Researchers have been trying to find the cause of RLS since Ekbom’s description of this condition appeared 65 years ago. Today we know a great deal about RLS— but not exactly what causes RLS or which part of the nervous system, if any, is affected.
It is generally thought that RLS is a disorder arising from the central nervous system (CNS), even though no specific structural abnormality has been identified. Is the problem located in the cerebral hemisphere (the main part of the brain), the brain stem (the lower part of the brain, which is connected to the main portion of the brain and controls vital functions such as circulation, respiration, and sleep), or the spinal cord (the long tubular structure of the CNS that connects to the brain stem and runs through the vertebral column)? Various stud-ies indicate probable involvement of all levels of the CNS. No structural alteration in the cells or the connections of the CNS has so far been noted. Thus, RLS most likely results from a functional—rather than a structural—abnormality in some site of the CNS.
Based on research studies, it appears that the problem lies somewhere between the main portion of the brain and the spinal cord. Patients’ response to RLS treatments and other studies point to a problem with a chemical called dopamine, a neurotransmitter made in the nerve cells that helps transmit nerve impulses to other nerve cells. Dopamine is deficient in Parkinson’s disease—there is loss of cells manufacturing dopamine in Parkinson’s disease. The problem with dopamine in patients with RLS, however, seems to involve a different mechanism than is present in Parkinson’s disease. The results do not clearly show that dopamine is deficient in RLS. Perhaps there is a wide variation of dopamine levels between day and night, with a marked decline in levels occurring in the evening and during the night in RLS patients.
The contemporary thinking or understanding of RLS suggests that this disease may be caused by an abnormality in the body’s use and storage of iron, at least in a subgroup of RLS patients. Iron is needed for dopamine synthesis; consequently, a deficiency of iron in the brain may contribute to the dopamine dysfunction. Iron deficiency aggravates RLS symptoms, and iron treatment in these patients ameliorates these symptoms, suggesting a role for iron in RLS. Low stores of iron in the brain and dysfunction of iron metabolism and intracellular iron may play key roles in RLS pathophysiology. This iron–dopamine model suggests that brain iron deficiency causes an abnormality in the dopaminergic system, in turn leading to RLS symptoms.
Neurophysiological and functional magnetic resonance imaging (fMRI) studies suggest that the dysfunction may occur somewhere in the region of the brain stem. In most cases of RLS, however, no clear cause is found. In some patients, RLS symptoms may arise secondary to other disorders, such as an abnormality of the nerves conducting impulses outside the CNS, chronic failure of the kidneys (the organs responsible for urine production and excretion from the body), iron deficiency, diabetes mellitus, or chronic joint disease (see Question 14).
RLS may also be associated with or caused by some medica-tions (e.g., antidepressants, antihistamines; see Question 82). Because we do not know the exact cause of RLS, we can only treat the symptoms but not cure the dis-ease at present. The good news is that most patients get relief, although they may have to continue taking medication indefinitely.