Restless Legs Syndrome

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 Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disturbance. The syndrome can be idiopathic, or due to secondary causes such as iron deficiency, pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, diabetes mellitus Diabetes mellitus 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, uremia, and Parkinson’s disease. Some drugs, most notably antidepressants and metoclopramide, can also trigger the syndrome. Management involves treatment of the underlying condition, supportive measures, and dopamine agonists.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology and Pathology

Epidemiology

  • Prevalence:
    • Approximately 2% of the population are affected by a severe form of restless legs syndrome (RLS).
    • Approximately 20% experience a milder form of RLS at some point in their lives.
    • Highest prevalence: Northern Europe and North America
    • Lowest prevalence: Africa
  • More common in women than men (attributed to pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care as risk factor)
  • Positive family history 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 Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System:
    • Reduced central iron stores
    • Abnormalities in dopaminergic systems 
    • Thalamic dysfunction 
    • Impaired neurotransmitter metabolism (glutamate, glutamine, GABA, 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 Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System:
    • A-delta fiber sensitization (transmits signals of hyperalgesic, neuropathic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain)
    • Altered, intramuscular blood flow 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
    • Peripheral hypoxia 
    • Altered endothelial function
  • Other:
    • Family history and genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics
    • Iron deficiency anemia Iron Deficiency Anemia Iron deficiency anemia is the most common type of anemia worldwide. This form of anemia is caused by insufficient iron due to a decreased supply, an increased loss, or an increased demand. Iron deficiency anemia is seen across all ages, sexes, and socioeconomic strata; however, children, women of childbearing age, and patients from lower socioeconomic strata are at higher risk. Iron Deficiency Anemia and low iron stores
    • Pregnancy (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)
    • Parkinson’s disease
    • Multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis
    • Diabetes mellitus
    • Thyroid disorders
    • 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 receptor antagonists 
      • Caffeine

Clinical Presentation and Diagnosis

Clinical presentation

  • Patients 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
    • 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

Diagnosis

The diagnosis is made clinically using the criteria above.

  • Laboratory studies to exclude secondary causes:
    • Iron studies
    • BUN
    • Creatinine
    • Fasting blood glucose
    • Thyroid-stimulating hormone (TSH)
    • Vitamin B12
    • 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
  • Needle electromyography (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 is suspected.

Management and Prognosis

Nonpharmacologic management

  • Recommended for mild to moderate RLS
  • Avoid aggravating medications or substances (caffeine).
  • 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 massages, heating pads, education)
  • Treat the underlying cause:
    • Iron replacement if ferritin is ≤ 75 μg/L
    • Hemodialysis in the case of renal failure

Pharmacologic management

  • Recommended for chronic to severe RLS
  • Levodopa: used for intermittent RLS (not daily symptoms)
  • Alpha-2-delta calcium channel ligands:
    • 1st-line treatment
    • Best for patients with comorbid pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, anxiety, 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 agonists
    • Examples: gabapentin, pregabalin 
  • Dopamine agonists: 
    • 1st-line treatment
    • Best for patients 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, ropinirole, rotigotine
  • Anticonvulsants:
    • Consider in severe cases (daily symptoms).
    • Examples: carbamazepine, valproate
  • 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

  • Spontaneous remission rates: 30%–60%
  • Risk factors for chronicity: positive family history, higher age of onset

Differential Diagnosis

  • Periodic limb movement disorder: a sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disorder defined by an excessive number of periodic limb movements during sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep. The disorder can cause sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disturbance, daytime fatigue, and polysomnography 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 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 Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disorder marked by unusual actions, activities, or physiological events occurring during sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep or sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep-wake transitions. Symptoms may include abnormal movements, emotions, dreams, and autonomic activity. Unlike RLS, symptoms manifest during sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep and do not cause continued disturbance.

References

  1. Latha Ganti, Matthew Kaufman, and Sean Blitzstein. (2016). First Aid for the Psychiatry Clerkship, 4th edition. Chapter 15, sleep-wake disorders, page 169.
  2. Matthew Sochat, Tao Le, and Vikas Bhushan. (2019). First Aid for the USMLE Step 1, (29th ed.), page 507.
  3. Sadock, B. J., Sadock, V. A., & Ruiz, P. (2014). Kaplan and Sadock’s synopsis of psychiatry: Behavioral sciences/clinical psychiatry (11th ed.). Chapter 16, Sleep-wake disorders, pages 533–563. Philadelphia, PA: Lippincott Williams and Wilkins.
  4. Ondo, W. (2021). Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults Retrieved March 28, 2021, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-restless-legs-syndrome-and-periodic-limb-movement-disorder-in-adults 
  5. Mansur A, Castillo PR, Rocha Cabrero F, et al. Restless Leg Syndrome. [Updated 2020 Oct 23]. In: StatPearls [Internet]. Treasure Island (FL). https://www.ncbi.nlm.nih.gov/books/NBK430878/
  6. Lee, C. S., Kim, T., Lee, S., Jeon, H. J., Bang, Y. R., & Yoon, I. Y. (2016). Symptom Severity of Restless Legs Syndrome Predicts Its Clinical Course. The American journal of medicine, 129(4), 438–445. https://doi.org/10.1016/j.amjmed.2015.12.020

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