Restless legs syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Mohamadmostafa Jahansouz M.D.[2]

Restless legs syndrome is a condition that is characterised by an irresistible urge to move one’s legs. It is poorly understood, often misdiagnosed, and believed to be a neurological disorder. Many people tap their feet or shake their legs resulting from a nervous tic, consumption of stimulants, drug side-effects or other factors; this is usually innocuous, unnoticed, and does not interfere with daily life, quite distinct from Restless Leg Syndrome.

It is sometimes mistakenly called “Ekbom’s syndrome,” but that is an entirely different condition that shares part of the Wittmaack-Ekbom syndrome eponym: delusional parasitosis, as both syndromes were described by the same person, Karl-Axel Ekbom. ^[1]

In a 1945 publication titled ‘Restless Legs’, Karl-Axel Ekbom described the disease and presented eight cases used for his studies.^[2]

Earlier studies were done by Thomas Willis (1622-1675) and by Theodor Wittmaack.^[1] Another early description of the disease and its symptoms were made by George Miller Beard (1839-1883).^[1]

As with many diseases with diffuse symptoms, there is controversy among physicians, if RLS is a distinct syndrome. The US National Institute of Neurological Diseases and Stroke publishes an information sheet ^[3] characterizing the syndrome but acknowledging it is a difficult diagnosis. Some physicians doubt that RLS actually exists as a legitimate clinical entity, but believe it to be a kind of “catch-all” category, perhaps related to a general heightened sympathetic nervous system (SNS) response that could be caused by any number of physical or emotional factors. Other clinicians associate it with lumbosacral spinal subluxations and life stress.

Many doctors express the view that the incidence of restless leg syndrome is exaggerated by manufacturers of drugs used to treat it.^[4] Other physicians consider it a real entity that has specific diagnostic criteria. ^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

• In 1672, Sir Thomas Willis, a British anatomist and physician was the first to discover the leg discomfort experienced by some of his patients.^[1][2]
• In a 1945, Karl-Axel Ekbom a Swedish neurologist described the disease and presented eight cases used for his studies.^[3]
• In 1995, a large International Restless Legs Syndrome (RLS) Study Group has been formed. As its first task, the group has taken upon itself the role of defining the clinical features of the RLS.^[3]
• In 2002, National Institutes of Health in Bethesda, MA, USA, formulated a revised criteria for the diagnosis of RLS.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

Restless leg syndrome (RLS), may be classified into two groups:^[1]

• Primary and secondary:
  • Primary RLS is idiopathic and the cause of that is unknown which is familial in up to two thirds of patients. Primary RLS usually begins before approximately 40 to 45 years of age, and can even occur as early as the first year of life. In primary RLS, the onset is often slow.^[2]
  • Secondary RLS may also be secondary to a number of conditions including:^{[3][4][5][6][7][8]}
    • Iron deficiency
    • Pregnancy
    • End-stage renal failure
    • varicose vein
    • Venous reflux
    • folate deficiency
    • sleep apnea
    • uremia
    • Diabetes
    • Thyroid problems
    • Peripheral neuropathy
    • Parkinson’s disease
    • Certain auto-immune disorders such as:
      • Sjögren’s syndrome,
      • Celiac Disease
      • rheumatoid arthritis
  • Secondary RLS is most common in those presenting for the first time in later life.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

• Generally most scientists consider restless legs syndrome(RLS) as a central nervous system (CNS)-related disorder, but no specific lesion has been found to be associated with the syndrome.^[1]

• It is thought that RLS is the result of central nervous system anatomic lesions.^[1]
• Findings in imaging of CNS witch suggest the relation between the anatomic lesions in CNS and RLS include:^[1][2][3][4]
  • Presence of morphologic changes in the somatosensory cortex, motor cortex and thalamic gray matter in MRI
  • Abnormal bilateral cerebellar and thalamic activation during the manifestation of sensory symptoms, with additional red nucleus and reticular formation activity during periodic leg movements (PLMS), in functional MRI study
  • Evidences of the role of the limbic and opioid systems in SPECT and PET studies
  • Low brain iron concentrations and dysfunction of iron metabolism and intracellular iron
    • The “iron-dopamine model” explains that iron deficiency in the brain causes an abnormality in the dopaminergic system leading to manifestation of RLS.

• RLS symptoms seem to depend on abnormal spinal sensorimotor integration at the spinal cord level and abnormal central somatosensory processing
• In animal models, studies suggest that the All dopaminergic system and the D3 receptor participates in RLS symptoms

• Genes involved in the pathogenesis of RLS include: RLS 1: 12q and RLS 2: 14q and RLS 3: 9p and RLS 4: 2q and RLS 5: 20p.^[1]
• 40% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.

Conditions which may be associated with RLS include:^[5][6][7]

• Hypertension
• Cardiovascular diseases
• Anxiety
• Depression
• Iron deficiency
• Anemia
• Kidney diseases
• Stroke
• Parkinson disease
• Polyneuropathy
• Multiple sclerosis

• The exact neuroanatomical substrate imbalance which causes restless legs syndrome (RLS) is unknown.^[8]
• Chronic ischemic changes were found in some brain tissue samples of patients whit RLS.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

The exact cause of RLS is not clear yet but the disease may be related to this conditions:^[1][2][3][4]

• Hypertension
• Cardiovascular diseases
• Anxiety
• Depression
• Iron deficiency
• Anemia
• Kidney diseases
• Stroke
• Parkinson disease
• Polyneuropathy
• Multiple sclerosis

• Genes involved in the pathogenesis of RLS include: RLS 1: 12q and RLS 2: 14q and RLS 3: 9p and RLS 4: 2q and RLS 5: 20p.^[5]
• 40% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.

List the causes of the disease in alphabetical order.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2]

• Chronic insomnia
• Deep vein thrombosis
• Delayed deep sleep disorder
• Hyperthyroidism
• Peripheral neuropathy
• Peripheral vascular disease
• Sleep disturbance due to medications
• Vertebral disc disease^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

In community-based epidemiological surveys, RLS (Restless Leg Syndrome) has been studied as:^[1]

1. A symptom only
   • In this kind of symptoms ,prevalence estimates in the general adult population ranged from 9400 to 1500 per 100,000 individuals worldwide.
2. A set of symptoms meeting minimal diagnostic criteria of the IRLSSG
   • In this kind of symptoms ,prevalence estimates in the general adult population ranged from 3900 to 1400 per 100,000 individuals worldwide.

• When frequency/severity is added, prevalence ranged from 2.2% to 7.9% and when differential diagnosis is applied prevalence estimates are between 1.9% and 4.6%. In all instances, RLS prevalence is higher in women than in men.

• The incidence of RLS increases with age.^[2]

• RLS usually affects individuals of the non-African American race. African American race individuals are less likely to develop RLS.^[3]

• Women are more commonly affected by RLS than men.^[1] The women to men ratio is approximately 2 to 1.^[2]

• The worldwide prevalence of RLS is not clear, however, it appears that Asian countries have a lower prevalence of RLS than European and North American countries.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

There are no established risk factors for [disease name].

OR

The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

OR

Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.

• Common risk factors in the development of RLS include:^{[1][2][3][4][5][6]}
  • Advancing age
  • Family history of restless legs syndrome
  • Female gender
  • European descent

• • Anxiety
  • Deprtession
  • Iron deficiency Anemia
  • Kidney diseases
  • Stroke
  • Polyneuropathy
  • Multiple sclerosis

• Less common risk factors in the development of [disease name] include:^[1][2][3][4]
  • Parkinson disease
  • Cardiovascular diseases
  • Hypertension

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

There is insufficient evidence to recommend routine screening for [disease/malignancy].

According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].

There is insufficient evidence to recommend routine screening for restless leg syndrome but, screening for restless leg syndrome may be recommended among patients with:

• Chronically dialysed patients^[1]
• Iron deficiency^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

OR

Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

OR

Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

• The symptoms of restless leg syndrome usually develop in the elderly patients, and start with symptoms such as Urge to move the legs and Uncomfortable and bothersome sensations in the affected limbs.^[1][2]
• Complication of untreated restless leg syndrome are more prominent among children:
  • If left untreated, children with restless leg syndrome may progress to develop cardiovascular problems, cognitive deficits, attention-deficit hyperactivity disorder (ADHD), sleepwalking, nightmares, and parasomnias.^[3][4]

• Common complications of restless leg syndrome in children include:^[3][4]
  • Cognitive deficits
  • Attention-deficit hyperactivity disorder (ADHD)
  • Sleepwalking
  • Nightmares
  • Parasomnias
  • Cardiovascular problems

• Men with RLS had a higher overall mortality and this association was independent of known risk factors.^[5]
  • The increased mortality in RLS in men is more frequently associated with:
    • Respiratory disease
    • Endocrine disease
    • Nutritional/metabolic disease
    • Immunologic disorders
• Women with RLS has a higher cardiovascular mortality rate.^[6]
• mortality in end-stage renal disease patients is not influenced by concomitant RLS.^[7]

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