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Iron status and restless legs syndrome in the elderly.

The relationship between iron status and the restless legs syndrome (RLS) was examined in 18 elderly patients with RLS and in 18 matched control subjects. A rating scale with a maximum score of 10 was used to assess the severity of RLS symptoms. Serum ferritin levels were reduced in the RLS patients compared with control subjects (median 33 [micro]g/1 vs. 59 [micro]g/1, p < 0.01, Wilcoxon signed rank test); serum iron, vitamin [B.sub.12] and folate levels and haemoglobin levels did not differ between the two groups. Serum ferritin levels were inversely correlated with the severity of RLS symptoms (Spearman's rho -0.53, p < 0.05). Fifteen patients with RLS were treated with ferrous sulphate for 2 months. RLS severity score improved by a median value of 4 points in six patients with an initial ferritin [less than or equal to] 18 [micro]g/1, by 3 points in four patients with ferritin > 18 [micro]g/1, [less than or equal to] 45 [micro]g/1 and by 1 point in five patients with ferritin > 45 [micro]g/1, < 100 [micro]g/1.

Iron deficiency, with or without anaemia, is an important contributor to the development of RLS in elderly patients, and iron supplements can produce a significant reduction in symptoms.


Several studies have reported low serum (or plasma) iron or ferritin levels in psychiatric patients who develop akathisia during neuropleptic treatment compared with matched controls who do not develop akathisia (1)(2)(3). A correlation has also been reported between the degree of iron depletion and the severity of neuroleptic-induced akathisia (1)(2). Other authors have failed to confirm these findings (4)(5)(6), and the matter remains controversial.

An association between low serum iron levels or iron deficiency anaemia and development of the restless legs syndrome (RLS], a condition with many similarities to akathisia, was reported more than 30 years ago (7)(8)(9)(10). Indeed, it was knowledge of this relationship that prompted investigation of iron status in akathisia (1)(11). However, little systematic research into the relationship between iron status and RLS has been reported in the intervening decades. Serum iron levels are of limited value in assessing iron status because of the large number of clinical conditions which influence iron transport (12). Serum ferritin, an indicator of iron stores, declines before a fall in serum iron and is now regarded as the most useful indicator of iron deficiency (13). In a recent prospective study of elderly hospital patients, we identified iron deficiency (defined as a serum ferritin [less than or equal to] 18 [micro]g/1) in four (31%) of 13 patients with insomnia due to RLS (14). However, it is uncertain whether depletion of iron stores, in the absence of overt iron deficiency, is associated with RLS, or whether the severity of symptoms in RLS correlates with the degree of iron deficiency. Also, vitamin [B.sub.12] and folate deficiencies are common in elderly patients and have been reported in association with RLS (14)(15), but the importance of these deficiencies in the pathogenesis of RLS has not been examined in detail.

We studied serum iron, ferritin, folate and vitamin [B.sub.12] levels in 18 elderly patients with RLS and in 18 matched control patients. The influence of initial serum iron and ferritin levels on the response to iron supplements in the patients with RLS was also evaluated.

Subjects and Methods

The study sample comprised 36 patients recruited from the wards and outpatient clinics of an acute-care geriatric unit. Eighteen patients with RLS were pair-matched with 18 patients without RLS by age, sex, location (inpatient or outpatient) and reason for referral. Subjects taking iron supplements, non-steroidal anti-inflammatory agents, omeprazole or [H.sub.2] blockers and subjects with liver disease, malignancy (except skin cancer) or peripheral neuropathy were excluded. A diagnosis of RLS was made if a patient had bilateral nocturnal leg discomfort which satisfied the following criteria(10): the site included the calf or shin; the sensation was accompanied by an urge to move the legs and was relieved by movement; symptoms were not of tingling, pins-and-needles, numbness, cramps or burning sensations alone; the patient was not taking neuroleptic or anti-parkinsonian medications. The severity of the symptoms was assessed using the scale shown in Table I. All RLS patients had a score of more than 2, and all controls had a score of 0. The RLS severity score was reassessed after 4-6 weeks, before iron therapy was commenced, in ten patients with RLS; the score was the same for eight patients and there was a change of 1 point for two patients. Inter-rater reliability using the scale was excellent (Cohen's kappa = 0.98). Morning venous blood samples were analysed, as previously described, for estimation of full blood count, serum iron, ferritin, [B.sub.12], folate and red-cell folate levels (14).

Table I. Restless legs rating scale
  Do you get an unpleasant restless feeling in your legs at
night which is relieved by moving the legs?
0 = never
1 = rarely (less than once a month)
2 = occasionally (less than once a week)
3 = often (at least once a week)
4 = almost every night

  How distressing is this sensation?
0 = no distress
1 = mild
2 = moderate
3 = severe

  How long do these sensations usually last?
0 = no time or a few seconds
1 = < 30 minutes
2 = > 30 minutes, < 1 hour
3 = > 1 hour

  Maximum score = 10

Patients with a serum ferritin [less than or equal to] 45 [micro]g/1 were prescribed iron supplements as ferrous sulphate 200 mg three times daily. Patients with serum ferritin levels between 46 and 100 [micro]g/1 were informed that their blood tests showed the possibility of a mild iron deficiency and a course of iron supplements might be beneficial. If they agreed, they were also started on iron supplements. The possibility of an improvement in symptoms of RLS or insomnia was not mentioned. Patients who were already receiving treatment for restless legs or insomnia were maintained on this treatment for the duration of the study. RLS severity score and blood tests were repeated after a minimum of 2 months' treatment with iron supplements.

Results were analysed by Wilcoxon matched-pairs signed rank test and Spearman's rank correlation.


There were 13 women and five men and the median age was 81 years (range 70-87) in each group. Of the 18 patients in each group, five (28%) patients with RLS and two (11%) control patients were taking benzodiazepines at the onset of the study.

Serum ferritin levels were significantly lower in the RLS patients than in the controls (median 33 [micro]g/1 vs. 59 [micro]g/1, p < 0.01) (Table II). Serum iron, vitamin [B.sub.12] and folate and haemoglobin and mean corpuscular volume values did not differ between the two groups. There was a significant inverse correlation between serum ferritin and the restless legs rating score (Spearman's rho -0.53, p < 0.05) (Figure).



All of the patients with RLS who had serum ferritin < 100 [micro]g/1 (n = 17) were prescribed ferrous sulphate 200 mg three times daily. One patient was unable to tolerate iron, and another died before follow-up. Median follow-up for the remaining 15 patients was 12 weeks (range 8-20 weeks). All patients showed an increase in serum ferritin levels; the median change was + 34 [micro]g/1 (range + 69 to + 10 [micro]g/1). Median RLS rating score improved from 5 (range 3-9) to 3 (0-5) (Table III). It was possible to withdraw benzodiazepine therapy from three of the five patients with RLS taking this medication.


Four patients in the RLS group and two control subjects had anaemia (Hb < 11 g/dl); six RLS patients and two controls had serum ferritin < 18 [micro]g/1. No subject had folate deficiency. Two RLS patients had vitamin [B.sub.12] deficiency, and both were treated with intramuscular vitamin [B.sub.12] as well as with iron supplements: RLS score improved from 6 to 3 in one patient with an initial vitamin [B.sub.12] level of 184 ng/1 and ferritin of 7 [micro]g/1; there was no change in score for the other patient who had a vitamin [B.sub.12] level of 197 ng/1 and a ferritin of 24 [micro]g/1. Gastro-intestinal investigations in nine of the ten RLS patients with ferritin levels [less than or equal to] 45 [micro]g/1 revealed peptic ulcer disease (1), oesophagitis (3), carcinoma of the colon (1), benign rectal polyp (1) and no abnormality (3).


The significantly low serum ferritin levels in the RLS group, the correlation between ferritin levels and severity of RLS and the improvement in symptoms with iron repletion, especially in patients with lower ferritin levels, suggest that depletion of iron stores, with or without anaemia, is related to the development of RLS. Vitamin [B.sub.12] deficiency was an additional factor in one patient, but folate deficiency was not important in this study. This study was restricted to elderly patients among whom RLS is thought to be most common (16). One possible reason is the higher prevalence of medical conditions, including iron deficiency, which are associated with the syndrome. However, there is no evidence that susceptibility to akathisia increases with advancing age (17).

The explanation for the association between iron deficiency and RLS or akathisia may lie in altered dopaminergic neurotransmission (1). Studies with iron-chelating agents suggest that the dopamine [D.sub.2] receptor is an iron-containing protein (18). Iron deficiency is associated with hypofunction of this receptor, which can be reversed with iron repletion (19). Reduced levels of dopamine and homovanillic acid in the cerebrospinal fluid of RLS patients (20), and the clinical response to dopaminergic agents suggest that dopaminergic neurotransmission is important in the pathogenesis of the syndrome (21). Postsynaptic dopamine [D.sub.2] receptor blockade in mesocortical pathways has been reported as the likely cause of neuroleptic-induced akathisia (22). A reduction of striatal [D.sub.2] dopamine receptor binding sites with age may contribute to the pathogenesis of these disorders in older patients (23).

There are various limitations to our study. We used a subjective scale to assess the severity of RLS. All-night polysomnography and videotaping have been used by some investigators to quantify motor restlessness (24). However, these only provide information on a single night, while it is well recognized that the severity of RLS may vary considerably from night to night. Also, these tests do not take the distress caused by creeping sensations in the legs into account. Secondly, the treatment phase of this study was not blinded. Telsted and colleagues have demonstrated a high placebo effect in the treatment of RLS (25). However, our patients were not informed that iron supplements might relieve their symptoms. Also, many had been treated with benzodiazepines without relief.

RLS is notoriously difficult to treat, and side effects are common with agents such as carbamezapine, levodopa and clonazepam. This study shows the importance of measuring serum ferritin levels in patients with this condition. The optimal cut-off point for serum ferritin in the diagnosis of iron deficiency depends on the pretest probability of iron deficiency in the population being studied. Recent work suggests that a cut-off for serum ferritin of 45 [micro]g/1 is appropriate in elderly patients with (13) or without anaemia (26). Elderly patients with RLS have a particularly high prevalence of iron deficiency. The response to iron supplements in RLS patients with a ferritin level [less than or equal to] 45 [micro]g/1 is usually excellent. A trial of iron therapy should also be considered in patients with serum ferritin levels between 46 and 100 [micro]g/1, since some of these patients will also have a good response.


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Author:O'Keeffe, S.T.; Gavin, K.; Lavan, J.N.
Publication:Age and Ageing
Date:May 1, 1994
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