Table 2. Association of iron deficiency and restless legs syndrome.

CSF, cerebrospinal fluid; RLS, restless legs syndrome; IRLSSG, International Restless Legs Syndrome Study Group; PSG, polysomnography; FCM, ferric carboxymaltose; TSAT, transferrin saturation; ICSD-3, International Classification of Sleep Disorders, 3rd edn.; PLMD, periodic limb movement disorder; IV, intravenous; LMWID, low-molecular-weight iron dextran; HMWID, high-molecular-weight iron dextran; IDA, iron deficiency anemia

Study	Sample size	Type of study	Population characteristics	Iron markers assessed	RLS severity measure	Main outcome	Iron supplementation	P- value
O'Keeffe et al. [9]	18	Case-control	Elderly patients with RLS	Serum ferritin, serum iron, vitamin B12, folate, and hemoglobin	IRLSSG Rating Scale [50]	Lower ferritin levels were associated with more severe RLS symptoms. ID, with or without anemia, significantly affects RLS development among elderly patients.	Oral iron (ferrous sulfate)	<0.05
Sun et al. [10]	27	Retrospective observational with blinded procedures	Adult patients (aged 29-81 years) with RLS	Serum ferritin	Clinical ratings and  PSG measures	Lower ferritin levels correlated with greater RLS severity and reduced sleep efficiency	Not studied	N/A
Earley et al. [11]	24	Observational	16 RLS patients, 8 healthy individuals	CSF ferritin and transferrin, serum iron, ferritin, and transferrin	Clinical ratings and  PSG measures	RLS patients had significantly lower CSF ferritin and higher CSF transferrin levels compared to controls, while no significant differences were observed in serum markers.	Not studied	<0.001
Trenkwalder et al. [27]	110	Randomized clinical trial	Patients with RLS nonanemic but iron-deficient	Serum ferritin, TSAT	IRLSSG Rating Scale [50]	FCM treatment significantly increased serum ferritin and TSAT levels compared to placebo. No correlation was found between baseline serum ferritin levels or changes in iron parameters and improvements in RLS symptoms.	IV FCM	<0.001
Cielo et al. [42]	167	Observational	Children aged 5-12 years with a history of prematurity	Serum ferritin	ICSD-3 and PSG measures [51]	Higher prevalence of RLS in preterm children	Not studied	<0.001
Allen et al. [12]	31	Systematic review/guideline formulation	Adults and children with RLS or PLMD	Serum ferritin, TSAT	IRLSSG Rating Scale [50]	Oral iron is the first-line treatment. IV iron should be considered when serum ferritin levels are too high for effective oral absorption or when oral iron is not tolerated or contraindicated.	Oral options include ferrous sulfate combined with vitamin C, while IV options include FCM, iron sucrose, low molecular weight iron dextran (LMWID), iron gluconate, high molecular weight iron dextran (HMWID), ferumoxytol, and iron isomaltoside.	N/A
Rosen et al.  [49]	47	Cohort	Pediatric patients aged 5-18 years with RLS	Serum ferritin	Pediatric IRLSSG Rating Scale [52]	A modest, yet nonsignificant, improvement was observed in children with RLS symptoms, despite a significant increase in ferritin levels.	Oral iron (ferrous sulfate + vitamin C)	>0.05
Macher et al. (2020) [48]	176	Randomized clinical trial	Iron-deficient blood donors	Ferritin, TSAT, hemoglobin	IRLSSG Rating Scale [50]	A significant improvement in RLS symptoms between baseline and after IV or oral iron was seen. IV iron is more effective than oral.	IV (FCM) vs. oral iron (iron fumarate)	<0.001
Bae et al. [46]	124	Observational cohort study with a case-control comparison	Adults with IDA and RLS	Ferritin, TSAT, hemoglobin, iron, total iron binding capacity	IRLSSG Rating Scale [50]	There is a high prevalence of RLS among patients with IDA, with the majority displaying severe to very severe symptoms.	Not studied	<0.001