Introduction to Restless Legs Syndrome

What Causes Restless Legs Syndrome?

Although an extensive amount of research has been conducted over the past decade, researchers and doctors still do not exactly understand why people develop restless legs syndrome. In fact, most cases of restless legs syndrome are referred to as being "idiopathic", meaning that no known underlying cause can be identified. Restless legs syndrome, however, can be associated with other underlying medical conditions. Doctors refer to this form of restless legs syndrome as "secondary restless legs syndrome".

Estimates are that approximately 55-90% of patients have a positive family history for restless legs syndrome and in the case of identical twins, up to 80% of the twins of restless legs syndrome patients will also be affected by restless legs syndrome. Recent research suggests an autosomal dominant mode of inheritance and a major genetic susceptibility locus for restless legs syndrome has been identified on chromosome 12q and has more recently been identified on chromosome 14 as well.

Although the exact etiology of restless legs syndrome is unknown, recent developments highlight the possible dysfunction of the central nervous system (brain and spinal cord) and the dopamine system (a neurotransmitter produced by the body and used in the brain to send messages among the cells). Involvement of the dopamine system is clearly manifested by symptom response to dopaminergic drugs which is in itself a confirmation of a diagnosis of restless legs syndrome. Some studies have noted modest reduction of dopamine function in key centers of the brain responsible for movement, such as the striatum and putamen though the significance of these findings is not yet clearly understood. There is some evidence that opioid neurotransmitters may be involved as well since many people achieve relief from their symptoms when taking opioid medication.

In addition, the role of iron deficiency, a common finding in patients with restless legs syndrome, is also being vigorously investigated. It is known that the lower the concentration of serum ferritin, the more severe are the symptoms of restless legs syndrome. Studies have also noted a reduction of ferritin in the cerebrospinal fluid of patients with restless legs syndrome as well as a reduction in the brain's storage of iron. As iron levels and dopamine levels vary with the circadian cycle, it seems to point to a relationship between the two systems and the possibility that iron deficiency may play a role in dopamine abnormalities in patients with restless legs syndrome. Periodic limb movements may also be related to dopamine abnormalities as they are found in other dopamine-related conditions, such as Parkinson's disease.

The central nervous system is thought to also play a significant role in restless legs syndrome. For example, studies have shown that patients with restless legs syndrome and PLMS exhibit a disinhibition of the flexor reflex during sleep meaning the reflex action is not suppressed as it would be under normal circumstances. This results in the flexor reflex (extension of the great toe or all toes due to firm pressure on the deep flexor muscles of the calf or leg) occurring even without a stimulus. This is further indication of altered activity of the CNS.

There are many patients with restless legs syndrome and other neuropathic conditions, such as peripheral neuropathy or radiculopathy although restless legs syndrome appears to be a condition of the central nervous system. This seems to indicate that there may be a complex process relating to the interaction between these two nervous systems that may be related to restless legs syndrome and is as yet not understood.

Dopamine activity and iron levels are regulated by the circadian rhythm of the body. Their levels are higher during the day than at night. Since restless legs syndrome symptoms are so much more severe in the late afternoon, evening and nighttime, many researchers believe that the circadian mechanism may be closely related to restless legs syndrome so that fluctuations of dopamine and/or ferritin may be responsible for the symptoms emerging nightly for restless legs syndrome. In addition, iron levels in the blood follow a circadian rhythm and can decrease up to 50% at night which is the time of greatest severity of restless legs syndrome symptoms. One small study examining iron levels in the brain indicated that there is a lower iron content in the substantia nigra and putamen of patients with restless legs syndrome. These are the areas of the brain deeply involved with smooth movement of the muscles.

Some researchers have hypothesized that restless legs syndrome may be related to low levels of various other substances in the body, such as vitamin B12, folate, and magnesium.

There is also an association between restless legs syndrome and neural conditions such as peripheral neuropathy, where small studies show subtle nerve damage is common in patients with restless legs syndrome, especially those with late onset restless legs syndrome; myelopathy (conditions affecting the spinal cord), and Parkinson's disease, a degenerative nerve disorder that responds to the same class of medications as restless legs syndrome (dopaminergic therapy).