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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).