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Iron deficiency (ID) and restlessness are associated with sleep/wake-disorders (e.g., restless legs syndrome (RLS)) and neurodevelopmental disorders (attention deficit/hyperactivity and autism spectrum disorders (ADHD; ASD)). However, a standardized approach to assessing ID and restlessness is missing. We reviewed iron status and family sleep/ID history data collected at a sleep/wake behavior clinic under a quality improvement/quality assurance project. Restlessness was explored through patient and parental narratives and a 'suggested clinical immobilization test'. Of 199 patients, 94% had ID, with 43% having a family history of ID. ADHD (46%) and ASD (45%) were common conditions, along with chronic insomnia (61%), sleep-disordered breathing (50%), and parasomnias (22%). In unadjusted analysis, a family history of ID increased the odds (95% CI) of familial RLS (OR: 5.98, p = 0.0002, [2.35-15.2]), insomnia/DIMS (OR: 3.44, p = 0.0084, [1.37-8.64]), and RLS (OR: 7.00, p = 0.01, [1.49-32.93]) in patients with ADHD, and of insomnia/DIMS (OR: 4.77, p = 0.0014, [1.82-12.5]), RLS/PLMS (OR: 5.83, p = 0.009, [1.54-22.1]), RLS (OR: 4.05, p = 0.01, [1.33-12.3]), and familial RLS (OR: 2.82, p = 0.02, [1.17-6.81]) in patients with ASD. ID and restlessness were characteristics of ADHD and ASD, and a family history of ID increased the risk of sleep/wake-disorders. These findings highlight the need to integrate comprehensive blood work and family history to capture ID in children and adolescents with restless behaviors.

Current evidence suggests that iron deficiency (ID) plays a key role in the pathogenesis of conditions presenting with restlessness such as attention deficit hyperactivity disorder (ADHD) and restless legs syndrome (RLS). In clinical practice, ID and iron supplementation are not routinely considered in the diagnostic work-up and/or as a treatment option in such conditions. Therefore, we conducted a scoping literature review of ID guidelines. Of the 58 guidelines included, only 9 included RLS, and 3 included ADHD. Ferritin was the most frequently cited biomarker, though cutoff values varied between guidelines and depending on additional factors such as age, sex, and comorbidities. Recommendations surrounding measurable iron biomarkers and cutoff values varied between guidelines; moreover, despite capturing the role of inflammation as a concept, most guidelines often did not include recommendations for how to assess this. This lack of harmonization on the interpretation of iron and inflammation biomarkers raises questions about the applicability of current guidelines in clinical practice. Further, the majority of ID guidelines in this review did not include the ID-associated disorders, ADHD and RLS. As ID can be associated with altered movement patterns, a novel consensus is needed for investigating and interpreting iron status in the context of different clinical phenotypes.

Background: Behavioral observations support clinical in-depth phenotyping but phenotyping and pattern recognition are affected by training background. As Attention Deficit Hyperactivity Disorder, Restless Legs syndrome/Willis Ekbom disease and medication induced activation syndromes (including increased irritability and/or akathisia), present with hyperactive-behaviors with hyper-arousability and/or hypermotor-restlessness (H-behaviors), we first developed a non-interpretative, neutral pictogram-guided phenotyping language (PG-PL) for describing body-segment movements during sitting., Methodology & Results: The PG-PL was applied for annotating 12 1-min sitting-videos (inter-observer agreements >85%->97%) and these manual annotations were used as a ground truth to develop an automated algorithm using OpenPose, which locates skeletal landmarks in 2D video. We evaluated the algorithm's performance against the ground truth by computing the area under the receiver operator curve (>0.79 for the legs, arms, and feet, but 0.65 for the head). While our pixel displacement algorithm performed well for the legs, arms, and feet, it predicted head motion less well, indicating the need for further investigations., Conclusion: This first automated analysis algorithm allows to start the discussion about distinct phenotypical characteristics of H-behaviors during structured behavioral observations and may support differential diagnostic considerations via in-depth phenotyping of sitting behaviors and, in consequence, of better treatment concepts., (Copyright © 2020. Published by Elsevier Ltd.)

Iron deficiency (ID) is associated with sleep disorders, but standardized assessment of iron status in the diagnostic work-up and iron supplementation as treatment have not been considered in clinical practice. We investigated associations of ID with type and severity of sleep disorders and whether iron supplementation improves sleep-related symptoms. In 2017, we conducted a scoping review for the period 1972-2016 using the terms "iron deficiency anemia" and "sleep" on biomedical database search engines, and in 2019, we updated our review with an ad-hoc search. Among the 93 articles meeting our inclusion criteria, 74/93 studies investigated restless legs syndrome (RLS), 8/93 periodic limb movements in sleep (PLMs), 3/93 sleep disordered breathing (SDB), 6/93 general sleep disturbances (GSD), and 2/93 attention-deficit/ hyperactivity disorder related sleep disorders (ADHD-SDs). A statistically supported positive association with ID was found in 22/42 RLS, 3/8 PLMs, 1/2 SDB, 3/4 GSD, and 1/2 ADHD-SDs association studies. The ad-hoc literature search revealed eight additional association studies with a statistically supported positive association in 2/5 RLS, 1/1 SDB, 1/1 ADHD-SDs, and 1/1 restless sleep disorder (RSD) studies. Iron supplementation was beneficial in 29/30 RLS (including five randomized controlled trials [RCTs]), 1/1 SDB, and 2/2 GSD treatment studies. Iron supplementation was also beneficial in 2/2 RLS (including two RCTs), 1/1 GSD (RCT), and 1/1 RSD studies identified in the ad-hoc search. In pediatric populations, 1/1 RLS, 1/1 SDB, 2/5 PLMs, 2/3 GSD and 1/2 ADHD-SDs studies found positive associations, and 6/6 RLS and 2/2 GSD studies demonstrated a benefit with iron supplementation. In conclusion, iron investigation and supplementation should be considered in patients presenting with sleep disorders. To investigate the role of ID in sleep in the future, a harmonization of study designs, including outcome measures and standardized iron and inflammation status is necessary., Competing Interests: Conflicts of interest The authors do not have any conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Ltd.)