Cotter and O’Keefe and in older hospital patients, the diagnosis of iron deficiency is almost certain in those with ferritin less than 20 ng/mL and is likely in those with levels less than 50 ng/ mL. The severity of RLS symptoms correlates well with the serum ferritin level, even in patients who are not obviously iron deficient and who have normal hemoglobin and MCV levels (O’Keeffe et al 1994). A search for an underlying cause of iron deficiency is usually indicated and may lead to the detection of new cancers (Brocklehurst 2003; O’Keeffe 2005). RLS has been noted in 15% to 40% of patients with end-stage renal disease; it is particularly prominent in patients on hemodialysis, possibly because of the enforced rest (Collado-Seidel et al 1998). RLS is also common during the third trimester of pregnancy and resolves after delivery (Lee et al 2001). Development of transient RLS during pregnancy may suggest a predisposition to develop the condition in later life (Ulfberg et al 2001; Berger et al 2004). There is also good evidence to support associations between RLS and rheumatoid arthritis and Sjogren’s syndrome (Reynolds et al 1986; Gudbjornsson et al 1993; Salih et al 1994). As was noted earlier, the relationship between RLS and peripheral neuropathy is unclear. There have also been conflicting reports regarding a possible association between RLS and Parkinson’s disease (PD) are associated (Garcia- Borreguero et al 2003). A recent study noted that 21% of PD patients had RLS, with lower ferritin levels being the main predicting factor for development of RLS (Ondo et al 2002). Disturbance of iron metabolism may also influence the relationships between RLS and conditions such as uremia, pregnancy, and rheumatoid arthritis. Thus, physicians faced with a patient with RLS should inquire about factors predisposing to iron deficiency, including menorrhagia in premenopausal women, coeliac disease, gastrointestinal and urinary blood loss, and frequent blood donation. Full blood count to exclude anemia, serum ferritin and transferrin saturation, serum urea and creatinine and blood glucose should be performed, at a minimum. With symptoms or physical findings suggestive of nerve root damage or neuropathy, the patient should be evaluated for neuropathy and for factors contributing to neuropathy. Iron–dopamine hypothesis The improvement in RLS with dopaminergic agonists and the worsening of symptoms with dopaminergic antagonists that cross the blood–brain barrier, combined with the lack of effect of the dopamine antagonist domperidone, which does not cross the blood–brain barrier, suggest an important role for the dopamine neurotransmitter system in the central nervous system in the pathogenesis of RLS. Positron emission tomography and single photon emission computed tomography studies have found a decreased activity of the dopamine D2-receptor in the striatum in RLS, consistent w i t h a r o l e f o r a s u b c o r t i c a l d y s f u n c t i o n o f t h e dopaminergic system in RLS (Turjanski et al 1999; Michaud et al 2002). Reflex studies suggest that RLS involves increased (rather than the normal decreased) spinal cord excitability with sleep, probably due to impaired subcortical regulation of spinal function (Bara-Jimenez et al 2000; Aksu and Bara- Jimenez 2002). Functional MRI studies showing activation of the thalamus and cerebellum during sensory events (without movements), and of the pons and red nucleus during sensory events that were accompanied by movements in RLS are also consistent with subcortical dysfunction (Bucher et al 1997). The dopaminergic A11 cell group is postulated as being centrally involved as they are the only neurones which provide dopaminergic axons to the spinal cord; lesions of the subcortical A11 dopamine system in rats produces increased startle response and increased locomotion, possibly suggesting the motor restlessness of RLS (Ondo, He, et al 2000). Iron is an essential cofactor for tyrosine hydoxylase, the rate-limiting enzyme for dopamine synthesis. In animal studies, iron deficiency is associated with hypofunction of dopamine D2 receptors that is corrected by iron replacement (Erikson et al 2003; Burhans et al 2005). The fact that the established secondary causes of RLS share disturbance of iron metabolism as a common feature, that the degree of iron deficiency correlates well with symptoms, and that iron is an effective therapy, at least in iron-deficient patients provide clinical support for the importance of iron deficiency in the pathogenesis of RLS. Further support comes from cerebrospinal fluid analysis of iron indices suggesting brain iron deficiency (Earley et al 2000), and from magnetic resonance imaging (MRI) (Allen et al 2001) and autopsy findings of regional basal ganglia iron deficiency (Connor et al 2004). Thus, the current hypothesis is that RLS involves a functional disturbance of dopamine neurotransmission in subcortical areas of the brain, provoked by regional iron deficiency or by genetic factors or both, resulting in decreased inhibition of the sensorimotor cortical system and (particularly during sleep) of the spinal system. 470 Therapeutics and Clinical Risk Management 2006:2(4)