Restless Legs Syndrome
Pathophysiology
Although the underlying cause of RLS has not been determined with certainty, considerable progress has been made in understanding of the common disorder.
Genetics
The increase of RLS among first-degree relatives, as compared with the prevalence among the general population, led researchers to investigate the genetic basis of RLS. Five positive linkage regions for RLS have been reported and formally classified as loci RLS1 to RLS5 in a few families, with additional linkage regions continuing to be identified. However, no "causative" gene has been identified, the findings have not been widely replicated, and the difficulty in ascertaining affected status leaves the significance of these results in question. Nonetheless, the RLS1 linkage locus on chromosome 12, identified in a large number of families from multiple populations, remains an area of interest.
Steffanson et al. have completed genome-wide association studies in patients with RLS and control subjects in Iceland and the US. A SNP in the BTBD9 gene on chromosome 6 was associated with an increased risk of RLS with periodic limb movements of sleep (PLMS) of 70% to 80% for those individuals who carried one copy, compared to those without the gene variant. Winkelmann et al. have identified additional associations to the Meis1 gene on chromosome 2p14 and the MAP2K5/LBXCOR1 genes on chromosome 15q23 in German and French-Canadian patients with RLS. Combined, the three genetic variants account for 70% of the population-attributable risk for RLS with PLMS in individuals of European ancestry.
Combined, the three genetic variants account for 70% of the population-attributable risk for RLS with PLMS in individuals of European ancestry. Although it remains unclear how and why BTBD9 risk variants translate into symptoms in only a subgroup of individuals, the variants are likely to give way to a plausible biologic substrate, given the dose-dependent relationship between the variants and PLMS, decrements in total body iron stores, and ethnic differences in RLS prevalence.
Dopaminergic System
Multiple etiologies likely impact the dopamine system in RLS. The primary evidence for this comes from clinical experience over the past 20 years. Most RLS symptoms respond to treatment with dopaminergic agents, and, conversely, the use of dopamine receptor antagonists exacerbates the symptoms RLS. However, a clear understanding of any defect in the metabolism or signaling in the dopamine system remains elusive. Postmortem and imaging studies have not provided clear evidence of dysfunction in the dopamine system. The results of SPECT and PET studies are inconclusive or conflict with one another. Ultrasound studies of the substantia nigra identified hypoechogenicity; however, the results of this study do not clearly implicate the dopamine system in the etiology of RLS. Furthermore, a genetic association study that compared single nucleotide polymorphisms (SNPs) within eight genes involved in dopamine signaling found no differences between patients with RLS and controls subjects.
The equivocal nature of these results may reflect the fact that the studies were not performed during the night, when RLS symptoms are typically most severe, or that the studies focused on the nigrostriatal system when, instead, the pathology may arise in the diencephalospinal A11 pathway.
Iron
Studies of cerebrospinal fluid, magnetic resonance imaging of the brain, and postmortem tissue have demonstrated the role of iron deficiency in the brain in the pathogenesis of some cases of RLS; however, not all patients with RLS are iron deficient and not all patients who are iron deficient exhibit symptoms of RLS. In general, an inverse relationship has been shown between symptom severity (and augmentation) and serum ferritin levels.
Further support for the iron-RLS connection comes from the efficacy of therapeutic trials of intravenously administered iron and erythropoietin and orally administered iron in patients with evidence of low ferritin levels. Finally, studies of children have shown that measures of iron stores correlate significantly with the PLMS index, symptoms of RLS, or both.
Neurophysiologic Testing
Although traditional studies of electromyography and nerve conduction velocity and evoked potentials are typically normal in patients with RLS, research evidence from studies seeking to identify the generator of the periodic movements and sensations of RLS have been mixed. Pain thresholds, H-reflex testing, and quantitative sensory testing have been shown to be abnormal in patients with RLS.
