Restless legs syndrome


Restless legs syndrome, also known as Willis–Ekbom disease, is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporarily by moving them. This feeling is often described as aching, tingling, or crawling in nature. Occasionally, arms may also be affected. The feelings generally happen when at rest and therefore can make it hard to sleep. Sleep disruption may leave people with RLS sleepy during the day, with low energy, and irritable or depressed. Additionally, many have limb twitching during sleep, a condition known as periodic limb movement disorder. RLS is not the same as habitual foot-tapping or leg-rocking.

Signs and symptoms

RLS sensations range from pain or aching in the muscles, to "an itch you can't scratch", a "buzzing sensation", an unpleasant "tickle that won't stop", a "crawling" feeling, or limbs jerking while awake. The sensations typically begin or intensify during quiet wakefulness, such as when relaxing, reading, studying, or trying to sleep.
The sensations, and the need to move, may return immediately after ceasing movement or at a later time. RLS may start at any age, including childhood, and is a progressive disease for some, while the symptoms may remit in others. In a survey among members of the Restless Legs Syndrome Foundation, it was found that up to 45% of patients had their first symptoms before the age of 20 years.
  • "An urge to move, usually due to uncomfortable sensations that occur primarily in the legs, but occasionally in the arms or elsewhere." The sensations are unusual and unlike other common sensations. Those with RLS have difficulty describing them, using words or phrases such as uncomfortable, painful, 'antsy', electrical, creeping, itching, pins and needles, pulling, crawling, buzzing, and numbness. It is sometimes described as similar to a limb 'falling asleep' or an exaggerated sense of positional awareness of the affected area. The sensation and the urge can occur in any body part; the most cited location is the legs, followed by the arms. Some people have little or no sensation but still have a strong urge to move.
  • "Motor restlessness, expressed as activity, which relieves the urge to move." Movement usually brings immediate relief, although temporary and partial. Walking is most common; however, stretching, yoga, biking, or other physical activity may relieve the symptoms. Continuous, fast up-and-down movements of the leg, and/or rapidly moving the legs toward then away from each other, may keep sensations at bay without walking. Specific movements may be unique to each person.
  • "Worsening of symptoms by relaxation." Sitting or lying down can trigger the sensations and urge to move. Severity depends on the severity of the person's RLS, the degree of restfulness, the duration of the inactivity, etc.
  • "Variability throughout the day-night cycle, with symptoms worse in the evening and early in the night." Some experience RLS only at bedtime, while others experience it throughout the day and night. Most people experience the worst symptoms in the evening and the least in the morning.
  • "Restless legs feel similar to the urge to yawn, situated in the legs or arms." These symptoms of RLS can make sleeping difficult for many patients and a 2005 National Sleep Foundation poll shows the presence of significant daytime difficulties resulting from this condition. These problems range from being late for work to missing work or events because of drowsiness. Patients with RLS who responded reported driving while drowsy more than patients without RLS. These daytime difficulties can translate into safety, social and economic issues for the patient and for society.
RLS may contribute to higher rates of depression and anxiety disorders in RLS patients.

Primary and secondary forms

RLS is categorized as either primary or secondary.
  • Primary RLS is considered idiopathic or with no known cause. Primary RLS usually begins slowly, before approximately 40–45 years of age, and may disappear for months or even years. It is often progressive and gets worse with age. RLS in children is often misdiagnosed as growing pains.
  • Secondary RLS often has a sudden onset after age 40 and may be daily from the beginning. It is most associated with specific medical conditions or certain drugs.

    Causes

While the cause is generally unknown, it is believed to be caused by changes in the neurotransmitter dopamine resulting in an abnormal use of iron by the brain. RLS is often due to iron deficiency and could be a sign of anemia caused by internal bleeding or bone marrow issues. Other associated conditions may include end-stage kidney disease and hemodialysis, folate deficiency, magnesium deficiency, sleep apnea, diabetes, peripheral neuropathy, Parkinson's disease, and certain autoimmune diseases, such as multiple sclerosis. RLS can worsen in pregnancy, possibly due to elevated estrogen levels. Use of alcohol, nicotine products, and caffeine may be associated with RLS. A 2014 study from the American Academy of Neurology also found that reduced leg oxygen levels were strongly associated with restless legs syndrome symptom severity in untreated patients.

ADHD

An association has been observed between attention deficit hyperactivity disorder and RLS or periodic limb movement disorder. Both conditions appear to have links to dysfunctions related to the neurotransmitter dopamine, and common medications for both conditions among other systems, affect dopamine levels in the brain. A 2005 study suggested that up to 44% of people with ADHD had comorbid RLS, and up to 26% of people with RLS had confirmed ADHD or symptoms of the condition.

Medications

Certain medications may cause or worsen RLS, or cause it secondarily, including the following:
Both primary and secondary RLS can be worsened by surgery of any kind; however, back surgery or injury can be associated with causing RLS.
The cause vs. effect of certain conditions and behaviors observed in some patients is not well established. Loss of sleep due to RLS could cause the condition, or medication used to treat a condition could cause RLS.

Genetics

More than 60% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.
Research and brain autopsies have implicated both the dopaminergic system and iron insufficiency in the substantia nigra. Iron is well understood to be an essential cofactor for the formation of L-DOPA, the precursor of dopamine.
Six genetic loci identified by linkage are listed below. Other than the first one, all linkage loci were identified using an autosomal-dominant inheritance model.
  1. The first genetic locus was discovered in one large French Canadian family and maps to chromosome 12q. This locus was discovered using an autosomal recessive inheritance model. Evidence for this locus was also found using a transmission disequilibrium test in 12 Bavarian families.
  2. The second RLS locus maps to chromosome 14q and was discovered in one Italian family. Evidence for this locus was found in one French Canadian family. Also, an association study in a large sample 159 trios of European descent showed some evidence for this locus.
  3. This locus maps to chromosome 9p and was discovered in two unrelated American families. Evidence for this locus was also found by the TDT in a large Bavarian family, in which significant linkage to this locus was found.
  4. This locus maps to chromosome 20p and was discovered in a large French Canadian family with RLS.
  5. This locus maps to chromosome 2p and was found in three related families from population isolated in South Tyrol.
  6. The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008.
Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to RLS.
Their role in RLS pathogenesis is still unclear. More recently, a fourth gene, PTPRD was found to be associated with RLS.
There is also some evidence that periodic limb movements in sleep are associated with on chromosome 6p21.2, MEIS1, MAP2K5/SKOR1, and PTPRD. The presence of a positive family history suggests that there may be a genetic involvement in the etiology of RLS.

Mechanism

Although it is only partly understood, pathophysiology of restless legs syndrome may involve dopamine and iron system anomalies. There is also a commonly acknowledged circadian rhythm explanatory mechanism associated with it, clinically shown simply by biomarkers of circadian rhythm, such as body temperature. The interactions between impaired neuronal iron uptake and the functions of the neuromelanin-containing and dopamine-producing cells have roles in RLS development, indicating that iron deficiency might affect the brain dopaminergic transmissions in different ways.
Medial thalamic nuclei may also have a role in RLS as part as the limbic system modulated by the dopaminergic system which may affect pain perception. Improvement of RLS symptoms occurs in people receiving low-dose dopamine agonists.

Diagnosis

Diagnosis of RLS is generally based on a person's symptoms after ruling out other potential causes. Risk factors include low iron levels, kidney failure, Parkinson's disease, diabetes mellitus, rheumatoid arthritis, pregnancy and celiac disease. A number of medications may also trigger the disorder including antidepressants, antipsychotics, antihistamines, and calcium channel blockers.
RLS may either be of early onset, occurring before age 45, or late-onset, occurring after age 45. Early-onset cases tend to progress more slowly and involve fewer comorbidities, while cases in older patients may progress suddenly and alongside other conditions.
There are no specific tests for RLS, but non-specific laboratory tests are used to rule out other causes such as vitamin deficiencies. Five symptoms are used to confirm the diagnosis:
  • A strong urge to move the limbs, usually associated with unpleasant or uncomfortable sensations.
  • It starts or worsens during inactivity or rest.
  • It improves or disappears with activity.
  • It worsens in the evening or night.
  • These symptoms are not caused by any medical or behavioral condition.
The symptoms below are not essential, like the ones above, but occur commonly in RLS patients:
  • genetic component or family history with RLS
  • good response to dopaminergic therapy
  • periodic leg movements during the day or sleep
  • most strongly affected are people who are middle-aged or older
  • other sleep disturbances are experienced
  • decreased iron stores can be a risk factor and should be assessed
According to the International Classification of Sleep Disorders, the main symptoms have to be associated with a sleep disturbance or impairment to support RLS diagnosis. As stated by this classification, RLS symptoms should begin or worsen when being inactive, be relieved when moving, should happen exclusively or mostly in the evening and at night, not be triggered by other medical or behavioral conditions, and should impair one's quality of life. Generally, both legs are affected, but in some cases there is an asymmetry.