Iron Dysregulation in Restless Legs Syndrome

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Chapter 10 Iron Dysregulation in Restless Legs Syndrome

In the 1940s and 1950s, while Ekbom1,2 was proposing a vascular model for restless legs syndrome (RLS), Nordlander3 was establishing a role for iron in RLS. He noted that his patients with RLS had a high prevalence of iron deficiency and that their symptoms improved on treatment of the iron deficiency. In 1953, Nordlander formally proposed “that restless legs might … be a sign of iron deficiency.”3 Ekbom acknowledged Nordlander’s finding and reported a 24.6% prevalence of iron deficiency among his patient population.4 O’Keefe and colleagues5 also reported a high prevalence of iron deficiency among their patients with RLS. In addition, there is a high prevalence of RLS in populations with iron deficiency (20% to 30%),4,6 in populations associated with a high prevalence of iron deficiency like pregnancy79 and blood donors (14% to 26%)10,11 and in populations with altered iron metabolism like occurs in dialysis (14% to 68%).1214 Although the elderly may have low iron stores due to aging or chronic disease and therefore suffer RLS,5 in the pediatric population, where RLS may be associated with attention-deficit/hyperactivity disorder (ADHD),1517 low iron stores measured by serum ferritin levels have been associated with ADHD,17 RLS,16 and comorbid ADHD and RLS.1618

Two independent studies demonstrated a strong inverse correlation between serum ferritin levels and RLS severity: as serum ferritin declined, symptom severity increased.5,19 One of the studies also showed a strong correlation between serum ferritin level and sleep efficiency: as ferritin declined, sleep efficiency also declined.19 Despite the findings of these two studies there are limitations to their interpretation. Both evaluated relatively small populations. O’Keefe and associates5 studied an elderly population where the majority of the patients had low-normal or abnormal ferritin levels with a median ferritin level for the group of 33 µg/L (range of 6 to 124 µg/L). Although the patient population studies by Sun and coworkers19 had a much broader range of ferritin levels (5 to 229 µg/L), the mean ferritin was in the low-normal range (60 µg/L). On further analysis of these data,19 patients with low ferritin levels (<50 µg/L) had greater disease severity by several different outcomes measures compared with those with high ferritin levels (>50 µg/L). This finding and others20 suggest that the relation between RLS symptoms and a broad range of body iron storage states may be poor. The relation is strongest when the patients have low or deficient body iron stores, suggesting that iron deficiency per se may be more important than general iron status.

Nordlander3 successively treated RLS symptoms with intravenous iron. The surprising fact is that the majority of these patients had normal blood iron levels. The study implicates a causal link between iron and RLS symptoms and supports his initial premise that “there can exist an iron deficiency in the tissues in spite of normal serum iron.”3 More recent studies have considered the possibility that the brain per se could have low iron stores despite the presence of normal blood or systemic levels of iron. Using magnetic resonance imaging techniques to quantify iron concentrations in 11 brain regions, a first study of RLS patients found lower iron concentrations in their substantia nigra than in age-matched control subjects.21,22 In addition, lower iron concentrations in the substantia nigra were significantly correlated with increasing RLS symptom severity. A second, expanded study confirmed this finding but primarily for early-onset RLS.23 Several studies using transcranial Doppler have confirmed the presence of low levels of iron in the substantia nigra of RLS patients.2426 The distinction between regulation of body and brain iron levels is made most strikingly by the finding that patients with hemochromatosis—who retain iron and have high ferritin levels—may have reduced brainstem iron.27

Another study examined cerebrospinal fluid (CSF) ferritin and transferrin as the indicator of brain iron status28 (Figs. 10-1, 10-2, and 10-3 ). Subjects were chosen who had normal blood levels of both of these factors. Despite having normal systemic iron stores that were comparable with those of control subjects, patients with RLS had reduced CSF ferritin and increased CSF transferrin, findings that suggest a relative iron-insufficient state within the central nervous system (CNS). The correlation between serum and CSF ferritin was different for control subjects and RLS patients. The slope of the curve in the RLS group was lower than that found in the control group. This would suggest that CNS iron regulation might be somewhat independent of the systemic iron status in RLS patients. In additional studies using immunoblot techniques and controlling for overall protein quantity, decreased H and L subunits were found in early-, but not late-onset RLS.29 Similarly, depressed levels of prohepcidin, a precursor of the iron regulatory protein hepcidin, were also found in early-onset patients.30

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FIGURE 10-1. Serum concentrations for iron, ferritin, and transferrin in patients with restless legs syndrome (RLS) and in control subjects (Normal). The mean for the individual values is indicated by the blue bar.

Reprinted with permission from the American Academy of Neurology. Source: Earley CJ, Connor JR, Beard JL, et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000;54:1698-1700.

image

FIGURE 10-2. CSF concentrations for iron, ferritin, and transferrin in patients with restless legs syndrome (RLS) and control subjects (Normal). The mean for the individual values is indicated by the blue bar.

Reprinted with permission from the American Academy of Neurology. Source: Earley CJ, Connor JR, Beard JL, et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000;54:1698-1700.

image

FIGURE 10-3. A linear regression plot of the relation between serum ferritin and cerebrospinal fluid ferritin for patients with restless legs syndrome (RLS; •) and control subjects (image).

Reprinted with permission from the American Academy of Neurology. Source: Earley CJ, Connor JR, Beard JL, et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000;54:1698-1700.

The most conclusive data on the relation of brain iron metabolism to RLS are from brain autopsy analyses31 (Figs. 10-4 and 10-5). General histological assessment of brains from seven RLS patients and five control subjects showed no obvious pathology, cell loss, gliosis, or signs of Parkinson’s or Alzheimer’s disease. Assessments of iron and iron-regulator proteins were specifically evaluated in the substantia nigra because of its high iron and dopaminergic concentrations and because of the previous magnetic resonance imaging findings indicating low iron levels in this area in RLS. In tissues from patients with RLS, iron and H-ferritin were decreased, transferrin was increased, and L-ferritin was the same as for control subjects. However, L-ferritin appeared more concentrated in glial cells in RLS tissue, whereas L-ferritin was predominantly found in oligodendrocytes of control tissues.