Iron and restless legs syndrome: treatment, genetics and pathophysiology

Connor, James R.; Patton, Stephanie M.; Oexle, Konrad; Allen, Richard P.

doi:10.1016/j.sleep.2016.07.028

Cited by 103 publications

(63 citation statements)

References 121 publications

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“…It may be hypothesized that the primary change is the reduction of brain iron content, likely due to decreased acquisition of iron by cells in the brain [132], which leads to a dysfunction of mesolimbic and nigrostriatal dopaminergic pathways, and in turn to a dysregulation of limbic network and sensorimotor networks resulting in the signs and symptoms of RLS (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

Brain imaging and networks in restless legs syndrome

Rizzo

Galantucci

et al. 2017

Sleep Medicine

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Several studies provide information useful to our understanding of restless legs syndrome (RLS), using various imaging techniques to investigate different aspects putatively involved in the pathophysiology of RLS, although there are discrepancies between these findings. The majority of magnetic resonance imaging (MRI) studies using iron-sensitive sequences supports the presence of a diffuse, but regionally variable low brain-iron content, mainly at the level of the substantia nigra, but there is increasing evidence of reduced iron levels in the thalamus. Positron emission tomography (PET) and single positron emission computed tomography (SPECT) findings mainly support dysfunction of dopaminergic pathways involving not only the nigrostriatal but also mesolimbic pathways. None or variable brain structural or microstructural abnormalities have been reported in RLS patients; reports are slightly more consistent concerning levels of white matter. Most of the reported changes were in regions belonging to sensorimotor and limbic/nociceptive networks. Functional MRI studies have demonstrated activation or connectivity changes in the same networks. The thalamus, which includes different sensorimotor and limbic/nociceptive networks, appears to have lower iron content, metabolic abnormalities, dopaminergic dysfunction, and changes in activation and functional connectivity. Summarizing these findings, the primary change could be the reduction of brain iron content, which leads to dysfunction of mesolimbic and nigrostriatal dopaminergic pathways, and in turn to a dysregulation of limbic and sensorimotor networks. Future studies in RLS should evaluate the actual causal relationship among these findings, better investigate the role of neurotransmitters other than dopamine, focus on brain networks by connectivity analysis, and test the reversibility of the different imaging findings following therapy.

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Section: Resultsmentioning

confidence: 99%

Brain imaging and networks in restless legs syndrome

Rizzo

Galantucci

et al. 2017

Sleep Medicine

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“…However, these studies have several limitations, as they did not provide mechanistic insights into the possible underlying mechanisms. A causative relationship between iron deficiency and RLS has not been established so far . Nevertheless, a systemic analysis of iron homeostasis in RLS patients has not been performed up to now.…”

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confidence: 99%

“…A causative relationship between iron deficiency and RLS has not been established so far. 9,10 Nevertheless, a systemic analysis of iron homeostasis in RLS patients has not been performed up to now.…”

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confidence: 99%

Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome

et al. 2018

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Background Restless legs syndrome is a sensorimotor neurological disorder of the limbs that impairs quality of life and disturbs sleep. However, there has been progress in understanding the disease involving the dopaminergic system as well as iron metabolism. The exact pathophysiological mechanisms of restless legs syndrome remain elusive. We tried to elucidate the underlying mechanisms in iron metabolism in restless legs syndrome subjects on a systemic, cellular, and mitochondrial level. Methods We conducted a study prospectively recruiting 168 restless legs syndrome patients and 119 age‐matched healthy controls focusing on iron metabolism using human monocytes as surrogates. Results Evaluation of systemic iron metabolism parameters in the circulation showed no significant difference between patients and controls. We observed a significant reduction in mRNA levels of heme oxygenase 1 and mitochondrial iron genes like mitoferrin 1 and 2 in monocytes isolated from restless legs syndrome patients, indicating mitochondrial iron deficiency. Interestingly, we also observed reduced expression of iron regulatory protein 2 along with impaired activity of mitochondrial aconitase and reduced mitochondrial superoxide formation in restless legs syndrome subjects. Along this line, patients had reduced mitochondrial respiratory capacity that improved in restless legs syndrome subjects under treatment with dopaminergic drugs compared with untreated patients. Conclusions Our data suggest that restless legs syndrome is linked to mitochondrial iron deficiency and associated impairment of mitochondrial function. This is partly corrected by treatment with dopaminergic drugs compared with untreated patients, which may be linked to an effect of dopamine on cellular iron homeostasis. © 2018 International Parkinson and Movement Disorder Society

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“…In RLS patients, iron storage and release from endothelial cells of blood-brain bar-rier are altered. 8 After iron-regulatory protein expressions are up-or down-regulated in response to systemic iron depletion, iron levels in brain tissue are decreased. Thus from iron depletion to symptom development, it may take several days or weeks.…”

Section: Discussionmentioning

confidence: 99%

Symptom Aggravation in Restless Legs Syndrome during Menstrual Cycle

2019

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Objectives:The purpose of this study is to confirm restless legs syndrome (RLS) symptom aggravation during menstrual period and verify factors related to symptom aggravation. Methods: A total of 20 premenopausal female RLS patients were classified into two groups according to symptom aggravation during menstrual period (menstrual RLS group and non-menstrual RLS group). They answered a questionnaire including duration and quantity of menstruation, other medical conditions, and premenstrual syndrome symptoms. Laboratory tests including iron panel and hemoglobin levels were done. Results: Six out of 20 patients (30%) complained of symptom aggravation during menstrual period. RLS symptoms were aggravated by 40±33.47% compared to non-menstrual period in menstrual RLS group. One patient was taking additional medication for aggravated symptoms. Menstrual duration, quantity of menstrual bleeding showed no difference between menstrual RLS and non-menstrual RLS groups. On laboratory tests, two patients from non-menstrual RLS group were diagnosed with iron deficiency anemia. Serum iron levels, total iron binding capacity, serum iron saturation, and serum ferritin levels did not show difference between the two groups, while hemoglobin levels were significantly lower (13.8 vs. 12.4 g/dL) in non-menstrual RLS group (p=0.044). Conclusions: RLS symptoms aggravate during menstrual period in 30% of premenopausal RLS patients. Low ferritin levels were not related to menstrual RLS symptom aggravation. Further study is required to verify other factors such as hormonal fluctuations. J Sleep Med 2019;16(2):109-112

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Iron and restless legs syndrome: treatment, genetics and pathophysiology

Cited by 103 publications

References 121 publications

Brain imaging and networks in restless legs syndrome

Brain imaging and networks in restless legs syndrome

Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome

Symptom Aggravation in Restless Legs Syndrome during Menstrual Cycle

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