Richard P. Allen

Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health.

BACKGROUND Restless legs syndrome is a common yet frequently undiagnosed sensorimotor disorder. In 1995, the International Restless Legs Syndrome Study Group developed standardized criteria for the diagnosis of restless legs syndrome. Since that time, additional scientific scrutiny and clinical experience have led to a better understanding of the condition. Modification of the criteria is now necessary to better reflect that increased body of knowledge, as well as to clarify slight confusion with the wording of the original criteria. SETTING The restless legs syndrome diagnostic criteria and epidemiology workshop at the National Institutes of Health. PARTICIPANTS Members of the International Restless Legs Syndrome Study Group and authorities on epidemiology and the design of questionnaires and scales. OBJECTIVE To modify the current criteria for the diagnosis of restless legs syndrome, to develop new criteria for the diagnosis of restless legs syndrome in the cognitively impaired elderly and in children, to create standardized criteria for the identification of augmentation, and to establish consistent questions for use in epidemiology studies. RESULTS The essential diagnostic criteria for restless legs syndrome were developed and approved by workshop participants and the executive committee of the International Restless Legs Syndrome Study Group. Criteria were also developed and approved for the additional aforementioned groups.

Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome

Article abstract CSF and serum were obtained from 16 patients with idiopathic restless legs syndrome (RLS) and 8 age-matched healthy control subjects. Patients with RLS had lower CSF ferritin levels (1.11 ± 0.25 ng/mL versus 3.50 ± 0.55 ng/mL; p = 0.0002) and higher CSF transferrin levels (26.4 ± 5.1 mg/L versus 6.71 ± 1.6 mg/L; p = 0.018) compared with control subjects. There was no difference in serum ferritin and transferrin levels between groups. The presence of reduced ferritin and elevated transferrin levels in CSF is indicative of low brain iron in patients with idiopathic RLS.

MRI measurement of brain iron in patients with restless legs syndrome

Brain iron insufficiency in the restless legs syndrome (RLS) has been suggested by a prior CSF study. Using a special MRI measurement (R2′), the authors assessed regional brain iron concentrations in 10 subjects (five with RLS, five controls). R2′ was significantly decreased in the substantia nigra, and somewhat less significantly in the putamen, both in proportion to RLS severity. The results show the potential utility of this MRI measurement, and also indicate that brain iron insufficiency may occur in patients with RLS in some brain regions.

Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome

Objective: To assess neuropathology in individuals with restless legs syndrome (RLS). Methods: A standard neuropathologic evaluation was performed on seven brains from individuals who had been diagnosed with RLS. The substantia nigra was examined in greater detail for iron staining and with immunohistochemistry for tyrosine hydroxylase and proteins involved in iron management. Five age-matched individuals with no neurologic history served as controls. Results: There were no histopathologic abnormalities unique to the RLS brains. Tyrosine hydroxylase staining in the major dopaminergic regions appeared normal in the RLS brains. Iron staining and H-ferritin staining was markedly decreased in the RLS substantia nigra. Although H-ferritin was minimally detected in the RLS brain, L-ferritin staining was strong. However, the cells staining for L-ferritin in RLS brains were morphologically distinct from those in the control brains. Transferrin receptor staining on neuromelanin-containing cells was decreased in the RLS brains compared to normal, whereas transferrin staining in these cells was increased. Conclusions: RLS may not be rooted in pathologies associated with traditional neurodegenerative processes but may be a functional disorder resulting from impaired iron acquisition by the neuromelanin cells in RLS. The underlying mechanism may be a defect in regulation of the transferrin receptors.

Restless legs syndrome: a review of clinical and pathophysiologic features.

Summary Restlesslegs syndrome (RLS), although long ignored and still much underdiagnosed,disrupts the life and sleep considerably of those who have it. Recent clinicaland basic research provides for better definition and pathophysiologicunderstanding of the disorder. The body of knowledge about this disorder hasbeen expanding rapidly during the past decade and it has altered our conceptsof this disorder. This review of RLS covers history, diagnosis, morbidity ofsleep disturbance, relation to periodic limb movements in both sleep andwaking, secondary causes, severity assessment methods, phenotypes for possiblegenetic patterns, epidemiology, pathophysiology, and medical treatmentconsiderations. The emphasis on pathophysiology includes consideration ofcentral nervous system localization, neurotransmitter and other systemsinvolved, and the role of iron metabolism. Studies to date support theauthors’ recently advanced iron–dopamine model ofRLS.

Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: Updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria - history, rationale, description, and significance

BACKGROUND In 2003, following a workshop at the National Institutes of Health, the International Restless Legs Syndrome Study Group (IRLSSG) developed updated diagnostic criteria for restless legs syndrome/Willis-Ekbom disease (RLS/WED). These criteria were integral to major advances in research, notably in epidemiology, biology, and treatment of RLS/WED. However, extensive review of accumulating literature based on the 2003 NIH/IRLSSG criteria led to efforts to improve the diagnostic criteria further. METHODS The clinical standards workshop, sponsored by the WED Foundation and IRLSSG in 2008, started a four-year process for updating the diagnostic criteria. That process included a rigorous review of research advances and input from clinical experts across multiple disciplines. After broad consensus was attained, the criteria were formally approved by the IRLSSG executive committee and membership. RESULTS Major changes are: (i) addition of a fifth essential criterion, differential diagnosis, to improve specificity by requiring that RLS/WED symptoms not be confused with similar symptoms from other conditions; (ii) addition of a specifier to delineate clinically significant RLS/WED; (iii) addition of course specifiers to classify RLS/WED as chronic-persistent or intermittent; and (iv) merging of the pediatric with the adult diagnostic criteria. Also discussed are supportive features and clinical aspects that are important in the diagnostic evaluation. CONCLUSIONS The IRLSSG consensus criteria for RLS/WED represent an international, interdisciplinary, and collaborative effort intended to improve clinical practice and promote further research.

An Algorithm for the Management of Restless Legs Syndrome

Restless legs syndrome (RLS) is a common disorder with a prevalence of 5% to 15%. Primary care physicians must become familiar with management of this disorder. This algorithm for the management of RLS was written by members of the Medical Advisory Board of the Restless Legs Syndrome Foundation and is based on scientific evidence and expert opinion. Restless legs syndrome is divided into intermittent, daily, and refractory types. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and addressing the possibility of iron deficiency, are discussed. The role of carbidopa/levodopa, dopamine agonists, opioids, benzodiazepines, and anticonvulsants for the different types of the disorder is delineated.

Restless legs syndrome: prevalence and impact in children and adolescents--the Peds REST study.

OBJECTIVES. Restless legs syndrome, a common neurologic sleep disorder, occurs in 5% to 10% of adults in the United States and Western Europe. Although ∼25% of adults with restless legs syndrome report onset of symptoms between the ages of 10 and 20 years, there is very little literature looking directly at the prevalence in children and adolescents. In this first population-based study to use specific pediatric diagnostic criteria, we examined the prevalence and impact of restless legs syndrome in 2 age groups: 8 to 11 and 12 to 17 years. METHODS. Initially blinded to survey topic, families were recruited from a large, volunteer research panel in the United Kingdom and United States. Administration was via the Internet, and results were stratified by age and gender. National Institutes of Health pediatric restless legs syndrome diagnostic criteria (2003) were used, and questions were specifically constructed to exclude positional discomfort, leg cramps, arthralgias, and sore muscles being counted as restless legs syndrome. RESULTS. Data were collected from 10523 families. Criteria for definite restless legs syndrome were met by 1.9% of 8- to 11-year-olds and 2.0% of 12- to 17-year-olds. Moderately or severely distressing restless legs syndrome symptoms were reported to occur ≥2 times per week in 0.5% and 1.0% of children, respectively. Convincing descriptions of restless legs syndrome symptoms were provided. No significant gender differences were found. At least 1 biological parent reported having restless legs syndrome symptoms in >70% of the families, with both parents affected in 16% of the families. Sleep disturbance was significantly more common in children and adolescents with restless legs syndrome than in controls (69.4% vs 39.6%), as was a history of “growing pains” (80.6% vs 63.2%). Various consequences were attributed to restless legs syndrome, including 49.5% endorsing a “negative effect on mood.” Data were also collected on comorbid conditions and restless legs diagnosis rates. CONCLUSIONS. These population-based data suggest that restless legs syndrome is prevalent and troublesome in children and adolescents, occurring more commonly than epilepsy or diabetes.

The role of iron in restless legs syndrome.

The impressive relief from restless legs syndrome (RLS) symptoms provided by levodopa treatment indicates RLS is caused by a dopaminergic abnormality. But similar and more lasting relief also occurs for iron treatment in some patients. Thus there are two major putative causes for RLS: CNS dopaminergic abnormality and CNS iron insufficiency. This article presents the data documenting that both peripheral and CNS iron insufficiency occur with RLS symptoms. Brain iron insufficiency is supported by independently replicated cerebrospinal fluid and brain imaging studies for patients without iron deficiency (ID) anemia. Autopsy studies and intravenous iron treatment further link brain iron insufficiency to RLS. The brain iron insufficiency in patients with RLS is now well established. In this article the data are reviewed that support the following postulates combining dopaminergic and iron causes of RLS: (1) All conditions that compromise iron availability will increase the risk of RLS leading to a higher than expected prevalence of RLS in these conditions. (2) Some patients with RLS have marginal CNS iron status that can become insufficient when deprived of normal access to adequate peripheral iron or may be insufficient even with normal access to adequate peripheral iron. (3) The change or reduced CNS iron status produces RLS symptoms largely through its effects on the dopaminergic system and the corollary to 3. (4) Dopaminergic system abnormalities producing RLS symptoms will be included in those produced by brain ID. Study of the iron model of RLS offers hope for developing new treatment approaches and perhaps methods to prevent or cure the disorder.

Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome.

Restless leg syndrome (RLS) is a sensorimotor disorder. Clinical studies have implicated the dopaminergic system in RLS, while others have suggested that it is associated with insufficient levels of brain iron. To date, alterations in brain iron status have been demonstrated but, despite suggestions from the clinical literature, there have been no consistent findings documenting a dopaminergic abnormality in RLS brain tissue. In this study, the substantia nigra and putamen were obtained at autopsy from individuals with primary RLS and a neurologically normal control group. A quantitative profile of the dopaminergic system was obtained. Additional assays were performed on a catecholaminergic cell line and animal models of iron deficiency. RLS tissue, compared with controls, showed a significant decrease in D2R in the putamen that correlated with severity of the RLS. RLS also showed significant increases in tyrosine hydroxylase (TH) in the substantia nigra, compared with the controls, but not in the putamen. Both TH and phosphorylated (active) TH were significantly increased in both the substantia nigra and putamen. There were no significant differences in either the putamen or nigra for dopamine receptor 1, dopamine transporters or for VMAT. Significant increases in TH and phosphorylated TH were also seen in both the animal and cell models of iron insufficiency similar to that from the RLS autopsy data. For the first time, a clear indication of dopamine pathology in RLS is revealed in this autopsy study. The results suggest cellular regulation of dopamine production that closely matches the data from cellular and animal iron insufficiency models. The results are consistent with the hypothesis that a primary iron insufficiency produces a dopaminergic abnormality characterized as an overly activated dopaminergic system as part of the RLS pathology.