Restless Leg Syndrome, or Willis-Ekbom Disease, Causes

There are two categories of restless legs syndrome, primary RLS (of unknown cause and often familial in origin) and secondary RLS that results from other conditions. There are many conditions that may independently lead to symptoms of RLS, including iron deficiency and pregnancy.

Woman's legs in bed
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Iron Deficiency

One condition that is strongly linked to symptoms of RLS is iron deficiency. The relationship between iron deficiency and RLS symptoms has been extensively studied. The research shows that low iron levels can be found in the blood and spinal fluid of individuals suffering from RLS. The lower the iron levels, the worse the symptoms.

Magnetic resonance imaging (MRI) has shown that the iron content in an area of the brain called the substantia nigra is lower in those with RLS compared to normal individuals, which may contribute to the disorder. In addition, pathological studies have confirmed this change within the brain.

If you have symptoms of RLS, it is typically recommended that you have your serum ferritin level (a marker of iron stores) checked. If the levels are low, a trial run of oral supplementation or iron replacement should be undertaken. Even some individuals with normal levels respond positively to iron replacement.


End-Stage Kidney Disease

RLS is very common among individuals suffering from end-stage kidney disease, especially those who are dependent upon dialysis, a procedure that removes waste products and excess fluids from the body the way healthy kidneys would. The incidence of RLS has been reported to range from 6%–62%.

It is unclear what may be contributing to RLS in this group. Based on various studies, anemia (lack of healthy red blood cells) or iron deficiency may play a role. In some cases, treating anemia with erythropoietin therapy or iron replacement has been effective.



RLS may develop in people with type 2 diabetes. If diabetes is left uncontrolled, nerve damage can result due to high levels of glucose within the blood. This can lead to damage of small blood vessels that supply the nerves called vaso nervorum. When these become clogged, the nerve itself will become damaged.

Often this leads to peripheral neuropathy, which consists of pain and a pins-and-needles sensation in the feet. This may progress up the legs and even involve the hands. Associated with these sensory changes, some people will also have symptoms of RLS.

Therefore, it is thought that diabetes may be an independent risk factor for developing RLS. In people who have undergone kidney transplants, their symptoms of RLS have improved.


Multiple Sclerosis (MS)

There is a growing body of evidence that multiple sclerosis is associated with an increased risk of RLS. A review of 25 studies on the subject found that RLS affected 26% of women and 17% of men with the disease. RLS may contribute to fatigue, which responds well to a class of medications called amantadines.


Parkinson's Disease

It is thought that RLS and Parkinson’s disease may be caused by a similar problem, namely disruptions in the neurotransmitter dopamine. This is not fully understood, however. Regardless, RLS may be present in individuals who have Parkinson’s disease, with a prevalence ranging from 0%–20.8%, varying based on the study.

Parkinson’s disease often involves a sense of restlessness (called akathisia) that overlaps with RLS, which may make it difficult to differentiate between the disorders. When both conditions are present, RLS usually occurs after Parkinson’s disease has become apparent.



Not all conditions that may lead to RLS are disorders. In fact, being pregnant seems to increase not only the incidence but also the degree of RLS symptoms. Studies have shown the incidence if RLS among pregnant women to be anywhere from 10%–30%.

The good news is that the symptoms rapidly improved after giving birth. It is not clear what causes the increased frequency of RLS during pregnancy. It may be due to iron or folate deficiency or even because of hormonal changes associated with being pregnant.


Rheumatic Disease

There are many conditions such as the autoimmune disorders rheumatoid arthritis (RA, which causes severe joint pain and damage throughout the body) and Sjogren’s syndrome (with symptoms such as dry eye and dry mouth), as well as fibromyalgia, that have an association with symptoms of RLS. The exact relationship is unclear.

In one study, 25% of individuals with rheumatoid arthritis had RLS symptoms compared to only 4% of those with osteoarthritis (arthritis caused by wear and tear). Another study found that the incidence of RSL was 10 times higher among patients with fibromyalgia than it was in controls without the disease. The exact reason for this association is not fully understood.


Varicose Veins

In some instances, poor blood flow in the legs has been associated with RLS. In particular, weak veins that distend and become uncomfortable have been blamed. These varicose veins are often engorged and blue in color and may be a sign of venous insufficiency.

Treatment of varicose veins has proven to be effective in alleviating some of the symptoms of RLS. This includes procedures like scleropathy and medication, such as hyrdoxyethylrutoside, which has been shown to be modestly effective.


Other Conditions

Beyond the conditions described above, there are many other disorders that seem to be associated with RLS symptoms. These include:

  • Obesity
  • Hypothyroidism (underactive thyroid)
  • High blood pressure
  • Heart disease
  • Peripheral neuropathies
  • Vitamin deficiencies
  • Excessive caffeine intake
  • Low blood sugar
  • Lumbosacral radiculopathy (syndrome caused by painful compression or irritation of nerve roots in the lower back)
  • Spinal stenosis (narrowing of spaces in the spine)
  • Use of certain medications such as antihistamines, dopamine antagonists, antidepressants (particularly mirtazapine), lithium, beta-blockers, and selective serotonin reuptake inhibitors (SSRIs).

If you have restless legs symptoms, fortunately, there are effective medications that are used in treatment.

13 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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Additional Reading
  • Manconi, M et al. “Multicenter Case-Control Study on Restless Legs Syndrome in Multiple Sclerosis: the REMS Study.” Sleep 2008; 31:944.

  • Merlino, G. et al. “Association of Restless Legs Syndrome and Quality of Sleep in Type 2 Diabetes: a Case-Control Study.”​ Sleep 2007; 30:866.

  • Walters, A. “Restless Legs Syndrome and Periodic Limb Movements of Sleep.”​ Continuum. Neurol 2007;13(3):115-138.

  • Allen, RP et al. “MRI Measurement of Brain Iron in Patients With Restless Legs Syndrome.”  Neurology 2001; 56:263.
  • Connor, JR et al. “Neuropathological Examination Suggests Impaired Brain Iron Acquisition in Restless Legs Syndrome.”  Neurology 2003; 61:304.
  • Earley, CJ et al. “Abnormalities in CSF Concentrations of Ferritin and Transferrin in Restless Legs Syndrome.”  Neurology 2000; 54:1698.
  • Kavanagh, D et al. “Restless Legs Syndrome in Patients on Dialysis.” Am J Kidney Dis 2004; 43:763.
  • Lee, JE et al. “Factors Contributing to the Development of Restless Legs Syndrome in Patients With Parkinson Disease.”  Mov Disord 2009; 24:579.

By Brandon Peters, MD
Brandon Peters, MD, is a board-certified neurologist and sleep medicine specialist.