SEEMEDJ 2020, VOL 4, NO.

1 Restless Legs Syndrome and Iron

Review article

Restless Legs Syndrome and Iron 1

Josipa Pulić* 1
1
Institute of Emergency Medicine of Koprivnica- Križevci County, Koprivnica, Croatia

*Corresponding author: Josipa Pulić, [email protected]

Abstract

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is one of the most
common neurological disorders that significantly affects quality of life and sleep. It manifests itself in
involuntary movements of the lower limbs due to the feeling of discomfort and restlessness that
patients feel in their lower limbs.
RLS is of great interest to the experts in various fields of medicine, especially to neurologists,
general practitioners, internists and psychiatrists. Numerous clinical conditions and diseases play a
role in the pathophysiology of RLS. Some of them are pregnancy, some kidney and stomach
diseases, iron deficiency and some disorders of the metabolism.
Moreover, iron is a very important micronutrient in the human body. It is involved in many
metabolic processes and, in addition to RLS, it is also associated with other diseases such as
hemochromatosis and anemia. This neurological disorder has wide therapeutic choices, which
include lifestyle changes, dopaminergic agonists, opioids and iron therapy. Many non-anemic
patients with RLS showed reduced levels in brain iron levels compared to healthy control groups in
several research. The best course of treatment for this group of patients is iron supplementation.
Oral iron supplementations are the first choice of therapy for patients with low serum ferritin
levels. However, when serum ferritin levels are normal or high or when oral iron is not tolerated,
intravenous iron is a better choice. There are many intravenous iron formulations, but low molecular
weight dextran and ferric carboxymaltose have very efficient effects on the treatment of RLS.

(Pulić * J. Restless Legs Syndrome and Iron. SEEMEDJ 2020; 4(1); 55-62)

Received: Feb 21, 2020; revised version accepted: Mar 18, 2020; published: Apr 27, 2020

KEYWORDS: restless legs syndrome, Willis-Ekbom disease, iron metabolism, serum ferritin levels, treatment

55 Southeastern European Medical Journal, 2020; 4(1)

 SEEMEDJ 2020, VOL 4, NO. 1 Restless Legs Syndrome and Iron

Introduction disorder with worsening symptoms, which vary

in intensity and frequency. Therefore, in patients
Restless legs syndrome (RLS) has been with chronic form of this disorder, symptoms
described as a neurological disorder, related to occur at least twice a week if patients do not
uncontrolled leg movements, and, in much follow their therapy (1, 5).
smaller number of patients, it is associated with
uncontrolled hand movements. Uncontrolled RLS has prevalence between 8 and 10% (6) in
limb movements are preceded by a sense of adult and 2% in children population (7). The study
discomfort, described by patients as annealing, conducted by Manconi et al. has shown that RLS
burning, tickling, etc. It occurs more frequently occurs more frequently in women, age 35 and
during inaction. Therefore, it is a common cause above, than in men of the same age (8).
of sleep disorders (1-3). In the 17th century, sir
Thomas Willis noticed the connection between This disorder can be inherited or be a result of a
sleep disorders and lower extremity discomfort clinical condition such as kidney diseases
among his patients. However, Karl- Axel Ekbom (hemodialysis patients) (9), pregnancy
first used the term 'restless legs syndrome' in (evaluated progesterone and estrogen levels,
1945. That is why this disorder is also known as iron deficiency) (10), anemia, stomach damage,
Willis-Ekbom disease (4). etc. In addition, some substances such as
neuroleptic drugs, caffeine, lithium,
Unlike some other disorders with similar metoclopramide, antihistamines, dopaminergic
problems, such as polyneuropathy, the agents (1, 11) may increase the risk of developing
symptoms of RLS decrease with leg RLS symptoms (Figure 1).
movements. In most cases, it is a chronic

Kidney diseases
(hemodiallysis
patients)

Drugs (caffeine, classical

neuroleptic drugs, lithium, Pregnancy (iron deficiency,
metoclopramide, elevated progesteron and
antihistamines, treatment estrogen levels)
with dopaminergic agents)

Stomach damage Anemia

Figure 1. Non-hereditary causes of restless legs syndrome

Summarized findings from studies to date on the most common diseases/clinical conditions/drugs that are
associated with restless legs syndrome.

Treatment for RLS depends on its cause. dopaminergic agents, lifestyle changes, iron
Therefore, the treatment can include therapy, α-2-δ- ligands, opioids, etc (1).
56 Southeastern European Medical Journal, 2020; 4(1)
 SEEMEDJ 2020, VOL 4, NO. 1 Restless Legs Syndrome and Iron

Compared to the previous European Federation oligodendrocytes, the presence of the

of Neurological Societies (EFNS) guidelines on transferrin has been confirmed, but a greater
the management of RLS from 2004, new amount of brain iron is nevertheless related with
guidelines from 2012 bring news. Numerous ferritin (13, 22). Iron plays a large role in
drug studies have been made during this period neurotransmitter synthesis and mitochondrial
and new treatments have been examined that respiration and its status is regulated at the level
could be a potential therapy for RLS. The of the blood- brain barrier (BBB) (13, 23, 24).
majority of research deals with dopaminergic
It has long been known that iron excess causes
agents, considered the first line therapy. The
hemochromatosis, characterized by skin
crucial role of iron in pathophysiology of RLS has
changes, weakness, loss of sex drive, abdominal
also been confirmed. Alternative forms of
pain and symptoms of diabetes; but recent
therapy have been investigated; folate, vitamin
studies have associated brain iron excess with
E, physiotherapy, aerobic training and
the onset of neurodegenerative diseases such
magnesium. Nevertheless, there is still not
as Parkinson's disease. On the other hand, iron
enough evidence of their effectiveness (12).
deficiency in the central nervous system (CNS) is
associated with irritability, concentration
Iron in relation to health and diseases
disorder, tiredness and it may play a role in the
Iron is one of the most important micronutrient pathophysiology of RLS (13).
in human body. It has many functions such as a
role in metabolic processes; it can cause Correlation between restless legs
oxidative stress because it participates in the syndrome and iron
formation of oxygen radicals (13), and it is a
cofactor of numerous enzymes (13, 14). The first person who noticed that low serum iron
level could be a risk factor for developing
There are about 4,2 grams of iron in the human restless legs syndrome was Nordlander (25, 26).
body, and much of it is bound to hemoglobin Ekbom observed iron deficiency among his
and involved in oxygen transfer (12). About 10% patients. Although he noticed repeated
of the iron ingested through food is absorbed in occurrence of low iron level in RLS, most of his
the digestive system, mostly in the duodenum patients suffered from uremia, anemia or were
(15). pregnant women (27). In another research,
Ferritin is an intracellular protein that stores iron O'Keeffe found low serum iron and ferritin
and plays an important role in regulating iron values in patients who complained of RLS
homeostasis, while transferrin is a glycoprotein symptoms. It was observed that the lower the
that binds iron and transports it into the cells (16). ferritin level were, the more severe RLS
The major regulator of iron homeostasis is symptoms appeared (28, 29). Iron
hepcidin, 25-amino acid peptide hormone, supplementation has caused improvement in
which is mainly secreted by hepatocytes (17, 18). some patients. The potential cause of this is
Its deregulation is linked with excess iron and altered management of brain iron in patients
iron deficiency. Therefore, when level of with RLS (30, 31).
hepcidin is very high, like in case of Two studies have shown that almost 2/5 of the
inflammation, the absorption of iron is reduced patients suffering from iron deficiency anemia
and this can lead to the development of anemia also had symptoms of RLS. Nevertheless, these
studies used small groups of participants (32, 33).
(17-19).
However, one study, conducted by Allen et al.
It is proved that brain and liver contain high among the general population, has shown that
levels of iron (13). The highest concentration of the percentage of people with symptoms of RLS
brain iron is found in substantia nigra, globus is several times higher in the group of
pallidus, red nucleus, putamen and dentate participants with iron deficiency anemia than in
nucleus of the cerebellum (20, 21). In the general population (34). Abnormalities in the

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 SEEMEDJ 2020, VOL 4, NO. 1 Restless Legs Syndrome and Iron

concentrations of ferritin, transferrin in the vitamin C in order to improve absorption in the

cerebrospinal fluid (CSF), low CSF ferritin, and small intestine (44, 45).
high CSF transferrin levels have been noticed
According to the American Academy of Sleep
(35).
Medicine (AASM) guidelines, iron treatment is
Circadian pattern is characteristic for RLS, with
effective for RLS only in patients who have low
symptoms being dominant at nighttime. Serum
ferritin levels. In addition, it is preferred oral over
iron has a circadian variation, with 30 to 50% drop
parenteral iron formulations, because parenteral
at night. This can lead to clinically significant
forms are associated with a number of side
drop in brain iron levels with patients with RLS
effects that can endanger patients’ life and
and create the symptoms (36).
health (46).
Lower iron concentration in substantia nigra and
putamen were found in some patients with On the other hand, intravenous iron
idiopathic RLS and capillary transport of iron in supplementations bypass the intestinal- blood
the brain probably plays a major role in this. In barrier and restriction of iron absorption (47).
addition, it has been observed that the iron Intravenous iron forms take precedence over
levels in substantia nigra increase with aging (37- oral iron only in two cases. First is when the
39). patient is severely bleeding and rapidly losing
There is a small number of studies that have iron, and the second case is when patients have
compared the connection between serum problems with oral iron absorption (44, 48).
hepcidin levels and RLS. However, one of them
found higher prohepcidin (inactive form of There are several intravenous iron formulations
hepcidin) in putamen and substantia nigra in available: ferric carboxymaltose, iron sucrose,
patients with RLS. This opens up the possibility iron gluconate, low and high molecular weight
of discovering new medications, such as dextrans (LMW and HMW dextrans),
hepcidin antagonists, for the treatment of RLS ferumoxytol and iron isomaltose (44). LMW
(40-42). dextran and ferric carboxymaltose have the best
clinical evidences for treatment of RLS (1, 44).
Infusion of 1000 mg LMW dextran improves the
Iron treatment health of RLS patients with early symptoms and
significantly increases iron levels in substantia
Iron deficiency anemia is present in more than nigra (49). Both oral and intravenous iron
1/5 of the patients with RLS (34). Accordingly, preparations have numerous limitations in the
oral and intravenous iron supplements are used treatment of RLS. The most dangerous side
as therapy for those patients. When serum effect is related to HMW dextran and it involves
ferritin level is lower than 75 μg/l, oral iron anaphylactic shock. On the other hand, ferric
supplementation is the therapy of choice. While carboxymaltose is safe to use because its side
in patients with serum ferritin level higher than effects, such as nausea and headache, are much
300 μg/l intravenous iron preparations are a milder (50).
better choice (43, 44). O'Keeffe observed among There are not enough studies on intravenous
his patients, who had different serum ferritin sucrose, as well as on most intravenous iron
values, that oral iron supplements had better preparations. Nevertheless, it is known that
effect on patients with lower serum ferritin intravenous sucrose is not effective for patients
values. However, the problem with this study that do not have anemia (50). In addition, for iron
was that it did not have a control group (25, 29). gluconate, ferumoxytol and iron isomaltose,
Furthermore, oral iron supplements have almost there are insufficient clinical evidences (44, 51)
the same effect whether taken once a day or (Table 1)..
divided into two doses. In addition, in both cases
these supplementations should be taken with

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 SEEMEDJ 2020, VOL 4, NO. 1 Restless Legs Syndrome and Iron

Table 1. Iron preparation limitations in the treatment of restless legs syndrome

Oral ferrous sulfate: gastrointestinal upset;

not effective for patients with serum
ferritin level>75 μg/l

Ferric carboxymaltose: headache

nausea

Iron sucrose: not effective in iron deficiency patients

without anemia

High molecular weight dextran: high incidence of anaphylactic shock

Low molecular weight dextran: not so effective in patients with symptoms

of late onset RLS

Iron isomaltose, ferumoxytol, iron gluconate: not enough clinical evidences

Note: Summarized findings from studies to date on oral and intravenous iron preparations for the treatment of restless
legs syndrome.

Avni et al. have proven in their research that iron uncertainties related to iron therapy and a need
preparations are safe and effective for RLS. for further research on that topic. The reason is
However, there is still a great need for further the fact that many intravenous iron formulations
research, especially for the research that could lack sufficient clinical evidences regarding their
determine the exact drug dosages and effect on reducing the symptoms of RLS.
therapeutic regimen (43) Furthermore, many studies have a small or
inadequate sample of participants. In addition,
Conclusion for many intravenous iron formulations the exact
dosage required for the treatment of RLS has not
Numerous studies on the relationship between been determined..
RLS and iron in the body have provided better .
insight into the pathophysiology of this disorder
and have opened up new possibilities related to
therapeutic approaches, such as hepcidin
antagonists. Nevertheless, there are still many

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