Restless Legs Syndrome (Clinical)

Epidemiology and Pathology

Epidemiology^[4‒6,8,9]

• 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 RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome).
  • Approximately 20% experience a milder form of RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome 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 RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome has been described in all age groups.
  • Most common and most severe in the middle-aged and elderly populations

Pathophysiology^[4,5,11]

The exact pathophysiology of RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome is still under investigation. Although more frequent in advanced age, neurodegenerative processes are not shown to play a role in RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome. 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^[4‒6,8]

• 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 RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome 
• 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^[7,14]

The diagnosis of RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome 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 RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome (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.

Clinical course criteria^[7,8]

The following specifiers are based on the frequency of symptoms (on average, and without treatment):

• Intermittent RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome:
  • Symptoms have occurred < 2 times/week for the past year.
  • ≥ 5 occurrences over the individual’s lifetime
• Chronic persistent RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome: Symptoms have occurred ≥ 2 times/week for the past year.
• Refractory RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome: Symptoms are not responsive to appropriate monotherapy owing to:
  • Reduced efficacy
  • Augmentation (worsening symptoms)
  • Adverse effects

Additional evaluation^[4,5,8]

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 RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome)
  • 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

Management of RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome may vary based on practice location. The following summarizes US and international literature and medical society recommendations for adults. UK guidelines can be found on the National Institute for Health Care Excellence site.

Nonpharmacologic management^[8]

• Recommended for mild to moderate RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome
• 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

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^[8,9,11]

• A trial of iron supplementation Iron Supplementation Iron Deficiency Anemia may be considered if either:
  • 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 OR 
  • Transferrin Transferrin An iron-binding beta1-globulin that is synthesized in the liver and secreted into the blood. It plays a central role in the transport of iron throughout the circulation. Heme Metabolism saturation is < 45%
• Oral 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:
  • Recommended for most individuals
  • Dosage Dosage Dosage Calculation: ferrous sulfate 325 mg daily or every other day with vitamin C Vitamin C A six carbon compound related to glucose. It is found naturally in citrus fruits and many vegetables. Ascorbic acid is an essential nutrient in human diets, and necessary to maintain connective tissue and bone. Its biologically active form, vitamin C, functions as a reducing agent and coenzyme in several metabolic pathways. Vitamin C is considered an antioxidant. Water-soluble Vitamins and their Deficiencies 100‒200 mg (enhances absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption)
• IV 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
  • 1st-line therapy for:
    • Moderate-to-severe chronic persistent or refractory RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome with 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 levels of 76–100 µg/L
    • Individuals with inadequate oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of 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 (e.g., GI disorders, bariatric surgery Bariatric surgery Bariatric surgery refers to a group of invasive procedures used to surgically reduce the size of the stomach to produce early satiety, decrease food intake (restrictive type) and/or alter digestion, and artificially induce malabsorption of nutrients (malabsorptive type). The ultimate goal of bariatric surgery is drastic weight loss. Bariatric Surgery) and 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 < 100 µg/L
    • Individuals who cannot tolerate oral 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 and 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 < 100 µg/L
    • Individuals who do not improve with a 3-month trial of oral 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 and 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 < 100 µg/L
  • Options:
    • Ferric carboxymaltose:
      • Dose: 1000 mg as a single infusion OR 2 doses of 500 mg at 5- or 7-day intervals
      • Clinical response may take 4‒6 weeks (or longer).
      • Hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome can occur in some individuals.
    • Low-molecular-weight 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 dextran:
      • Single infusion of 1000 mg
      • Can cause allergic reactions Allergic Reactions Type I hypersensitivity reaction against plasma proteins in donor blood Transfusion Reactions (recommend starting with a test dose of 25 mg)
    • Ferumoxytol: Single infusion of 1020 mg
• Follow-up iron studies Iron Studies Iron Deficiency Anemia after 3‒4 months, and repeat every 3‒6 months, until 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 > 100 μg/L 

Pharmacologic management^[8,9,12]

These medications should be considered in addition to nonpharmacologic strategies, and their administration varies based on the persistence of symptoms:

Intermittent RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome: 

• Carbidopa/ 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:
  • Intermittent doses of 25 mg/100 mg; recommended to use ≤ 3 times/week
  • May be dosed for:
    • Evening or bedtime
    • Waking due to symptoms
    • Specific circumstances that may trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation symptoms (e.g., long car or plane rides)
  • Controlled-release formulations can be used.
  • Avoid taking with high-protein food.
  • Augmentation and rebound can occur with daily use.
• Intermittent low-potency 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, 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, or benzodiazepine 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 agonists may be considered before bed.
  • Beware of adverse effects and the development of tolerance Tolerance Pharmacokinetics and Pharmacodynamics with these medications.
  • Take care in prescribing these to the elderly.

Chronic-persistent RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome:

• 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:
  • Current 1st-line treatment
  • May be especially beneficial for those with:
    • Chronic pain Chronic pain Aching sensation that persists for more than a few months. It may or may not be associated with trauma or disease, and may persist after the initial injury has healed. Its localization, character, and timing are more vague than with acute pain. Pain Management (especially peripheral neuropathy Neuropathy Leprosy)
    • 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/ sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbances
    • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
    • Parkinson disease Parkinson disease Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability. Parkinson’s Disease, already on dopaminergic therapy
  • 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:
    • Start with 300 mg 1‒2 hours before usual onset of symptoms (typically in evening or bedtime)
    • For those > 65 years old: start with 100 mg
    • Can titrate up every few days, as needed
    • Individuals often need doses of 1200‒1800 mg daily, but others may require doses up to 3600 mg daily.
  • 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 enacarbil ( prodrug Prodrug Nitroimidazoles of 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):
    • Start with 600 mg in the evening (approximately 5 PM, in order to reach therapeutic levels by bedtime) 
    • For those > 65 years old: start with 300 mg
    • Some individuals may need doses up to 1200 mg.
  • 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 ( prodrug Prodrug Nitroimidazoles of 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):
    • Start with 75 mg nightly
    • For those > 65 years old: start with 50 mg
    • Can titrate up every few days, as needed
    • Individuals often need doses of 150‒450 mg daily.
• Nonergot 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:
  • Former 1st-line treatment, but may be considered if alpha-2-delta ligands are ineffective or contraindicated
  • Associated with a high incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of augmentation and impulse control disorders (e.g., compulsive eating, gambling)
  • 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:
    • Start with 0.125 mg 2 hours before symptoms usually begin
    • Titrate by 0.125 mg every 2‒3 days
    • A 2nd dose may need to be added in early afternoon.
    • Maximum: 0.5 mg daily
  • Ropinirole Ropinirole Parkinson’s Disease Drugs:
    • Start with 0.25‒0.5 mg 1.5 hours before symptoms usually begin
    • Titrate by 0.25‒0.5 mg every 2‒3 days
    • A 2nd dose may need to be added in early afternoon.
    • Maximum: 4 mg daily (usually ≤ 2 mg is required)
  • Rotigotine Rotigotine Parkinson’s Disease Drugs patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes:
    • Start with 1 mg daily
    • Can increase to 2‒3 mg to control symptoms, if needed
    • Typically given to those who are affected by RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome throughout the day
  • Note: Because of the potential for withdrawal symptoms, these medications should not be stopped abruptly. If switching medication regimens (e.g., to alpha-2-delta therapy), there should be an overlap period, or 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 can be reduced before discontinuation.

Refractory RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome:

• Consider the following:
  • Recheck 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 and if less than 100 mg/L, administer IV 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
  • Combine agents from different classes:
    • Precautions should be taken for adverse effects.
    • When a 2nd drug is added, a lower dose of the initial drug should be tried.
• 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 for appropriate candidates:
  • Can start with short-acting 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
  • Extended-release/long-acting therapy is appropriate for many individuals.
  • Screen for risk factors for opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation abuse and monitor closely ( opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation contracts are frequently necessary).
• Note: If an individual never had any relief of symptoms with standard therapy, consider alternative diagnoses.

Pregnant or lactating individuals:^[8,10,13]

• Nonpharmacologic therapy (preferred):
  • Moderate-intensity exercise
  • Avoid triggers (can include insufficient sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep, 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 or nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants use)
  • Correction of 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
• Pharmacologic therapy:
  • Generally reserved for severe symptoms or nonresponse to nonpharmacologic intervention
  • Medications:
    • Clonazepam Clonazepam An anticonvulsant used for several types of seizures, including myotonic or atonic seizures, photosensitive epilepsy, and absence seizures, although tolerance may develop. It is seldom effective in generalized tonic-clonic or partial seizures. The mechanism of action appears to involve the enhancement of gamma-aminobutyric acid receptor responses. Benzodiazepines 0.25‒0.5 mg before bedtime in the 2nd and 3rd trimesters and in lactating individuals
    • Carbidopa/ 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 25 mg/100 mg or 50 mg/200 mg (controlled-release) is an option during 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, but avoid with lactation Lactation The processes of milk secretion by the maternal mammary glands after parturition. The proliferation of the mammary glandular tissue, milk synthesis, and milk expulsion or let down are regulated by the interactions of several hormones including estradiol; progesterone; prolactin; and oxytocin. Breastfeeding owing to potential inhibition of prolactin Prolactin A lactogenic hormone secreted by the adenohypophysis. It is a polypeptide of approximately 23 kd. Besides its major action on lactation, in some species prolactin exerts effects on reproduction, maternal behavior, fat metabolism, immunomodulation and osmoregulation. Breasts: Anatomy production.
    • 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 and tramadol Tramadol A narcotic analgesic proposed for severe pain. It may be habituating. Opioid Analgesics are additional options during lactation Lactation The processes of milk secretion by the maternal mammary glands after parturition. The proliferation of the mammary glandular tissue, milk synthesis, and milk expulsion or let down are regulated by the interactions of several hormones including estradiol; progesterone; prolactin; and oxytocin. Breastfeeding.
    • For severe/refractory cases: low-dose oxycodone Oxycodone A semisynthetic derivative of codeine. Opioid Analgesics (5‒10 mg) before bedtime is an option in the 2nd and 3rd trimesters.

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^[6]

• 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 RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome. Periodic limb movement disorder is a diagnosis of exclusion and should always be considered as a differential diagnosis to RLS RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome. 
• 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 RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome, 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 RLS Restless legs syndrome (RLS), also known as willis-ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome, 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.