Injury)
  • Fasting blood glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance ( diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus)
  • TSH ( thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy disorders)
  • Vitamin B₁₂ (peripheral neuropathy Neuropathy Leprosy from vitamin B₁₂ deficiency)
  • Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12
  • Magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes (for magnesium deficiency Magnesium Deficiency A nutritional condition produced by a deficiency of magnesium in the diet, characterized by anorexia, nausea, vomiting, lethargy, and weakness. Symptoms are paresthesias, muscle cramps, irritability, decreased attention span, and mental confusion, possibly requiring months to appear. Deficiency of body magnesium can exist even when serum values are normal. In addition, magnesium deficiency may be organ-selective, since certain tissues become deficient before others. Electrolytes)
• Needle electromyography Electromyography Recording of the changes in electric potential of muscle by means of surface or needle electrodes. Becker Muscular Dystrophy (EMG) and nerve conduction studies should be considered if polyneuropathy Polyneuropathy Polyneuropathy is any disease process affecting the function of or causing damage to multiple nerves of the peripheral nervous system. There are numerous etiologies of polyneuropathy, most of which are systemic and the most common of which is diabetic neuropathy. Polyneuropathy or radiculopathy Radiculopathy Disease involving a spinal nerve root which may result from compression related to intervertebral disk displacement; spinal cord injuries; spinal diseases; and other conditions. Clinical manifestations include radicular pain, weakness, and sensory loss referable to structures innervated by the involved nerve root. Rheumatoid Arthritis is suspected

Management and Prognosis

Nonpharmacologic management

• Recommended for mild to moderate RLS
• Avoid aggravating medications or substances ( caffeine Caffeine A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine’s most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. Stimulants).
• Supportive measures (exercise, leg Leg The lower leg, or just “leg” in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg: Anatomy massages, heating pads, education)
• Treat the underlying cause:
  • Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements replacement if ferritin Ferritin Iron-containing proteins that are widely distributed in animals, plants, and microorganisms. Their major function is to store iron in a nontoxic bioavailable form. Each ferritin molecule consists of ferric iron in a hollow protein shell (apoferritins) made of 24 subunits of various sequences depending on the species and tissue types. Hereditary Hemochromatosis is ≤ 75 μg/L
  • Hemodialysis Hemodialysis Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. Crush Syndrome in the case of renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome

Pharmacologic management

• Recommended for chronic to severe RLS
• Levodopa Levodopa The naturally occurring form of dihydroxyphenylalanine and the immediate precursor of dopamine. Unlike dopamine itself, it can be taken orally and crosses the blood-brain barrier. It is rapidly taken up by dopaminergic neurons and converted to dopamine. It is used for the treatment of parkinsonian disorders and is usually given with agents that inhibit its conversion to dopamine outside of the central nervous system. Parkinson’s Disease Drugs: used for intermittent RLS (not daily symptoms)
• Alpha-2-delta calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channel ligands:
  • 1st-line treatment
  • Best for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with comorbid pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia, or addiction Addiction Substance use disorders are a significant cause of morbidity and mortality, especially among adolescents and young adults. A substance-related and addictive disorder is the continued use of a substance despite harmful consequences; these include significant impairment to one’s health or relationships or failure to fulfill major responsibilities at work, school, or home because of substance use. Substance-Related and Addictive Disorders to dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS agonists
  • Examples: gabapentin Gabapentin A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of partial seizures; neuralgia; and restless legs syndrome. Second-Generation Anticonvulsant Drugs, pregabalin Pregabalin A gamma-aminobutyric acid (gaba) derivative that functions as a calcium channel blocker and is used as an anticonvulsant as well as an anti-anxiety agent. It is also used as an analgesic in the treatment of neuropathic pain and fibromyalgia. Second-Generation Anticonvulsant Drugs 
• Dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS agonists:
  • 1st-line treatment
  • Best for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with comorbid depression or obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity/ metabolic syndrome Metabolic syndrome Metabolic syndrome is a cluster of conditions that significantly increases the risk for several secondary diseases, notably cardiovascular disease, type 2 diabetes, and nonalcoholic fatty liver. In general, it is agreed that hypertension, insulin resistance/hyperglycemia, and hyperlipidemia, along with central obesity, are components of the metabolic syndrome. Metabolic Syndrome
  • Examples: pramipexole Pramipexole A benzothiazole derivative and dopamine agonist with antioxidant properties that is used in the treatment of parkinson disease and restless legs syndrome. Parkinson’s Disease Drugs, ropinirole Ropinirole Parkinson’s Disease Drugs, rotigotine Rotigotine Parkinson’s Disease Drugs
• Anticonvulsants:
  • Consider in severe cases (daily symptoms).
  • Examples: carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs, valproate Valproate A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs
• Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines and opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics can relieve symptoms, but are best avoided due to potential for misuse and dependency. 
• Consider augmentation therapy (combination of 2 medications) in cases where monotherapy fails.

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• Spontaneous remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches rates: 30%–60%
• Risk factors for chronicity: positive family history Family History Adult Health Maintenance, higher age of onset

Differential Diagnosis

• Periodic limb movement disorder: a sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disorder defined by an excessive number of periodic limb movements during sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep. The disorder can cause sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbance, daytime fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, and polysomnography Polysomnography Simultaneous and continuous monitoring of several parameters during sleep to study normal and abnormal sleep. The study includes monitoring of brain waves, to assess sleep stages, and other physiological variables such as breathing, eye movements, and blood oxygen levels which exhibit a disrupted pattern with sleep disturbances. Physiology of Sleep changes. Management is similar to RLS. Periodic limb movement disorder is a diagnosis of exclusion and should always be considered as a differential diagnosis to RLS. 
• Akathisia: a movement disorder marked by an inner feeling of generalized restlessness and inability to sit down, and an intense urge to move. Akathisia is usually associated with the use of antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics medications (especially dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS antagonists). Unlike RLS, symptoms are not only present at night, are not accompanied by unpleasant sensations in the legs or other body parts, and do not improve with movement. 
• Parasomnias Parasomnias Parasomnias are a pattern of sleep disorders marked by unusual actions, activities, or physiological events that occur during sleep or sleep-wake transitions. Parasomnias are divided into which sleep phase the symptoms occur, either rapid eye movement (REM) or non-REM (NREM). Parasomnias: a pattern of sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disorder marked by unusual actions, activities, or physiological events occurring during sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep or sleep-wake transitions. Symptoms may include abnormal movements, emotions, dreams, and autonomic activity. Unlike RLS, symptoms manifest during sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep and do not cause continued disturbance.