Restless legs syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Overview
Pathophysiology
Pathogenesis
- Generally most scientists consider restless legs syndrome(RLS) as a central nervous system (CNS)-related disorder, but no specific lesion has been found to be associated with the syndrome.
- It is thought that RLS is the result of central nervous system anatomic lesions.
- Findings in imaging of CNS witch suggest the relation between the anatomic lesions in CNS and RLS include:
- Presence of morphologic changes in the somatosensory cortex, motor cortex and thalamic gray matter in MRI
- Abnormal bilateral cerebellar and thalamic activation during the manifestation of sensory symptoms, with additional red nucleus and reticular formation activity during periodic leg movements (PLMS), in functional MRI study.
- Evidences of the role of the limbic and opioid systems in SPECT and PET studies
- Low brain iron concentrations and dysfunction of iron metabolism and intracellular iron
- The "iron-dopamine model" explains that iron deficiency in the brain causes an abnormality in the dopaminergic system leading to manifestation of RLS.
- RLS symptoms seem to depend on abnormal spinal sensorimotor integration at the spinal cord level and abnormal central somatosensory processing
- In animal models, studies suggest that the All dopaminergic system and the D3 receptor participates in RLS symptoms
Genetics
- Genes involved in the pathogenesis of RLS include: RLS 1: 12q and RLS 2: 14q and RLS 3: 9p and RLS 4: 2q and RLS 5: 20p.
- 40% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.
Associated Conditions
Restless Legs Syndrome and Acidosis
Another possible explanation of RLS is acidosis, though this claim needs to be explored further. RLS as a result of acidosis/insufficient oxygen being circulated to the legs (which reduces acid build up) would explain why symptoms worsen when the legs are at rest, and why moving them (increasing circulation) offers some relief. The fact that iron offers relief for many can be explained by its vital role in hemoglobin, which is responsible for oxygen dispersion to the tissues. The legs would be more prone to the restless condition since they are furthest from the heart and lungs. Additionally, one may see below that many of the "lifestyle changes and other non-medicinal approaches" are related in some way or form to circulation (e.g. heat, stretching, movement), acid build up (e.g. too much exercise, ketosis from high-fat diets), or the amount of oxygen being dispersed in the blood (e.g. deep breathing, iron levels). It should be noted that this potential causal relationship between RLS and acidosis is purely speculative the time being, as far as the contributing editor is aware. If this causal relationship holds true, then finding the cause of the acidosis would most likely lead to the best treatment.
Some experts believe RLS and periodic limb movement disorder are strongly associated with ADHD in some children. Both conditions are hereditary and dopamine is believed to be involved. Many types of medication for both conditions are affecting the dopamine levels in the brain.[1]
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- The exact neuroanatomical substrate imbalance which causes restless legs syndrome (RLS) is unknown.
- Chronic ischemic changes were found in some brain tissue samples of patients whit RLS