Effects of iron supplementation on attention deficit hyperactivity disorder in children

Iron deficiency has been suggested as a possible contributing cause of attention deficit hyperactivity disorder (ADHD) in children. This present study examined the effects of iron supplementation on ADHD in children. Twenty-three nonanemic children (aged 5-8 years) with serum ferritin levels <30 ng/mL who met DSM-IV criteria for ADHD were randomized (3:1 ratio) to either oral iron (ferrous sulfate, 80 mg/day, n = 18) or placebo (n = 5) for 12 weeks. There was a progressive significant decrease in the ADHD Rating Scale after 12 weeks on iron (-11.0 +/- 13.9; P < 0.008), but not on placebo (3.0 +/- 5.7; P = 0.308). Improvement on Conners' Parent Rating Scale (P = 0.055) and Conners' Teacher Rating Scale (P = 0.076) with iron supplementation therapy failed to reach significance. The mean Clinical Global Impression-Severity significantly decreased at 12 weeks (P < 0.01) with iron, without change in the placebo group. Iron supplementation (80 mg/day) appeared to improve ADHD symptoms in children with low serum ferritin levels suggesting a need for future investigations with larger controlled trials. Iron therapy was well tolerated and effectiveness is comparable to stimulants.     

Sleep disturbances and serum ferritin levels in children with attention-deficit/hyperactivity disorder

Background  A subset of children with attention-deficit/hyperactivity disorder (ADHD) may present with impairing sleep disturbances. While preliminary evidence suggests that iron deficiency might be involved into the pathophysiology of daytime ADHD symptoms, no research has been conducted to explore the relationship between iron deficiency and sleep disturbances in patients with ADHD. The aim of this study was to assess the association between serum ferritin levels and parent reports of sleep disturbances in a sample of children with ADHD. Methods  Subjects: Sixty-eight consecutively referred children (6–14 years) with ADHD diagnosed according to DSM-IV criteria using the semi-structured interview Kiddie-SADS-PL. Measures: parents filled out the Sleep Disturbance Scale for Children (SDSC) and the Conners Parent Rating Scale (CPRS). Serum ferritin levels were determined using the Tinaquant method. Results  Compared to children with serum ferritin levels ≥45 μg/l, those with serum ferritin levels <45 μg/l had significantly higher scores on the SDSC subscale “Sleep wake transition disorders” (SWTD) (P = 0.042), which includes items on abnormal movements in sleep, as well as significantly higher scores on the CPRS–ADHD index (P = 0.034). The mean scores on the other SDSC subscales did not significantly differ between children with serum ferritin ≥45 and <45 μg/l. Serum ferritin levels were inversely correlated to SWTD scores (P = 0.043). Conclusion  Serum ferritin levels <45 μg/l might indicate a risk for sleep wake transition disorders, including abnormal sleep movements, in children with ADHD. Our results based on questionnaires set the basis for further actigraphic and polysomnographic studies on nighttime activity and iron deficiency in ADHD. Research in this field may suggest future trials of iron supplementation (possibly in association with ADHD medications) for abnormal sleep motor activity in children with ADHD.     

Hemochromatosis and iron therapy of Restless Legs Syndrome

Restless legs syndrome (RLS) occurs in some persons with iron deficiency, and some persons with RLS benefit from oral iron therapy. Approximately one in 200 persons of northern European ancestry have hemochromatosis attributable to inheritance of two common mutations of the hemochromatosis-associated HFE gene on chromosome 6. We evaluated and treated a 46-year-old man with RLS who was diagnosed as having hemochromatosis after he developed new symptoms associated with taking iron therapy for RLS. He had transferrin saturation 88%, serum ferritin 658 ng/ml, and C282Y homozygosity. Therapeutic phlebotomy of one unit of blood (450-500 ml) weekly (total 24 units) relieved his non-RLS symptoms, caused RLS symptoms to occur more frequently, and was associated with transient fatigue and mild dependent edema. His sister, who also has RLS, was subsequently diagnosed as having hemochromatosis. We conclude that serum transferrin saturation and ferritin levels should be measured before initiation of iron therapy of RLS. Patients with a history of iron deficiency or low serum iron parameters should undergo evaluation for iron deficiency; patients who have histories suggestive of hemochromatosis or iron overload or elevated pre-treatment transferrin saturation or serum ferritin levels should undergo evaluation to determine the cause of these abnormalities before they are treated with iron. In all persons with RLS treated with oral iron, serum iron parameters should be re-measured once or twice yearly during therapy.     

Rheumatologic serologies in secondary restless legs syndrome.

Diagnostic criteria for restless legs syndrome (RLS) have been established; however, the pathophysiology of this common condition remains elusive. Several secondary forms of RLS potentially include renal failure, iron deficiency, pregnancy, and neuropathy. RLS has also been reported in approximately 25% of patients diagnosed with rheumatoid arthritis and Sj?gren's syndrome. We performed clinical and serologic evaluations on 68 patients diagnosed with RLS to determine how many may have concurrent rheumatologic disease that could be causing their RLS symptoms. We compared these with other postulated secondary causes of RLS. No patient had clinical evidence of rheumatologic disease, and only four had any positive serologic evaluations (two positive SSA/SSB and two mildly elevated RF titers). Three of these had a positive family history for RLS. Patients without a family history of RLS did have lower ferritin levels, more cases of neuropathy, and an older age at symptom onset. We do not think rheumatologic disease represents a significant secondary cause of RLS and do not recommend serologic investigation unless there are overt clinical signs. In contrast, our study suggests that neuropathy and serum iron deficiency do represent secondary forms of RLS.     

PLAY AS THE BASIS OF ASSESSMENT AND DEVELOPMENTAL STIMULATION FOR YOUNG MENTALLY HANDICAPPED CHILDREN

Objective: Iron deficiency may play a role in the pathophysiology of attention deficit hyperactivity disorder (ADHD) by causing dopamine dysfunction, but there is conflicting evidence in the literature regarding this relationship. This study investigates the possible correlation between iron deficiency and ADHD in children and adolescents attending a South African child and adolescent psychiatry outpatient service.

Method: In this retrospective study, we gathered data from 245 outpatient children and adolescents who had their serum ferritin and/or iron levels tested between February 2011 and January 2016. Relevant statistical methods were used to test for correlations between ADHD and various demographic and clinical factors, including iron deficiency.

Results: Out of 245 patients, 88 (35.9%) had iron deficiency, 156 (63.7%) had ADHD and 55 (22.4%) had both iron deficiency and ADHD. Variables found to be significantly correlated with ADHD included gender, age, and methylphenidate treatment, but there was no significant correlation between ADHD and iron deficiency.

Conclusions: Our study emphasizes the great complexity involved in understanding ADHD. Comparisons between mentally-ill paediatric patients and matched healthy controls from the same communities are required to further explore the possible association between iron deficiency and ADHD.     

Iron metabolism and the risk of restless legs syndrome in an elderly general population--the MEMO-Study

Background: Low iron and ferritin blood levels have been observed in patients with Restless Legs Syndrome (RLS) with an inverse relation between symptom severity and ferritin level. All reports are based on single cases or case series of hospitalized patients or those from outpatient clinics. No data from population studies are available. Methods: Cross-sectional study examining the associations between 5 measures of iron metabolism and RLS in an elderly general population in southern Germany. All 365 participants, aged 65 to 83 years, were examined neurologically and interviewed using standardized questions addressing the four minimal criteria for RLS. Iron, ferritin, transferrin, soluble transferrin receptor and C-Reactive Protein were analysed with standard laboratory methods. Results: The prevalence of Restless Legs Syndrome in this population was 9.8 %. Odds Ratios associated with Restless Legs were significantly increased in the fourth quintile of iron (OR 3.08 95 % CI 1.02–9.29) and transferrin saturation (OR 5.68 95 % CI 1.18–27.26) compared with the third (middle) quintile. Increases in the first (lowest) quintile of both measures were not or borderline significant. No associations with ferritin and soluble transferrin receptor were found. Conclusions: No evidence was found that iron or ferritin deficiency are a major cause of RLS in this population study. The results support the hypothesis that changes in the complex regulation of iron metabolism contribute to the occurence of RLS. Received: 23 July 2001, Received in revised form: 1 March 2002, Accepted: 8 March 2002     

The relationship between Willis-Ekbom disease and serum ferritin levels among children in Northwestern Turkey

Objective:

To examine the incidence of restless legs syndrome (RLS) among children with iron deficiency, or iron deficiency anemia, or both, and the relationship between RLS prevalence and serum ferritin levels.

Methods:

This prospective, cross-sectional, case controlled study was carried out between January and June 2013, and included 98 iron deficiency and/or iron deficiency anemia, and 102 healthy children referred to the Neurology and Pediatric Departments of the Medical Faculty of Bezmialem Vakif University, Istanbul, Turkey. Both groups were evaluated according to the International Restless Legs Syndrome Study Group diagnostic criteria.

Results:

The range of ferritin levels was 0.01-12 mg/ml in patients while it was 12.3-91.8 mg/mL in the control group. Restless legs syndrome was detected in 61.2% of children with iron deficiency anemia, and in 37.3% of children with normal biochemistry values. A statistically significant correlation was found between serum ferritin levels and frequency of RLS. In patients with serum ferritin levels higher than 50 ng/ml, 92.3% had no RLS, while 55.2% of patients with serum ferritin levels lower than 50ng/ml had RLS. The patients with serum ferritin levels of >50ng/ml had a significantly higher incidence of RLS. Serum ferritin levels were significantly different between the 2 groups.

Conclusion:

The incidence of RLS, also known as Willis-Ekbom Disease, is high in children aged between 8-18 years with iron deficiency, or iron deficiency anemia, or both. This finding supports the importance of iron replacement therapy especially during the growth and development of children.Willis-Ekbom disease (WED), also known as restless legs syndrome (RLS), is a sensory-motor disorder affecting patients’ sleep quality, cognition, and quality of life.1 Studies have shown that genetic factors, dopaminergic dysfunction, and low serum iron levels play an important role in the pathogenesis of WED/RLS.2,3 Iron deficiency is one of the most important nutritional problems throughout the world. Anemia prevalence due to iron deficiency is high among underdeveloped and developing countries, while it is relatively low in developed countries.4-6 The anemia prevalence is still high in Turkey although some progress has been made.7,8 Two studies7,8 on the incidence of WED/RLS frequency in iron deficiency among adults showed an incidence rate of approximately 40%; however, there is a lack of data on the incidence of WED/RLS among children. The WED/RLS can be seen among all age groups, and diagnosis depends on subjective complaints. Unfortunately, there is no specific biological marker for the diagnosis of this disease. Our knowledge of WED/RLS among children is limited, and diagnosis cannot be made without polysomnography (PSG), especially among infants and preschool ages. The incidence of WED/RLS is approximately 2-4% among school aged children and adolescents.3,9,10 Four mandatory clinical features to establish the diagnosis of WED/RLS were first described by The International Restless Legs Syndrome Study Group (IRLSSG), namely: (i) an urge to move the legs, usually accompanied, or caused by uncomfortable and unpleasant sensations in the legs; (ii) these symptoms begin or worsen during periods of rest or inactivity, such as lying or sitting; (iii) are partially or totally relieved by movement; and (iv) symptoms are worse in the evening or nighttime.11 In 2013, special considerations of WED/RLS for children were determined.12 According to these considerations: (i) a child should be able to describe its symptoms in his/her own words; (ii) the person to diagnose WED/RLS in children and adolescents should be aware of the typical words used for the definition of disease; (iii) language and cognitive development rather than child’s age is important for WED/RLS diagnosis; (iv) the WED/RLS of children leads to behavioral and educational changes unlike adults; (v) periodic limb movements may be seen prior to WED/RLS diagnosis in some instances. We aimed to study the incidence of WED/RLS among children with iron deficiency, or iron deficiency anemia, or both and the relationship between WED/RLS prevalence and serum ferritin levels in this study. Our hypothesis was that WED/RLS frequency was much higher among children with iron deficiency than the normal population.     

Clinical efficacy and safety of intravenous ferric carboxymaltose treatment of pediatric restless legs syndrome and periodic limb movement disorder

BackgroundIron supplementation is the most commonly considered treatment option for children with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD); however, there is a scarcity of evidence on the effectiveness of intravenous preparations. In this study, we evaluated the effectiveness and tolerability of intravenous ferric carboxymaltose (IV FCM) on clinical symptoms and iron indices in children with RLS or PLMD.MethodsThis was a single-center retrospective data analysis. Children with a diagnosis of RLS or PLMD, who underwent a single infusion of IV FCM, were included. Clinical Global Impression (CGI) Scale scores, serum ferritin, and serum iron profile at baseline and after eight weeks post infusion were obtained. Adverse effects were assessed.ResultsThirty-nine children received IV FCM, 29 with RLS and 10 with PLMD. Pre-infusion CGI-Severity revealed moderate illness, with post-infusion CGI-Improvement between “very much improved” and “much improved”. Ferritin increased from 14.6 μg/L ± 7.01 to 112.4 μg/L ± 65.86 (p < 0.00001), together with improvements in iron, total iron binding capacity, and transferrin levels from baseline to post-treatment. When compared to children with RLS, those with PLMD had a similar improvement in clinical symptoms and laboratory parameters. Seven subjects (14.3%) experienced one or two adverse events; all were mild.ConclusionsChildren with RLS and PLMD responded to IV iron supplementation with improvement in both clinical severity and laboratory parameters. Treatment was well tolerated. Although larger, randomized-controlled trials are needed, IV FCM appears to be a promising alternative to oral iron supplementation for the treatment of pediatric RLS or PLMD.     

Iron deficiency with normal ferritin levels in restless legs syndrome

This report describes a patient with iron deficiency in bone marrow examination and iron-responsive restless legs syndrome (RLS), in whom serum ferritin levels were well above the conventional cutoff for considering iron deficiency. The predictive value of serum ferritin for iron deficiency in RLS depends on the cutoff employed, on the pre-test likelihood of iron deficiency and on coexisting inflammatory conditions. Bone marrow examination is helpful when ferritin levels are equivocal.     

Prevalence of RLS among subjects with chronic liver disease and its effect on sleep and mood

BackgroundEarlier studies have shown that prevalence of RLS among patients with chronic liver disease (CLD) ranges between 6.6% and 100%. However, most of these studies had used questionnaires to diagnose RLS reported contradictory findings regarding risk factors for RLS. This study was planned to assess prevalence, severity and correlates of RLS among patients with CLD. We also intend to assess effect of RLS on sleep and mood in this population.MethodsAdult population with CLD was included after excluding potential confounders. Etiology of CLD was investigated. Severity of liver disease was assessed using three variables- Child-Turcotte-Pugh (CTP) grade; Model for end-stage liver disease (MELD) score, and as presence of compensated or decompensated liver disease. Acute on chronic liver failure was also defined as per APASL criteria. RLS was diagnosed on clinical interview and examination. To assess the severity of RLS international RLS severity rating scale was used. Diagnosis of insomnia and depression was made using insomnia severity index and patient health questionnaire (PHQ-9) along with clinical examination, respectively. Sleep quality was assessed by Pittsburg Sleep Quality Index- Hindi version.ResultsThis sample had predominance of males (78.6%), average age of subjects was 48.70 + 12.31 years and 98.5% subjects had decompensated liver disease. RLS was reported by 19.1% subjects and 2.3% had positive family history of RLS. Subjects with RLS had lower serum iron and serum ferritin compared to subjects without RLS. Among subjects having RLS, 60% had moderately severe symptoms, 32% had severe symptoms and 4% had very severe RLS. Subjects with RLS had greater chances of having depression and poor sleep quality.ConclusionPresent study shows that prevalence of RLS among patients with CLD is greater than population prevalence. Iron deficiency increased risk for having RLS. Subjects with RLS had poorer sleep quality and RLS increased chances of having insomnia and depression.