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Celiac disease as possible cause for low serum ferritin in patients with restless legs syndrome
Abstract
To describe celiac disease (CD) as a possible cause for low serum ferritin in patients with restless legs syndrome (RLS).
Low iron stores have been found to be a risk factor for RLS with serum ferritin levels less than 45-50 ng/mL associated with increased severity of RLS. It has become routine clinical practice to test serum ferritin in the initial assessment of RLS. CD is a common genetic disorder that can cause iron deficiency.
Consecutive case series of four patients with RLS and serum ferritin below 25 ng/mL, who had positive screening tests for celiac disease.
We report four patients who had serum ferritin < 12 ng/mL and positive screening tests for CD. All had CD confirmed by duodenal biopsy and response to a gluten-free diet. RLS symptoms improved in all four, with two able to discontinue RLS medication and two responding without medication.
In patients with RLS and low serum ferritin who do not have an obvious cause for iron deficiency, we suggest looking for CD by simple, inexpensive serologic testing. Diagnosis and treatment of CD is likely to improve the outcome for RLS, as well as identify individuals who are at risk for the significant long-term complications of CD.
... Whether there is a link between RLS and CD or GS remains controversial. The first report suggesting an association between CD and RLS was by Manchanda et al. who presented a consecutive case series of four patients with RLS, low serum ferritin, and biopsy proven CD [33], which was considered to be the underlying cause for low serum ferritin. Subsequently, in two studies RLS was found to be more frequent in patients with CD than in controls [34,35]. ...
... All of the patients had biopsy proven CD. The information about response to GFS is limited; three out of four CD patients with RLS improved on GFD and iron supplementation, whereas one patient improved after being on a GFD without receiving iron supplementation and still having low ferritin levels [33]. Weinstock and colleagues reported that 50% of the CD patients found relief in their RLS symptoms being on GFD, and similarly not all were receiving iron supplementation [34], suggesting that GFD can independently improve the RLS symptoms in people with RLS and CD or GS. ...
Gluten related disorders (GRD) represent a wide spectrum of clinical manifestations that are triggered by the ingestion of gluten. Coeliac disease (CD) or gluten sensitive enteropathy is the most widely recognised, but extra-intestinal manifestations have also been increasingly identified and reported. Such manifestations may exist in the absence of enteropathy. Gluten sensitivity (GS) is another term that has been used to include all GRD, including those where there is serological positivity for GS related antibodies in the absence of an enteropathy. Gluten ataxia (GA) is the commonest extraintestinal neurological manifestation and it has been the subject of many publications. Other movement disorders (MDs) have also been reported in the context of GS. The aim of this review was to assess the current available medical literature concerning MDs and GS with and without enteropathy. A systematic search was performed while using PubMed database. A total of 48 articles met the inclusion criteria and were included in the present review. This review highlights that the phenomenology of gluten related MDs is broader than GA and demonstrates that gluten-free diet (GFD) is beneficial in a great percentage of such cases.
... In recent years, the literature has reported an association between RLS and CD, suggesting that it may be an additional extraintestinal manifestation of CD. [9][10][11]39 The underlying pathogenesis is thought possibly related to iron deficiency secondary to CD or another immune-mediated mechanism. Studies have found the prevalence of RLS to range from 25% to 31% in patients with CD ...
... Journal of compared with 3% to 10% in the general population. 1,[9][10][11]39 Our study was not designed to assess the association between RLS and CD, but one of the seven screening questions for PN inquired specifically of the symptom of restless legs. We found that 19.5% of the CD group, 16.8% of the IBD group, and 13% of the normal control group reported symptom of restless legs, the difference being statistically significant only between the CD and healthy control groups. ...
Objectives: An association between celiac disease (CD) and peripheral neuropathy (PN) has been reported. Methods: Patients with CD and/or inflammatory bowel disease (IBD) were recruited from the gastroenter-ology clinics at a medical center and local support groups. Control subjects without CD or IBD were recruited from the staff of the medical center as well as relatives and attendees at support groups. Each participant completed a survey that used two validated PN instruments to define and characterize PN. Results: In the CD group, 38.9% met criteria for PN compared with 38.7% in the IBD group (P = 0.97) and 20.5% in the control group (P < 0.001). On multiple logistic regression, the odds of PN after adjusting for age, gender, diabetes, vitamin B12 deficiency, and cancer history were increased for CD (odds ratio, 2.51; 95% confidence interval, 1.82–3.47) and IBD (odds ratio, 2.78; 95% confidence interval, 1.85–4.18). Conclusions: PN is more often found in patients with CD and/or IBD than in the general population.
... The correlation between RLS and celiac disease or gluten sensitivity is still unclear [100][101][102]. Most of the reported cases were treated with iron supplementation, with benefit, while some responded to GFD alone [100][101][102][103][104]. ...
Purpose of review
To summarize the state of the art of therapeutic approaches for movement disorders occurring in the context of systemic disorders. These secondary movement disorders, e.g., parkinsonism, tremor, chorea, dystonia, ballism, ataxia, and dyskinesia, among others, can be transitory manifestations of systemic diseases or part of syndromes that combine systemic and neurological symptoms (e.g., Wilson’s disease). These conditions are frequently treatable and in certain cases also curable. Therefore, their recognition and treatment impact the outcomes of these patients.
Recent findings
Most current knowledge on this topic is based on cohort studies and single case reports. There are a few large studies mostly in the context of movement disorders in cerebrovascular disease and Wilson’s disease.
Summary
The management of movement disorders due to systemic disease is mostly achieved by treatment of the systemic conditions together with appropriate medical and surgical treatments for each manifestation. Specific considerations must be taken into account when managing the medications commonly used for movement disorders in the context of systemic disease compared to primary degenerative processes.
... The most common movement disorder noted was restless leg syndrome, possibly as consequence of iron deficiency, a finding that is commonly implicated in CeD [87]. Studies suggest that restless leg syndrome symptoms typically improve with a GFD, with and without iron supplementation [88,89]. ...
... Celiac disease is another GIS disease that shows an association with RLS/WED. Iron deficiency anemia and excessive bacterial reproduction are thought to be responsible for RLS/WED development in celiac patients 11,25,26 . When the gastric biopsy specimens from the participants in the present study were evaluated in terms of celiac disease, two patients with RLS/WED had histopathologically compatible findings, and none was detected in the control group. ...
Background:
The effect of gastrointestinal system disorders on Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) has been previously demonstrated by using serological tests. However, this association has not been supported by histopathological studies so far.
Objective:
To investigate the relationship between RLS/WED, upper endoscopic imaging and histopathological results in patients diagnosed with RLS who underwent endoscopy because of gastrointestinal system (GIS) complaints.
Methods:
Case-control study, including 100 patients diagnosed with RLS who presented dyspeptic complaints and underwent upper GIS endoscopy and 106 age- and sex-matched controls. RLS diagnosis was evaluated according to the four main diagnostic criteria determined by the International RLS Study Group. All patients underwent upper GIS endoscopic intervention and at least one gastric and/or antral biopsy.
Results:
There was no significant difference between patients and controls in relation to endoscopically seen gastric ulcer, duodenal ulcer, gastroesophageal reflux disease (GERD) findings and Helicobacter pylori (HP) positivity (p>0.05). Intestinal metaplasia and mucosal atrophy were more common in RLS/WED patients compared to controls (p=0.026 and p=0.017, respectively). Additionally, ferritin levels were found to be lower than the reference value.
Conclusions:
The detection of increased severity of intestinal metaplasia, mucosal atrophy, and gastric inflammation in RLS/WED patients with dyspeptic complaints may entail the close gastrointestinal system evaluation of these patients. However, larger randomized and controlled trials are required on this subject where patients are evaluated by upper GIS endoscopic biopsy.
... However, the data about the association of iron stores with RLS in celiac patients is limited. Manchanda et al. 26 suggested the investigation for CD by simple serologic tests in patients with RLS and low serum ferritin levels without an obvious cause for iron deficiency. Although, there was not a significant difference regarding serum ferritin levels between CD patients and control cases, we determined significantly lower ferritin levels in celiac patients with RLS compared with the celiac patients without RLS, supporting this data. ...
Işıkay S, Işıkay N, Per H, Çarman KB, Kocamaz H. Restless leg syndrome in children with celiac disease. Turk J Pediatr 2018; 60: 70-75. Celiac disease (CD) is an immune-mediated enteropathy triggered by ingestion of dietary gluten in genetically predisposed individuals. The aim of the study was to determine the prevalence of restless leg syndrome (RLS) in children with CD and to investigate the associated factors for RLS. Totally 494 children with the ages ranging between 11-18 years were included. Among those, 226 were under follow-up with CD and constituted the study group while other 268 children did not have any symptoms or signs associated with CD and established the control group. The demographic data, educational status and routine laboratory data of children including complete blood count, ferritin, vitamin B12, foliate and 25 (OH) vitamin D levels were recorded. The RLS prevalence and associated symptoms of children were defined with a questionnaire. There was no statistically significant difference between the 2 groups regarding the age and gender. Moreover, RLS prevalence was also similar in both groups (3.5% vs 3.0% in CD and control groups, respectively, p=0.98). However, interestingly, in CD group, the mean age of the patients at the onset of RLS symptoms was statistically significantly younger (p=0.02) and the disease was more severe (p=0.026) than the control group. In correlation analysis in CD group, the RLS severity significantly negatively correlated with serum ferritin, folic acid or 25 (OH) vitamin D levels in Celiac disease group. In this study we did not determine an increased prevalence of RLS in children with CD. However, in CD group, the age at the onset of RLS symptoms was significantly younger and the disease was more severe in CD group compared with the control cases.
... Incidence of restless legs is higher in CD patients [86,87] and has traditionally been assigned to iron deficiency [88]. However, 60% of the restless legs cases in CD patients show no iron deficiency [86]. ...
We propose a biochemical mechanism for celiac disease and non-celiac gluten sensitivity that may rationalize many of the extradigestive disorders not explained by the current immunogenetic model. Our hypothesis is based on the homology between the 33-mer gliadin peptide and a component of the NMDA glutamate receptor ion channel - the human GRINA protein - using BLASTP software. Based on this homology the 33-mer may act as a natural antagonist interfering with the normal interactions of GRINA and its partners. The theory is supported by numerous independent data from the literature, and provides a mechanistic link with otherwise unrelated disorders, such as cleft lip and palate, thyroid dysfunction, restless legs syndrome, depression, ataxia, hearing loss, fibromyalgia, dermatitis herpetiformis, schizophrenia, toxoplasmosis, anemia, osteopenia, Fabry disease, Barret's adenocarcinoma, neuroblastoma, urinary incontinence, recurrent miscarriage, cardiac anomalies, reduced risk of breast cancer, stiff person syndrome, etc. The hypothesis also anticipates better animal models, and has the potential to open new avenues of research.
... Compromised iron absorption from the duodenum has also been postulated to favor RLS. The prevalence of RLS in individuals with gastrointestinal disorders, such as celiac disease [22][23][24] and Crohn's disease, 25 is higher than in the general population: 31% versus 4% of 100 Italian patients with celiac disease and 100 age-and sex-matched controls 23 and 35% versus 10% of 85 U.S. celiac disease subjects and their spouses 24 reported RLS symptoms. Decreased hemoglobin levels (P = 0.003) 23 and serum iron deficiency (40% vs. 6%; P < 0.001) 24 were more prevalent in individuals suffering from celiac disease with RLS than in those without RLS. ...
A link between restless legs syndrome (RLS) and iron has been recognized for several decades. Yet, the precise role that iron or other components of iron metabolism play in bringing about RLS is still a matter of debate. During the last few years, many new pieces of evidence from genetics, pathology, imaging, and clinical studies have surfaced. However, the way this evidence fits into the larger picture of RLS as a disease is not always easily understood. To provide a better understanding of the complex interplay between iron metabolism and RLS and highlight areas that need further elucidation, we systematically and critically review the current literature on the role of iron in RLS pathophysiology and treatment with a special emphasis on genetics, neuropathology, cell and animal models, imaging studies, and therapy.
... El diagnóstico se completó en los cuatro SPI con serología y biopsia duodenal positivas para EC. La DSG produjo una significativa mejoría en todos los pacientes, tanto respecto a la clínica como a los análisis [66]. La prevalencia del SPI en una serie de 100 pacientes con EC fue del 31% frente al 4% del grupo control (p < 0,001) en un estudio prospectivo italiano de un centro de sueño en colaboración con una unidad clínica de gastroenterología. ...
REVISIÓN Introducción Gluten La harina de trigo constituye el principal ingredien-te del pan, la bollería y la pasta, alimentos que for-man parte creciente de nuestra dieta. El 60-70% de su contenido es almidón, un hidrato de carbono de alto valor energético, y el 15-20% gluten, un con-junto proteico que dota a esos productos de carac-terísticas aperitivas (miga esponjosa y corteza cru-jiente). Otros cereales de menor consumo, que también contienen gluten, son la cebada, el centeno y la ave-na. En cambio, el arroz, el maíz, el sorgo y el mijo están libres de gluten. El trigo tiene el genoma más complejo de todos los cereales. La planta ha evolucionado a lo largo del tiempo, desde la forma silvestre a la variedad panadera, con capacidad de adaptación a climato-logías diversas. Los modernos cultivos, basados en el abonado nitrogenado intensivo, mejoran el ren-dimiento de las cosechas y producen granos cada vez más ricos en gluten. El gluten del trigo está compuesto por gliadinas y gluteninas. Las gliadinas son prolaminas (com-puestos con abundancia de glutamina y prolina) que tienen propiedades inmunotóxicas, sobre todo la alfagliadina, un péptido de 33 aminoácidos que resiste la acción de las proteasas del intestino hu-mano. Las hordeínas de la cebada y las secalinas del centeno son otras prolaminas equivalentes a las gliadinas del trigo [1]. Intolerancia al gluten Es un proceso sistémico de naturaleza autoinmune, que afecta a sujetos sensibles por predisposición genética, al exponerse al gluten. Aparece a cual-quier edad y permanece a lo largo de toda la vida. Es más frecuente en mujeres, como ocurre con otras enfermedades autoinmunes [2]. La intolerancia o sensibilidad al gluten tiende a verse hoy como un conjunto de patologías autoin-munes que se extienden a diferentes sistemas. Aun-que la patología intestinal es la más representativa, la neurológica también es común e importante [3]. Es típico hablar de enfermedad celíaca (EC) como proceso cardinal, al que pueden asociarse otros sín-dromes autoinmunes, en su mayoría extraintestina-les. La mayor dificultad conceptual reside en seguir denominado EC a las manifestaciones sistémicas cuando la enteropatía que las acompaña es escasa o nula [4,5]. Neurogluten: patología neurológica por intolerancia al gluten
... In a small case series (N ¼ 4) with apparent idiopathic RLS, iron deficiency led to the diagnosis of celiac disease and successful treatment. 21 In contrast, peripheral iron deficiency was correlated with RLS in only half of the patients in a study with 85 RLS patients. 19 Neither a gluten free diet or iron metabolism correlated with RLS in a similarly sized, controlled study. ...
Theories for restless legs syndrome (RLS) pathogenesis include iron deficiency, dopamine dysregulation and peripheral neuropathy. Increased prevalence of small intestinal bacterial overgrowth (SIBO) in controlled studies in RLS and case reports of post-infectious RLS suggest potential roles for inflammation and immunological alterations. A literature search for all conditions associated with RLS was performed. These included secondary RLS disorders and factors that may exacerbate RLS. All of these conditions were reviewed with respect to potential pathogenesis including reports of iron deficiency, neuropathy, SIBO, inflammation and immune changes. A condition was defined as highly-associated if there was a prevalence study that utilized an appropriate control group. Small case reports were recorded but not included as definite RLS-associated conditions. Fifty four diseases, syndromes and conditions have been reported to cause and/or exacerbate RLS. Of these, 38 have been reported to have a higher prevalence than age-matched controls, 9 have adequate sized reports and have general acceptance as RLS-associated conditions and 7 have been reported in case report form. Overall, 42 of the 47 RLS-associated conditions (89%) have also been associated with inflammatory and/or immune changes. In addition, 43% have been associated with peripheral iron deficiency, 40% with peripheral neuropathy and 32% with SIBO. Most of the remaining conditions have yet to be studied for these factors. The fact that 95% of the 38 highly-associated RLS conditions are also associated with inflammatory/immune changes suggests the possibility that RLS may be mediated or affected through these mechanisms. Inflammation can be responsible for iron deficiency and hypothetically could cause central nervous system iron deficiency-induced RLS. Alternatively, an immune reaction to gastrointestinal bacteria or other antigens may hypothetically cause RLS by a direct immunological attack on the central or peripheral nervous system.
... El diagnóstico se completó en los cuatro SPI con serología y biopsia duodenal positivas para EC. La DSG produjo una significativa mejoría en todos los pacientes, tanto respecto a la clínica como a los análisis [66]. La prevalencia del SPI en una serie de 100 pacientes con EC fue del 31% frente al 4% del grupo control (p < 0,001) en un estudio prospectivo italiano de un centro de sueño en colaboración con una unidad clínica de gastroenterología. ...
Gluten sensitivity is a systemic autoimmune disease that occurs in genetically susceptible individuals on ingesting gluten. It can appear at any age, then becoming a permanent condition. It is more frequent in women, as happens with other autoimmune diseases. Celiac disease is the intestinal form and the most important manifestation among a set of gluten-induced autoimmune pathologies that affect different systems. Neurological manifestations of gluten sensitivity, with or without enteropathy, are also frequent, their pathogenesis including an immunological attack on the central and peripheral nervous tissue accompanied by neurodegenerative changes. The clinical manifestations are varied, but the most common syndromes are cerebellar ataxia and peripheral neuropathy. Finally, gluten sensitivity is associated to a varying degree, with other complex diseases and could influence their evolution. The early detection of cases of gluten sensitivity with neurological manifestations and subsequent treatment with the gluten-free diet could provide remarkable benefits to the patients.
... 24 Recently, four patients with RLS and low serum ferritin levels have been diagnosed as having CD, suggesting that RLS was secondary to iron metabolism defect. 25 According to our results, it seems unlikely that RLS is related to nutritional status in CD patients. In fact, we found no significant difference in iron metabolism, BMI, and GFD adherence between CD1RLS and CD2RLS. ...
Restless legs syndrome (RLS) is a common neurological condition, frequently idiopathic, sometimes associated with specific disorders such as iron deficiency. We investigated RLS prevalence in celiac disease (CD), an autoimmune disease characterized by several features such as malabsorption-related iron deficiency anemia and peripheral neuropathy. We screened a population of 100 adult CD patients for CD features, iron metabolism, clinical and neurological conditions, and enrolled 100 age- and sex-matched controls in the general population. RLS was ascertained in CD patients and controls by both the presence of the four essential International RLS Study Group diagnostic criteria and neurological examination. The International RLS Study Group rating scale was used to measure RLS severity. We found a 31% prevalence of RLS in the CD population that was significantly higher than the prevalence in the control population (4%; P < 0.001). The average severity of RLS in CD population was moderate (17 +/- 6.5). In the CD population, no significant correlation was found between RLS and either gluten-free diet or iron metabolism, despite hemoglobin levels were significantly lower in CD patients with RLS than without RLS (P = 0.003). We found no correlation between RLS and other possible causes of secondary RLS, including signs of peripheral neuropathy, pregnancy, end-stage renal disease, and pharmacological treatments.Our study broadens the spectrum of neurological disorders associated with CD and indicates that RLS should be sought for in all patients with CD.
Restless legs syndrome/Willis-Ekbom Disease (RLS/WED) is a common but still underdiagnosed neurological disorder. RLS/WED might impair nocturnal rest causing decreased alertness, depression, reduced job performance and poor quality of life. RLS/WED can occur as an isolated disease, mostly at a young age, or can be associated with comorbidities such as cardiovascular disease, diabetes, renal failure, arterial hypertension and peripheral neuropathy. The literature also offers some evidence of an association with gastrointestinal, rheumatological, pneumological, and neoplastic disorders. It is important to be aware of these associations in order to promptly recognize RLS/WED and also to think about an underlying medical condition when a patient reports symptoms of RLS/WED.
Study objectives:
Postural orthostatic tachycardia syndrome (POTS) and restless legs syndrome (RLS) are both characterized by sleep disturbance along with autoimmune/inflammatory features and autonomic dysfunction. However, to our knowledge there has been no direct study looking at the prevalence of RLS in POTS patients compared to healthy participants (controls).
Methods:
Ninety-six physician diagnosed patients with POTS (89 F and 7 M) and 130 controls (99 F and 31 M) were administered the Cambridge Hopkins (CH-RLSq) Questionnaire. Participants who were diagnosed with probable or definite RLS on the CH-RLSq were then contacted to determine the severity of RLS with the International Restless Legs Scale (IRLS).
Results:
More patients with POTS (15/96; 15.6%) than controls (6/130; 4.6% were diagnosed with probable or definite RLS on the CH-RLSq (p = 0.0048). A sensitivity analysis with only female respondents yielded similar results. RLS severity was in the moderate range (12.23 ± 9.22).
Conclusions:
There is a higher prevalence of RLS in POTS patients compared to controls. This association may have to do with shared increased inflammatory/autoimmune load and autonomic dysfunction.
Objective
Although the etiology of restless legs syndrome (RLS) is yet to be discovered, some studies have mentioned the effect of infectious diseases in occurrence of RLS. This study aims to determine the association between common Helicobacter pylori (H. pylori) infection and occurrence of RLS.
Methods
In this descriptive analytical cross-sectional study, patients with RLS who were referred to the Internal Medicine Clinic of Fayazbakhsh Hospital in Tehran from September to December 2016 were evaluated. Patients with underlying diseases that would lead to secondary RLS were excluded from the study. The control group were matched with the patients group regarding their age and gender, but did not have RLS or diseases that would lead to secondary RLS. All participants underwent serologic tests for evaluating serum levels of IgA and IgG antibodies against H. pylori. Data were analyzed using Chi-Square test and Logistic Regression with SPSS Software Version 20. The significance level was ≤0.05.
Results
Fifty-seven RLS patients and 64 healthy controls were included in the study. In the RLS group, 36 participants (29.8%) had H. pylori infection. This number was 27 participants (22.3%) in the control group. Data analysis using logistic regression showed a significant relation between H. pylori and occurrence of RLS (p value ≤ 0.05).
Conclusions
Results of the present study indicated that infection with H. pylori is related with the occurrence of RLS. It seems that releasing inflammatory factors, iron deficiency, and small intestinal bacterial overgrowth are some of the involved mechanisms in this pathogenesis.
Restless legs syndrome (RLS) is a complex genetic disease characterized by dysesthesias primarily affecting the lower limbs, which are precipitated by rest and classically occur at night. Movement of the affected extremity leads to prompt symptom relief. Genetically, RLS is a complex disorder with a heritability of up to 60 %. While linkage analyses were largely unsuccessful, genome-wide association studies (GWAS) have identified six genomic loci, to date, which harbor common genetic variants associated with an increased risk for RLS. At least one of these regions also harbors rare variants, which contribute to the genetic architecture of the disease. The first functional follow-up studies in the post-GWAS era have implicated expression alterations and forebrain development as well as dysfunctional iron metabolism as the possible downstream effects of the RLS-associated genetic alterations.
The nonpharmacologic management of patients with restless legs syndrome (RLS) is an important part of the treatment. It can represent the entire treatment or it can be used as an adjuvant to pharmacologic options. The limited number of controlled studies allowed for a plethora of pseudoprofessional recommendations. Some of these suggestions may have a grain of truth and some are utterly dangerous. This review discusses the different potential treatments for RLS to facilitate the design of a tailored program for specific patients. Another goal of this review is to prompt the researcher to investigate some of the laymen suggestions.
Copyright © 2015 Elsevier Inc. All rights reserved.
Restless legs syndrome is a common sensorimotor disorder characterized by an urge to move, and associated with uncomfortable sensations in the legs (limbs). Restless legs syndrome can lead to sleep-onset or sleep-maintenance insomnia, and occasionally excessive daytime sleepiness, all leading to significant morbidity. Brain iron deficiency and dopaminergic neurotransmission abnormalities play a central role in the pathogenesis of this disorder, along with other nondopaminergic systems, although the exact mechanisms are still. Intensive care unit patients are especially vulnerable to have unmasking or exacerbation of restless legs syndrome because of sleep deprivation, circadian rhythm disturbance, immobilization, iron deficiency, and use of multiple medications that can antagonize dopamine.
Published by Elsevier Inc.
Although malabsorption is generally considered to be a gastrointestinal problem, the effects of malabsorption extend far beyond the gastrointestinal tract and can include neurologic dysfunction. Malabsorption may occur by a variety of mechanisms, both genetic and acquired, that interfere with the absorption of basic nutrients, vitamins, minerals, and trace elements. Disorders that interfere with fat absorption can lead to neurologic dysfunction as a consequence of associated impairment of fat-soluble vitamin absorption. Thus, individuals with genetic vitamin E deficiency and the familial hypocholesterolemias may develop symptoms of peripheral neuropathy, cerebellar ataxia, and other neurologic signs and symptoms. Disease processes that damage the enteric mucosa and produce malabsorption can trigger neurologic dysfunction both by immune-related processes, as in celiac disease, and by impairing absorption of essential vitamins and other nutrients, as in tropical sprue. Deficiencies of water-soluble vitamins, such as thiamine and niacin, can also develop in the setting of malabsorption and lead to neurologic dysfunction. Neurologists are aware of the neurologic damage that copper excess can cause in Wilson's disease, but copper deficiency due to malabsorption can also produce neurologic dysfunction in the form of myelopathy. It is vitally important for neurologists to be aware of the potential for malabsorptive processes to produce neurologic dysfunction, because effective treatment for such disorders is often available.
Women are more commonly affected than men by restless legs syndrome, and prevalence is highest amongst those of northern European heritage. The motor manifestations include nonvolitional myoclonus (periodic leg movements). Disinhibition of spinal sensorimotor circuits may underlie these primary features and can be affected by peripheral as well as supraspinal networks. Insufficient mobilizable iron stores increase expressivity in some individuals. The sensorimotor features are relieved by dopamine, especially dopamine agonists, gabapentin and its derivatives, and opioids. A diagnosis relies on recognition of key primary and supportive features, and treatments are generally well tolerated, efficacious, and life-changing.
An association between celiac disease (CD) and peripheral neuropathy (PN) has been reported.
Patients with CD and/or inflammatory bowel disease (IBD) were recruited from the gastroenterology clinics at a medical center and local support groups. Control subjects without CD or IBD were recruited from the staff of the medical center as well as relatives and attendees at support groups. Each participant completed a survey that used two validated PN instruments to define and characterize PN.
In the CD group, 38.9% met criteria for PN compared with 38.7% in the IBD group (P = 0.97) and 20.5% in the control group (P < 0.001). On multiple logistic regression, the odds of PN after adjusting for age, gender, diabetes, vitamin B12 deficiency, and cancer history were increased for CD (odds ratio, 2.51; 95% confidence interval, 1.82-3.47) and IBD (odds ratio, 2.78; 95% confidence interval, 1.85-4.18).
PN is more often found in patients with CD and/or IBD than in the general population.
The prevalence of restless legs syndrome (RLS) is increased in gluten sensitive enteropathy (GSE); but prevalence of GSE is not known in RLS. 96 RLS patients and 97 healthy controls, both with or without iron deficiency were enrolled. All secondary RLS patients except iron deficiency were excluded. Subjects underwent a thorough biochemistry and routine blood analyses, and tissue transglutaminase antibodies (TTGA), endomysium antibodies (EMA) and gliadin antibodies (AGA) were also tested. In RLS patients positivity rates of all GSE antibodies were similar to those in controls. The rate of iron deficiency anaemia in RLS patients with at least one positive GSE antibody was significantly higher than that of RLS patients whose GSE antibodies were all negative. The prevalence of GSE antibodies in RLS patients is not increased. GSE might have a role in the aetiology of RLS in association with iron deficiency anaemia. Since the prevalence of GSE antibodies is not increased in RLS, it seems unlikely that GSE is involved in the aetiology of RLS through different mechanisms (e.g. immunological mechanisms) other than iron deficiency as proposed in some published papers.
Celiac disease (CD) is an immune-mediated enteropathic condition triggered in genetically susceptible individuals by the ingestion of gluten. Although common in Europe, CD is thought to be rare in the United States, where there are no large epidemiologic studies of its prevalence. The aim of this study was to determine the prevalence of CD in at-risk and not-at-risk groups in the United States.
Serum antigliadin antibodies and anti-endomysial antibodies (EMA) were measured. In EMA-positive subjects, human tissue transglutaminase IgA antibodies and CD-associated human leukocyte antigen DQ2/DQ8 haplotypes were determined. Intestinal biopsy was recommended and performed whenever possible for all EMA-positive subjects. A total of 13 145 subjects were screened: 4508 first-degree and 1275 second-degree relatives of patients with biopsy-proven CD, 3236 symptomatic patients (with either gastrointestinal symptoms or a disorder associated with CD), and 4126 not-at-risk individuals.
In at-risk groups, the prevalence of CD was 1:22 in first-degree relatives, 1:39 in second-degree relatives, and 1:56 in symptomatic patients. The overall prevalence of CD in not-at-risk groups was 1:133. All the EMA-positive subjects who underwent intestinal biopsy had lesions consistent with CD.
Our results suggest that CD occurs frequently not only in patients with gastrointestinal symptoms, but also in first- and second-degree relatives and patients with numerous common disorders even in the absence of gastrointestinal symptoms. The prevalence of CD in symptomatic patients and not-at-risk subjects was similar to that reported in Europe. Celiac disease appears to be a more common but neglected disorder than has generally been recognized in the United States.
This article has no abstract; the first 100 words appear below.
Celiac disease is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains (including wheat, rye, and barley) in genetically susceptible persons. The disease is associated with HLA-DQ2 in 90 to 95 percent of cases and with HLA-DQ8 in 5 to 10 percent of cases and is self-perpetuating in the continued presence of gluten.¹ It is the interplay between genes (both HLA and other types) and environment (i.e., gluten) that leads to the intestinal damage that is typical of the disease.² Under physiologic circumstances, this interplay is prevented by competent intercellular tight junctions, structures that limit the passage of macromolecules . . .
Dr. Fasano reports having served as a paid lecturer to Prometheus.
Source Information
From the Center for Celiac Research and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore.
Restless legs syndrome (RLS), a common sensorimotor disorder, has a wide range of severity from merely annoying to affecting sleep and quality of life severely enough to warrant medical treatment. Previous epidemiological studies, however, have failed to determine the prevalence of those with clinically significant RLS symptoms and to examine the life effects and medical experiences of this group.
A total of 16 202 adults (aged >/=18 years) were interviewed using validated diagnostic questions to determine the presence, frequency, and severity of RLS symptoms; respondents reporting RLS symptoms were asked about medical diagnoses and the impact of the disorder and completed the Short Form-36 Health Survey (SF-36). Criteria determined by RLS experts for medically significant RLS (frequency at least twice a week, distress at least moderate) defined "RLS sufferers" as a group most likely to warrant medical treatment.
In all, 15 391 fully completed questionnaires were obtained; in the past year, RLS symptoms of any frequency were reported by 1114 (7.2%). Symptoms occurred at least weekly for 773 respondents (5.0%); they occurred at least 2 times per week and were reported as moderately or severely distressing by 416 (2.7%). Of those 416 (termed RLS sufferers), 337 (81.0%) reported discussing their symptoms with a primary care physician, and only 21 (6.2%) were given a diagnosis of RLS. The SF-36 scores for RLS sufferers were significantly below population norms, matching those of patients with other chronic medical conditions.
Clinically significant RLS is common (prevalence, 2.7%), is underdiagnosed, and significantly affects sleep and quality of life.
Celiac disease (CD) is one of the most common lifelong disorders in western countries. However, most cases remain currently undiagnosed in North America, mostly due to poor awareness of CD by primary care physicians.
The aims of this study were (a) to determine whether an active case-finding strategy in primary care could increase the frequency of CD diagnosis and (b) to determine the most common clinical presentations of the condition.
This was a multicenter, prospective study involving adult subjects during the years 2002-2004, attending one of the participating practices. All individuals with symptoms or conditions known to be associated with CD were tested for immunoglobulin A anti-transglutaminase (tTG) antibodies, and those with elevated anti-tTG were subsequently tested for IgA antiendomysial antibodies (EMA). All subjects who were positive for EMA were advised to undergo an intestinal biopsy and HLA typing.
The study group included 737 women and 239 men, with a median age of 54.3 yr. A positive anti-tTG test was found in 30 out of 976 investigated subjects (3.07%, 95% CI 1.98-4.16). CD was diagnosed in 22 patients (18 women, 4 men). The most frequent reasons for CD screening in these 22 cases were bloating (12/22), thyroid disease (11/22), irritable bowel syndrome (7/22), unexplained chronic diarrhea (6/22), chronic fatigue (5/22), and constipation (4/22). The prevalence of CD in the serologically screened sample was 2.25% (95% CI 1.32-3.18). The diagnostic rate was low at baseline (0.27 cases per thousand visits, 95% CI 0.13-0.41) and significantly increased to 11.6 per thousand visits (95% CI 6.8-16.4, P < 0.001) following active screening implementation.
This study demonstrates that an active case-finding strategy in the primary care setting is an effective means to improve the diagnostic rate of CD in North America.
Using blinded procedures, determine the relation between serum ferritin levels and severity of subjective and objective symptoms of the restless legs syndrome (RLS) for a representative patient sample covering the entire adult age range.
All patient records from the past 4 years were retrospectively reviewed to obtain data from all cases with RLS. All patients were included who had ferritin levels obtained at about the same time as a polysomnogram (PSG), met diagnostic criteria for RLS, and were not on iron or medications that would reduce the RLS symptoms at the time of the PSG.
Sleep Disorders Center.
27 (18 females, 9 males), aged 29-81 years.
None.
Measurements included clinical ratings of RLS severity and PSG measures of sleep efficiency and periodic limb movements (PLMS) in sleep with and without arousal. Lower ferritin correlated significantly to greater RLS severity and decreased sleep efficiency. All but one patient with severe RLS had ferritin levels < or = 50 mcg/l. Patients with lower ferritin (< or = 50 mcg/l) also showed significantly more PLMS with arousal than did those with higher ferritin, but the PLMS/hour was not significantly related to ferritin. This last finding may be due to inclusion of two 'outliers' or because of severely disturbed sleep of the more severe RLS patients.
These data are consistent with those from a prior unblinded study and suggest that RLS patients will have fewer symptoms if they have ferritin levels greater than 50 mcg/l.
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.
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.
The relationship between iron status and the restless legs syndrome (RLS) was examined in 18 elderly patients with RLS and in 18 matched control subjects. A rating scale with a maximum score of 10 was used to assess the severity of RLS symptoms. Serum ferritin levels were reduced in the RLS patients compared with control subjects (median 33 μg/1 vs. 59 μg/1, p<0.01, Wilcoxon signed rank test); serum iron, vitamin B12 and folate levels and haemoglobin levels did not differ between the two groups. Serum ferritin levels were inversely correlated with the severity of RLS symptoms (Spearman’s rho -0.53, p < 0.05). Fifteen patients with RLS were treated with ferrous sulphate for 2 months. RLS severity score improved by a median value of 4 points in six patients with an initial ferritin ≤ 18μg/1, by 3 points in four patients with ferritin > 18 μg/1,≤45 μg/1 and by 1 point in five patients with ferritin >45 μg/1, <100 μg/1.
Iron deficiency, with or without anaemia, is an important contributor to the development of RLS in elderly patients, and iron supplements can produce a significant reduction in symptoms.
The restless legs syndrome (RLS), defined by Gibb and Lees criteria, was investigated in patients with RA. RLS symptoms were
more frequent in RA patients (25%) than in non-RA controls with OA or seronegative arthropathy (4%). RLS was significantly
more common in females. Judged by a variety of clinical and laboratory indices, RA disease severity and current disease activity
were greater in patients with RLS than in RA patients unaffected by RLS. In five out of 14 RLS patients undergoing neurophysiological
study, delays in the P40 component of posterior tibial somatosensory evoked potentials (SSEPs) were observed suggesting the existence of myelopathy,
whilst in another four RLS patients evidence of peripheral neuropathy was found. Though the higher frequency of neurophysiological
abnormalities in RA patients with RLS was not statistically significant, possibly because of the small numbers of patients
studied, these data suggest that RLS symptoms in RA may reflect the presence of neurological disorder.
Restless legs syndrome is characterised by an unpleasant, difficult-to-describe sensation in the legs that produces an invariable urge to move them frequently.1 2 3 This symptom typically occurs at rest or before sleep and is alleviated by activity.1 2 3 Restless legs syndrome may occur without or with an associated condition, such as rheumatoid arthritis.1 3 We investigated the prevalence of restless legs syndrome and of leg cramps in patients with fibromyalgia syndrome, a common condition with widespread musculoskeletal aching and tender points,2 4 and in controls.
One hundred and thirty five consecutive new female patients referred with primary fibromyalgia, 54 women with rheumatoid arthritis without concomitant fibromyalgia, and 87 healthy, pain free women acting as controls were studied at our outpatient rheumatology clinic. All patients with fibromyalgia …
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.
Background: Restless legs syndrome (RLS) is a disorder characterized by disagreeable sensations in the legs that occur at rest and are relieved by movement. These symptoms, which are worse at night, may result in sleep onset or sleep maintenance insomnia. Most patients are found on polysomnography (PSG) to have periodic limb movements in sleep (PLMS). The disorder, idiopathic in most cases, may be sometimes associated with specific disorders.Methods: Using the Province of Manitoba Health database, we compared the diagnoses made in the 5 years prior to sleep laboratory evaluation of 218 patients (103 men and 115 women) with RLS and 872 matched control subjects from the general population.Results: We found that 43.7% of male RLS patients vs. 10.4% of male controls and 46.1% of female RLS patients vs. 22.8% of female controls had been diagnosed as having psychological/psychiatric (most often depression) disorders (P<0.05). Extrapyramidal disease or movement disorders were previously diagnosed in 17.5% of male RLS patients vs. 0.2% of male controls and in 23.5% of female patients vs. 0.2% of female controls (P<0.05). Many patients had been previously diagnosed with disorders of the musculoskeletal system: 35.9% of male patients vs. 22.8% of male controls and 49.6% of female RLS patients vs. 23.3% of female controls had been diagnosed as having diseases of joints (male; P=ns, female; P<0.05). Disorders of the back were also more frequently diagnosed in RLS patients: 21.4% of male patients vs. 13.1% of male controls and 38.3% of female patients vs. 15.0% of female controls (male; P=ns, female; P<0.05).Conclusions: We conclude that RLS patients are much more likely to have previously been diagnosed with extrapyramidal disorders, musculoskeletal disorders, depression, and painful conditions such as joint and back disorders.
To evaluate the role of CNS dopaminergic systems in Restless Legs Syndrome (RLS), homovanillic acid (HVA), tetrahydrobiopterin (BH4), and neopterin (NEOP), were assayed in CSF from RLS patients. The serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), was also measured.
CSF was taken from 16 RLS patients after 2 weeks off medication and from 14 control subjects. The CSF metabolites were determined using HPLC techniques.
There was no significant difference in HVA or 5-HIAA, but NEOP and BH4 were higher in RLS patients. The RLS group was significantly older than the control group (64.2 +/- 9.2 years vs. 51.4 +/- 6.3 years; P < 0.001). A multiple regression analysis showed a strong correlation between age and 5-HIAA (r = 0.46, P = 0.04) and between age and NEOP (r = 0.61, P < 0.01). To eliminate the potential error created by the age difference between groups, an age-adjusted subgroup of RLS and control subjects were compared. There was still no difference found for HVA; however, 5-HIAA was now significantly lower (P < 0.01) in the RLS subgroup. Age-adjustment eliminated the differences previously found for NEOP, (P = 0.12), but BH4 continued to remain higher in the RLS group (P < 0.01).
Differences in CSF HVA concentrations were not found. The changes in 5-HIAA and BH4 are of unclear clinical significance and require further assessment with appropriate age-matched controls.
A 45-year-old woman reports having had nightly insomnia for years. On further questioning, she reports having uncomfortable sensations in her legs when she lies down at night. She has a feeling of needing to move her legs, which is relieved only by getting up and walking around. How should this patient be evaluated and treated?
To assess neuropathology in individuals with restless legs syndrome (RLS).
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.
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.
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 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.
The restless legs syndrome diagnostic criteria and epidemiology workshop at the National Institutes of Health.
Members of the International Restless Legs Syndrome Study Group and authorities on epidemiology and the design of questionnaires and scales.
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.
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.
Restless legs syndrome (RLS) may be a cause of significant sleep disturbance. In a Swedish survey, the prevalence of RLS has been estimated to be 5.8% among men and 11.4% among women. Blood donation may result in iron deficiency, which is hypothesized to be one substantial cause of RLS.
Nine hundred and forty-six (618 men, 328 women) consecutive blood donors aged 18-64 years, who attended a blood donation unit in mid-Sweden, answered a questionnaire that included questions about sleep habits. Frequency of blood donation was recorded and intake of iron tablets was assessed. Red blood cell distribution width (RDW) was also recorded. The value of RDW increases in relation to iron deficiency.
RLS affected 14.7% of male and 24.7% of female blood donors. The mean intake of iron among the blood donors after each blood donation was only 781 mg, although the recommended intake is 2000 mg. Among the women, 7.4% presented an RDW of >14.5%, which strongly indicates iron deficiency. In this group of women, 37.5% were affected by RLS. The female RLS-sufferers were more affected than the female non-RLS subjects by problems initiating sleep (P=0.006 maintaining sleep (P<0.0001) and were also less refreshed upon awakening (P<0.001).
This study showed that RLS was common among female blood donors. Women with RLS were more iron-deficient than those without and were affected by impaired sleep.
Restless legs syndrome (RLS) is a sensory-movement disorder affecting 5 to 10% of the population. Its etiology is unknown, but MRI analyses and immunohistochemical studies on autopsy tissue suggest the substantia nigra (SN) of patients with RLS has subnormal amounts of iron.
Neuromelanin cells from the SN of four RLS and four control brains were isolated by laser capture microdissection, and a profile of iron-management protein expression was obtained by immunoblot analysis. Binding assays for iron regulatory protein activity were performed on cell homogenates.
Ferritin, divalent metal transporter 1, ferroportin, and transferrin receptor (TfR) were decreased in RLS neuromelanin cells compared with control. Transferrin was increased in RLS neuromelanin cells. This protein profile in RLS neuromelanin cells is consistent with iron deficiency with the exception that TfR expression was decreased rather than increased. The concentration and activity of the iron regulatory proteins (IRP1 and IRP2) were analyzed to determine whether there was a functional deficit in the post-transcriptional regulatory mechanism for TfR expression. Total IRP activity, IRP1 activity, and IRP1 protein levels were decreased in RLS, but total IRP2 protein levels were not decreased in RLS.
Restless legs syndrome may result from a defect in iron regulatory protein 1 in neuromelanin cells that promotes destabilization of the transferrin receptor mRNA, leading to cellular iron deficiency.
To evaluate the safety and efficacy of a single 1000 mg iron infusion in treating Restless Legs Syndrome (RLS).
A single 1000 mg intravenous (IV) [Am J Med Sci 31 (1999) 213] infusion of iron dextran was evaluated in an open-label study. Primary outcomes of efficacy were symptom severity assessed by global rating scale and periodic leg movements in sleep (PLMS) at 2 weeks post-infusion. Secondary outcomes included total sleep time (TST), hours/day of RLS symptoms, and changes in magnetic resonance imaging (MRI)-determined iron concentrations in the substantia nigra. Primary safety measures were reported adverse events and monthly serum ferritin levels.
IV iron therapy significantly improved the mean global RLS symptom severity, TST, hours with RLS symptoms and PLMS, but on an individual basis failed to produce any response in 3 of the 10 subjects who were fully treated. Brian iron concentrations at 2 weeks post-infusion as determined by MRI were increased in the substantia nigra and prefrontal cortex. Serum ferritin levels showed a greater than predicted rapid linear decrease. Side effects were mild, except in one subject who developed an acute allergic reaction.
The results in this study provide valuable information for future studies, but the efficacy and safety of IV iron treatment for RLS remain to be established in double-blind studies. The serum ferritin results suggest that greater than expected iron loss occurs after IV iron loading.
The evaluation of the pathophysiology of restless legs syndrome (RLS) stems largely from recognition of the information provided by both pharmacological treatment of the disorder and the secondary forms of the disorder. This article examines the pathophysiological implications of each of these clinical aspects of RLS.
The article reviews the existing literature in relation to possible pathology suggested by the clinical data. It will then explore other data supporting each of the possible pathologies and examine the relationships between these pathologies.
The pharmacological treatment data strongly support a dopaminergic abnormality for RLS. Other pharmacological data and some imaging data also support this, although the data are not entirely consistent. The secondary forms of RLS strongly support an iron deficiency abnormality for RLS, further documented by several other studies. Some animal studies have shown a relation between iron deficiency and dopaminergic abnormalities that have some similarity to those seen in the RLS patient.
It is concluded that there may be an iron-dopamine connection central to the pathophysiology of RLS for at least some if not most patients with this disorder.
To estimate prevalence and severity (using the International Restless Legs Syndrome Study Group Rating Scale (IRLS)) and to identify risk factors of restless legs syndrome (RLS).
Population-based cross-sectional study; 2005 randomly selected adults 18 years and above participated in a telephone interview in Norway and Denmark, employing the next-birthday technique.
Of the cross-section, 11.5% fulfilled the diagnostic criteria for RLS. Half of these reported the symptoms as moderate to very severe. Mean duration of the complaint was 10 years. Prevalence was higher in females than in males (13.4 vs 9.4%) and lowest in the youngest age group (18-29 years, 6.3%). From 30 years and above, no clear age-related difference was seen. Main predictors of RLS were insomnia (odds ratios: 1.71-3.16) and symptoms of periodic limb movements in sleep (3.20-7.85). The response rate was 47%, making the results less reliable.
This study indicates that there is a high occurrence of RLS among adults. Main predictors are insomnia and periodic limb movements in sleep.
To assess the prevalence and severity of restless legs syndrome (RLS) in the general community and to investigate its potential relationship with iron metabolism and other potential risk factors.
This was a cross-sectional study of a sex- and age-stratified random sample of the general population (50 to 89 years; n = 701). The diagnosis of RLS was established by face-to-face interviews; severity was graded on the RLS severity scale. Each subject underwent a thorough clinical examination and extensive laboratory testing.
The prevalence of RLS was 10.6% (14.2% in women, 6.6% in men); 33.8% of all patients with RLS had mild, 44.6% had moderate, and 21.6% had severe disease expression. None had been previously diagnosed or was on dopaminergic therapy. Free serum iron, transferrin, and ferritin concentrations were similar in subjects with and without RLS. However, soluble transferrin receptor (sTR) concentrations were different in subjects with and without RLS (1.48 vs 1.34 mg/L; p < 0.001). Female sex and high sTR independently predicted the risk of RLS.
This large survey confirms the high prevalence, female preponderance, and underrecognition of restless legs syndrome in the general community. Although two-thirds of patients had moderate to severe disease, none was on current dopaminergic therapy.
To evaluate in RLS patients the efficacy and safety of repeated infusions of iron in order to maintain symptomatic improvements achieved with a prior single 1000 mg infusion of iron.
Subjects who had demonstrated initial improvement in RLS symptoms after a single 1000 mg infusion of iron were evaluated monthly for serum ferritin and RLS severity. If symptoms returned at any time in the 2-year period after initial iron treatment, supplemental 450 mg iron gluconate infusions could be given, provided the ferritin was <300 mcg/l. The primary outcome measures were side effect profile, duration (weeks) of sustained improvement, and rate of change of serum ferritin.
Ten subjects received the initial single 1000 mg dose of iron dextran, but only five subjects were eligible to receive supplemental iron infusions. RLS symptoms returned on average 6 months after the initial 1000 mg infusion. Because of noncompliance with monthly visits one subject was dropped after receiving three supplemental iron infusions. Because of a ferritin >300 mcg/l, a second subject was dropped after having received one supplemental treatment. Three subjects completed the 2-year period of the study, having received between two and four courses of supplemental iron. After the initial 1000 mg iron infusion, the ferritin declined on average 6.6 mcg/l/week, which was substantially higher than the predicted value of <1 mcg/l per week. The rate of ferritin decline decreased toward normal with repeated IV iron treatments: the average rate of decline in ferritin for the last treatment course was 2.3 mcg/l/wk. The slower the rate of ferritin decline the more prolonged the symptom improvements.
Supplemental iron treatments can sustain previously achieved improvements with a single IV iron treatment, but achieving high ferritin levels was not in themselves a guarantee of sustained improvements. The most notable finding was the post-infusion changes in serum ferritin and its implication for altered iron excretion.
Celiac disease is a complex autoimmune enteropathy that affects the small bowel in genetically predisposed individuals. It is thought that celiac disease is the result of an inappropriate T cell-mediated immune response against ingested gluten protein. The characteristic lesion of the small intestinal mucosa includes loss of absorptive villi and infiltration of the lamina propria with inflammatory cells. The clinical presentation of celiac disease varies greatly depending on patient's age, duration and extent of the disease, and the presence of extraintestinal manifestations. Unfortunately, most patients with celiac disease have either silent or atypical presentations, thus escaping diagnosis for several years. Medical nutrition therapy with lifelong adherence to a strict gluten-free diet is the only accepted treatment of celiac disease. Individuals at risk for this entity should undergo appropriate serologic testing, but there is no evidence to support mass screening.
Cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and autopsy studies have suggested that brain iron may be reduced in restless legs syndrome (RLS). Further analysis of the data also suggests that diminished brain iron may selectively be for early-onset RLS. This study was designed to replicate and extend our previous findings, specifically with regard to early-onset RLS. In this study our primary hypothesis was that substantia nigra (SN) iron index would be decreased in early-onset RLS compared to controls.
The iron concentration or 'iron index' in 10 brain regions was determined using MRI in 39 controls and in 22 early-onset and 19 late-onset RLS subjects. The Johns Hopkins RLS severity (JHRLSS) scale was used to define disease severity.
The mean iron index from the SN was significantly lower in the early-onset RLS compared to controls (t=2.5, P=0.016), while late-onset RLS and controls did not differ. There was a significant negative Spearman rank correlation between SN iron index and JHRLSS scale for the control-early-onset-RLS cohort (rho=-0.32, P=0.016).
The current MRI results in combination with previous autopsy data support the role of low brain iron in the SN in at least those with early-onset RLS symptoms.
Celiac disease is considered to occur in approximately 1% of the U.S. population. It is, however, markedly underdiagnosed. In this issue, Fasano and his colleagues have continued their work in demonstrating just where all these patients are. Their current study explores a case finding policy in the primary practice setting. They identified patients who exhibited either symptoms that could be attributed to celiac disease, or had an associated condition. In this population, 2.25% had celiac disease. The study emphasizes the need for physician education in both the prevalence of celiac disease and the wide availability of the serological tests that can facilitate the diagnosis of celiac disease.
The prevalence of restless legs syndrome (RLS) in India is unknown.
The primary objective was to assess the occurrence of RLS in residents of Bangalore. The secondary objective was to correlate demographic and socioeconomic factors with RLS occurrence and severity.
This was a cross-sectional, questionnaire-based survey conducted during August 2005 among adult residents of Bangalore, who participated in a face-to-face interview. Diagnosis of RLS was based on fulfillment of all National Institutes of Health/International Restless Legs Syndrome Study Group (NIH/IRLSSG) essential criteria. Severity of RLS was assessed using the IRLSSG scale.
RLS occurred in 27 (2.1%) of 1266 respondents. Predominant symptoms included "pulling," "tingling" and "pain". RLS was associated with delayed sleep onset and RLS severity correlated with the duration of delay in sleep onset. RLS was associated with per-capita income less than the equivalent of US$1/day, education less than high school level, chronic daily alcohol consumption and chronic blood loss.
This is the first Indian population study on RLS which reveals prevalence of the disorder in a South Indian urban population at 2.1%. Larger studies are warranted to better characterize RLS in India.
Typescript. Thesis (M.S.)--Albany Medical Center, Graduate Studies Program, 2006. Bibliography: leaves 29-34
International classification of sleep disorders: diagnostic and coding manual
- American Academy
- Sleep
- Medicine
American Academy of Sleep Medicine. International classification of sleep disorders: diagnostic and coding manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine, 2005.
Restless legs syndrome in Indian patients having iron deficiency anemia in a tertiary care hospital
- Rangarajan
CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome
- Earley
Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome
- Connor