Sensory aspects of restless legs syndrome: Clinical, neurophysiological and neuroimaging prospectives.

Restless Legs Syndrome (RLS) is a complex sensorimotor disorder, classified among the sleep-related movement disorders. Although sensory symptoms appear as key features of the disorder, they are still poorly characterized from a clinical perspective and conceptualized from a pathophysiological point of view. In this review, we aim to describe the clinical and functional substrates of RLS, focusing mainly on its sensory symptoms and on their neurophysiological and anatomical correlates. Knowledge of both subjective sensory symptoms and objective sensory signs are still controversial. Current data also indicate that the sensory component of RLS seems to be subserved by anomalies of sensorimotor integration and by mechanism of central sensitization. Overall, electrophysiological findings highlight the involvement of multiple generators in the pathogenesis of RLS, eventually resulting in an increased nervous system excitability and/or alterations in inhibition within the somatosensory and nociceptive pathways. Structural and functional neuroimaging data show the involvement of several crucial areas and circuits, among which the thalamus appears to play a pivotal role. A holistic approach looking at brain connectivity, structural or functional abnormalities, and their interplay with molecular vulnerability and neurotransmitter alterations is warranted to disentangle the complex framework of RLS.

Large Muscle Group Movements during Sleep in Restless Leg Syndrome: Neurophysiological and Clinical Implications.

STUDY OBJECTIVES: Recently, criteria have been drawn up for Large Muscle group Movements during sleep (LMM), defined as movements lasting for 3-45 seconds in adults, which are often accompanied by changes in sleep stage, arousals, and increases in heart rate. The aim of this study was to characterize LMM in RLS, in order to better evaluate their impact on the neurophysiology of the disorder and, therefore, the possible clinical implications. METHODS: Consecutive, drug-free patients diagnosed with RLS and controls, aged 18 years or more, were retrospectively enrolled. Leg movement activity - short-interval (SILMS), periodic (PLMS) and isolated (ISOLMS) leg movements during sleep - and LMM were detected and scored. RESULTS: One-hundred patients and 67 controls were recruited. All movement measures were significantly higher in RLS. A significant positive correlation was found between LMM and ISOLMS index but not PLMS index in both groups. LMM index showed a significant negative correlation with total sleep time, sleep efficiency, and percentage of sleep stages N3 and R, as well as a significant positive correlation with number of awakenings, and percentage of sleep stages N1 and N2 only in patients with RLS. No significant correlation was found for either LMM or PLMS index and RLS severity. CONCLUSIONS: Different types of movements, including SILMS, ISOLMS, and LMM, play somewhat distinct roles in sleep neurophysiology in RLS. Notably, LMM, a newly recognized category of movements, demonstrate associations with sleep architecture instability and fragmentation, arousals, and awakenings, suggesting potential clinical implications.

Individualized approaches to pediatric chronic insomnia: Advancing precision medicine in sleep disorders.

The manifestations of chronic insomnia undergo age-related changes. In younger infants and children, behavioral insomnia emerges as the most prevalent form and typically responds to behavioral interventions. However, distinct clusters of clinical presentations suggest the presence of various phenotypes, potentially implicating the primary involvement of specific neurotransmitters. These conceptualizations, coupled with genetic studies on pleiotropy and polygenicity, may aid in identifying individuals at risk of persistent insomnia into adulthood and shed light on novel treatment options. In school-age children, the predominant presentation is sleep-onset insomnia, often linked with nighttime fears, anxiety symptoms, poor sleep hygiene, limit-setting issues, and inadequate sleep duration. The manifestations of insomnia in adolescence correlate with the profound changes occurring in sleep architecture, circadian rhythms, and homeostatic processes. The primary symptoms during adolescence include delayed sleep onset, sleep misperception, persistent negative thoughts about sleep, and physiological hyperarousal-paralleling features observed in adult insomnia. An approach centered on distinct presentations may provide a framework for precision-based treatment options. Enhanced comprehension of insomnia's manifestations across diverse developmental stages can facilitate accurate assessment. Efforts to subtype insomnia in childhood align with this objective, potentially guiding the selection of appropriate treatments tailored to individual neurobiological, clinical, and familial features.

Targeting the adenosinergic system in restless legs syndrome: A pilot, "proof-of-concept" placebo-controlled TMS-based protocol.

Restless Legs Syndrome (RLS) is a common sleep disorder characterized by an urge to move the legs that is responsive to movement (particularly during rest), periodic leg movements during sleep, and hyperarousal. Recent evidence suggests that the involvement of the adenosine system may establish a connection between dopamine and glutamate dysfunction in RLS. Transcranial magnetic stimulation (TMS) is a non-invasive electrophysiological technique widely applied to explore brain electrophysiology and neurochemistry under different experimental conditions. In this pilot study protocol, we aim to investigate the effects of dipyridamole (a well-known enhancer of adenosinergic transmission) and caffeine (an adenosine receptor antagonist) on measures of cortical excitation and inhibition in response to TMS in patients with primary RLS. Initially, we will assess cortical excitability using both single- and paired-pulse TMS in patients with RLS. Then, based on the measures obtained, we will explore the effects of dipyridamole and caffeine, in comparison to placebo, on various TMS parameters related to cortical excitation and inhibition. Finally, we will evaluate the psycho-cognitive performance of RLS patients to screen them for cognitive impairment and/or mood-behavioral dysfunction, thus aiming to correlate psycho-cognitive findings with TMS data. Overall, this study protocol will be the first to shed lights on the neurophysiological mechanisms of RLS involving the modulation of the adenosine system, thus potentially providing a foundation for innovative "pharmaco-TMS"-based treatments. The distinctive TMS profile observed in RLS holds indeed the potential utility for both diagnosis and treatment, as well as for patient monitoring. As such, it can be considered a target for both novel pharmacological (i.e., drug) and non-pharmacological (e.g., neuromodulatory), "TMS-guided", interventions.

Age related disparities in sleep apnea diagnosis using a wearable device: Implications of 4% vs. 3% hypopnea scoring criteria.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) diagnosis relies on the Apnea-Hypopnea Index (AHI), with discrepancies arising from the 3% and 4% desaturation criteria. This study investigates age-related variations in OSA severity classification, utilizing data from 1201 adult patients undergoing Home Sleep Apnea Testing (HSAT) with SleepImage Ring@. METHODS: The study employs Bland-Altman analysis to compare AHI values obtained with the 3% and 4% desaturation criteria. Age-stratified analysis explores discrepancies across different age groups. RESULTS: The analysis reveals a systematic bias favoring the 3% criterion, impacting the quantification of apnea events. Age-specific patterns demonstrate diminishing agreement between criteria with increasing age. CONCLUSION: This comprehensive study underscores the importance of standardized criteria in OSA diagnosis. The findings emphasize age-specific considerations and ethical concerns, providing crucial insights for optimizing patient care and advancing sleep medicine practices.

Unveiling the pathophysiology of restless legs syndrome through transcriptome analysis.

The aim of this study was to analyze signaling pathways associated with differentially expressed messenger RNAs in people with restless legs syndrome (RLS). Seventeen RLS patients and 18 controls were enrolled. Coding RNA expression profiling of 12,857 gene transcripts by next-generation sequencing was performed. Enrichment analysis by pathfindR tool was carried-out, with p-adjusted ≤0.001 and fold-change ≥2.5. Nine main different network groups were significantly dysregulated in RLS: infections, inflammation, immunology, neurodegeneration, cancer, neurotransmission and biological, blood and metabolic mechanisms. Genetic predisposition plays a key role in RLS and evidence indicates its inflammatory nature; the high involvement of mainly neurotropic viruses and the TORCH complex might trigger inflammatory/immune reactions in genetically predisposed subjects and activate a series of biological pathways-especially IL-17, receptor potential channels, nuclear factor kappa-light-chain-enhancer of activated B cells, NOD-like receptor, mitogen-activated protein kinase, p53, mitophagy, and ferroptosis-involved in neurotransmitter mechanisms, synaptic plasticity, axon guidance, neurodegeneration, carcinogenesis, and metabolism.

Sleep and follow-up characteristics of Hispanic patients: Insights from a comparative analysis with White patients in polysomnographic split-night studies.

BACKGROUND: Limited attention has been given to exploring the efficacy of titration in split-night polysomnography (PSG) and the factors influencing adherence to continuous positive airway pressure (CPAP) therapy. This study aims to evaluate the severity of OSA and PSG parameters in HP compared to WP. METHODS: Split-night PSG studies conducted on adults. Participants were categorized based on self-reported ethnicity as either HP or WP. RESULTS: The study enrolled 50 WP (15 women, 35 men, mean age 60.5 ± 13.60 years, mean BMI 34.2 ± 7.48) and 45 HP (24 women, 21 men, mean age 54.9 ± 13.06 years, mean BMI 37.3 ± 7.88). HP exhibited a mean apnea-hypopnea index (AHI) of 51.1 ± 33.67, saturation nadir of 77.8 ± 10.19, and time spent with saturation <90% of 21.0 ± 26.93 min. In WP, the mean AHI was 39.2 ± 24.49, saturation nadir 81.6 ± 9.04, and time spent <90% was 10.4 ± 17.17 min. All observed differences were statistically significant (p < 0.05). Auto CPAP was prescribed to all patients, with adherence at 3-4 months being 75% ± 30 for HP, with a usage of 5.5 ± 2.2 h, and a residual AHI of 3 ± 3.5. In WP, adherence was 79% ± 30, usage was 5.9 ± 2.1 h, and residual AHI was 3.6 ± 6.2. None of these differences reached statistical significance. Among HP, 37% missed follow-up appointments compared to 12% of WP. More HP used full-face masks, while more WP preferred nasal masks. CONCLUSIONS: HP exhibited significantly worse OSA parameters during the diagnostic phase of PSG compared to WP. HP had a significantly higher no-show percentage than WP. CPAP adherence and residual AHI were not statistically different, but more HP missed follow-up appointments than WP.

Changes in time structure of periodic leg movements during sleep in restless legs syndrome: Effects of sex and age.

BACKGROUND: The objective of this study was to check the hypothesis that in women with restless legs syndrome (RLS) different changes occur in periodic leg movements during sleep (PLMS) during the post-menopausal period (using >50 years as a proxy) than in men of the same age. METHODS: We recruited 36 untreated patients aged 18-50 years (19 men, median age 40 years, and 17 women, median age 37 years) while the remaining 67 were >50 years old (24 men, median age 66.6 years, and 43 women, median age 60.0 years). Leg movement activity during sleep was analyzed by means of an approach utilizing indexes especially suitable to assess leg movement periodicity. RESULTS: No significant difference was seen between men in the two age groups; conversely, in women, a clear and significant increase in Periodicity Index was observed in the older group, along with a decrease in isolated leg movements. In women, a clear age-related enhancement of PLMS was found in the intermovement interval graphs, especially in the 16-22 s range, which was more evident than that observed in men. The results remained unchanged also when they were replicated by selecting only subjects aged 18-45 years vs. those aged >55 years. CONCLUSIONS: Our findings indicate that assessing PLMS in women after menopause is clinically relevant because they are probably connected with the hormonal fluctuations of this period of life. Translationally, identifying and addressing PLMS in post-menopausal women is crucial for optimizing their sleep health and addressing potential health risks associated with sleep disturbances.

Polysomnographic features associated with clonazepam and melatonin treatment in isolated REM sleep behavior disorder: Time for new therapeutic approaches?

AIMS: Although clonazepam (CLO) and melatonin (MLT) are the most frequently used treatments for REM sleep behavior disorder, the polysomnographic features associated with their use are little known. The aim of this study was to evaluate polysomnographic and clinical parameters of patients with idiopathic/isolated REM sleep behavior disorder (iRBD) treated chronically with CLO, sustained-release MLT, alone or in combination, and in a group of drug-free iRBD patients. METHODS: A total of 96 patients were enrolled: 43 drug-free, 21 with CLO (0.5-2 mg), 20 with sustained-release MLT (1-4 mg), and 12 taking a combination of them (same doses). Clinical variables and polysomnography were collected. RESULTS: Although clinical improvement was reported in all groups, MLT impacted sleep architecture more than the other treatments, with significant and large increase in N3 stage, moderate reduction in N2 and REM sleep, and moderate increase in REM latency. CLO moderately increased the percentage of both REM sleep and especially N2, while reducing N1 and wakefulness. Patients treated with both CLO and MLT did not show major changes in sleep architecture. CONCLUSION: These results suggest that the administration of MLT or CLO impacts (positively) on sleep parameters of iRBD patients. However, there is a need to better stratify patients, in order to treat them in a targeted manner, depending on the patient's individual sleep architecture and expected differential effects of these agents.

Rethinking the Role of Orexin in the Regulation of REM Sleep and Appetite.

Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the current evidence on the role of orexin in the modulation of sleep and wakefulness and highlights that orexin should be considered essentially as a neurotransmitter inhibiting REM sleep and, to a much lesser extent, a wake promoting agent. Subsequently, the relationship between orexin, REM sleep, and appetite regulation is examined in detail, shedding light on their interconnected nature in both physiological conditions and diseases (such as narcolepsy, sleep-related eating disorder, idiopathic hypersomnia, and night eating syndrome). Understanding the intricate relationship between orexin, REM sleep, and appetite regulation is vital for unraveling the complex mechanisms underlying sleep-wake patterns and metabolic control. Further research in this field is encouraged in order to pave the way for novel therapeutic approaches to sleep disorders and metabolic conditions associated with orexin dysregulation.

Frequency of antidepressant use and clinical characteristics of children and adolescents undergoing polysomnography: an observational study.

BACKGROUND: Antidepressants are increasingly used in children for various psychiatric disorders but also for sleep disorders such as insomnia; however, it is currently unknown how many children undergoing polysomnography (PSG) are taking anti-depressants. The aims were: to determine the frequency of use of antidepressants in paediatric patients referred for PSG, to identify the most common antidepressants used, to investigate the reasons for their use, and to analyse the PSG parameters found in children taking antidepressants. METHOD: An observational cross-sectional retrospective chart review of all children undergoing PSG at Seattle Children's Hospital from 6/14/2020 to 12/8/2022 was carried out. Clinical features (such as diagnosis, especially psychiatric), sleep disorders (such as insomnia and restless sleep), and class of antidepressant used [selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCA), or atypical antidepressants], and PSG parameters were collected for further analysis. RESULTS: Among 3,371 patients who underwent PSG during the study, 367 children were selected who were taking one antidepressant only (154 boys and 213 girls, mean age was 13.7 ± years 3.69). A significantly decreased sleep stage N3 was found in girls, who were older than boys. Children with insomnia had longer sleep latency than children without, but more N3. There was a prolonged rapid eye movement (REM) sleep latency in children with attention-deficit/hyperactivity disorder and children with autism. REM latency was longer and REM percentage smaller in children taking SNRIs. Periodic leg movement index ≥ 5/hour was found in a higher number of children taking SSRIs or SNRIs (24.9%) than in subjects taking TCA or atypical antidepressants (13.3%) (chi-square 5.29, p = 0.013). CONCLUSIONS: Child and adolescent psychiatrists should question about the effects on sleep (both positive and negative) after initiating therapy with antidepressant medications.

Sleep counts! Role and impact of sleep in the multimodal management of multiple sclerosis.

BACKGROUND: In the last years, research on pharmacotherapy and non-pharmacological approaches to Multiple Sclerosis (MS) has significantly increased, along with a greater attention to sleep as a clinical outcome measure. This review aims to update the state of the art on the effects of MS treatments on sleep, but above all to evaluate the role of sleep and its management within the current and future therapeutic perspectives for MS patients. METHOD: A comprehensive MEDLINE (PubMed)-based bibliographic search was conducted. This review includes the 34 papers that met the selection criteria. RESULTS: First-line disease modifying therapies (especially the interferon-beta) seem to have a negative impact on sleep, assessed subjectively or objectively, while second-line treatments (in particular, natalizumab) do not seem to lead to the onset of daytime sleepiness (also evaluated objectively) and, in some cases, an improvement in sleep quality has been observed as well. Management of sleep is considered a major factor in modifying disease progression in pediatric MS; however, probably because only fingolimod has recently been approved in children, information is still scarce in this group of patients. CONCLUSIONS: Studies on the effect of drugs and non-pharmacological treatments for MS on sleep are still insufficient and there is a lack of investigations on the most recent therapies. However, there is preliminary evidence that melatonin, chronotherapy, cognitive-behavioral therapy, and non-invasive brain stimulation techniques might be further assessed as adjuvant therapies, thus representing a promising field of research.

Periodic leg movements during sleep associated with antidepressants: A meta-analysis.

Studies explicitly reporting data concerning the evaluation of the effect of antidepressants on the periodic leg movements during sleep (PLMS) index obtained by polysomnography were reviewed and selected. A random-effects model meta-analysis was carried out. The level of evidence was also assessed for each paper. Twelve studies were included in the final meta-analysis, seven interventional and five observational. Most studies were characterized by Level III evidence (non-randomized controlled trials), with the exception of four studies, which were classified as Level IV (case series, case-control, or historically controlled studies). Selective serotonin reuptake inhibitors (SSRIs) were used in seven studies. The analysis of the assessments involving SSRIs or venlafaxine showed an overall large effect size, clearly much larger than that obtained with studies using other antidepressants. Heterogeneity was substantial. This meta-analysis confirms the previous reports on the increase in PLMS often associated with the use of SSRIs (and venlafaxine); however, the absent or smaller effect of the other categories of antidepressants needs to be confirmed by more numerous and better controlled studies.

Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations.

After a detailed description of orexins and their roles in sleep and other medical disorders, we discuss here the current clinical evidence on the effects of dual (DORAs) or selective (SORAs) orexin receptor antagonists on insomnia with the aim to provide recommendations for their further assessment in a context of personalized and precision medicine. In the last decade, many trials have been conducted with orexin receptor antagonists, which represent an innovative and valid therapeutic option based on the multiple mechanisms of action of orexins on different biological circuits, both centrally and peripherally, and their role in a wide range of medical conditions which are often associated with insomnia. A very interesting aspect of this new category of drugs is that they have limited abuse liability and their discontinuation does not seem associated with significant rebound effects. Further studies on the efficacy of DORAs are required, especially on children and adolescents and in particular conditions, such as menopause. Which DORA is most suitable for each patient, based on comorbidities and/or concomitant treatments, should be the focus of further careful research. On the contrary, studies on SORAs, some of which seem to be appropriate also in insomnia in patients with psychiatric diseases, are still at an early stage and, therefore, do not allow to draw definite conclusions.

Periodic leg movements during sleep and iron status in infants with prematurity, Down syndrome and Prader-Willi syndrome.

Sleep disturbances including bedtime problems and night awakenings are common during infancy. Polysomnography during the first years of life is performed mainly to rule out sleep-disordered breathing; however, sleep-related movement disorders can constitute a significant contributor to sleep disruption in this age group. Almost no studies have investigated the presence of periodic limb movements during sleep and underlying iron deficiency in infants, especially in those born preterm or with an underlying genetic syndrome. In this retrospective study we included infants 3-24 months referred for polysomnography for snoring or frequent nocturnal awakenings. All children had bloodwork (ferritin and haemoglobin) conducted within 3 months of the overnight sleep study. We studied 79 infants, including 31 (39.2%) full-term without diagnosis, 10 (12.7%) born premature, 16 (20.3%) with Down syndrome, 15 (19.0%) with Prader-Willi syndrome, and the remaining seven (8.9%) had various disorders. Compared with those with Down syndrome, Prader-Willi syndrome and full-term infants, those with prematurity showed a statistically significant elevated periodic limb movement index and lower ferritin levels than the other groups. Both ferritin (r = -0.18) and haemoglobin (r = -0.30) were negatively correlated with periodic limb movement index; however, this correlation reached statistical significance only for haemoglobin. Iron deficiency is associated with increased periodic leg movements during sleep in infants. Infants with prematurity had higher periodic limb movement index and lower ferritin levels than infants with Down syndrome, Prader-Willi syndrome or without diagnosis.

Actigraphy evaluation before and after intravenous ferric carboxymaltose in 3 children with restless sleep disorder.

Restless sleep disorder has been described in the literature as a disorder affecting children and presenting with large muscle movements during sleep with an index of 5 events/h or more, leading to daytime impairment including sleepiness or behavioral problems. Children with restless sleep disorder have been found to have low ferritin levels. Studies with iron supplementation both oral or intravenous have been shown effective in clinically improving both nighttime and daytime symptoms. However objective data of the improvement is lacking. Repeating polysomnography is expensive, and alternative methods of assessing large muscle movements are needed. In this small case series we present actigraphy results in 3 children with restless sleep disorder collected for 1 week, a week before and 8 weeks after intravenous iron supplementation. Although actigraphy parameters were not highly consistent between our 3 patients, improvement in symptoms tend to parallel sleep parameters in actigraphy. CITATION: Chu ZYB, DelRosso LM, Mogavero MP, Ferri R. Actigraphy evaluation before and after intravenous ferric carboxymaltose in 3 children with restless sleep disorder. J Clin Sleep Med. 2023;19(3):633-637.

Effects of bupropion and SSRI antidepressants on leg movement activity and chin muscle tone during sleep in adolescents.

STUDY OBJECTIVES: To evaluate the effects of bupropion on periodic limb movements during sleep (PLMS) and chin electromyography tone in children taking it for their mood disorder, compared to the effects of selective serotonin reuptake inhibitors (SSRIs) and of bupropion combined with SSRIs. METHODS: Six adolescents (aged 16.0 ± 0.63 years) taking bupropion alone and 6 adolescents (aged 15.9 ± 1.36 years) taking bupropion in combination with an SSRI antidepressant were recruited, along with 10 adolescents (aged 16.2 ± 0.2 years) taking different SSRIs, and they were also enrolled together with 17 age- and sex-matched control patients (aged 15.5 ± 1.26 years). Polysomnographic studies were obtained, and participants' leg movement activity during sleep and muscle tone were assessed quantitatively (atonia index) during all sleep stages. RESULTS: Participants taking SSRIs showed PLMS indices significantly higher than those of control patients, whereas adolescents taking bupropion showed only slightly increased indexes of nonperiodic leg movements during sleep. No differences in PLMS were observed between adolescents taking bupropion alone or in association with SSRIs. The atonia index showed, within each sleep stage, the lowest values in the 2 groups taking SSRIs and the highest in the control patients; adolescents taking bupropion alone tended to show values slightly smaller than those of the control patients. CONCLUSIONS: We found that similar to adults, in adolescents SSRIs but not bupropion are associated with increased PLMS. Bupropion also seems to counteract the SSRI-induced increase of PLMS, when administered in combination; thus, the dopaminergic effect of bupropion seems to outmatch the antidopaminergic action of SSRIs. Conversely, bupropion does not counteract the effects of SSRIs on chin electromyography tone. CITATION: DelRosso LM, Mogavero MP, Fickensher A, Bruni O, Schenck CH, Ferri R. Effects of bupropion and SSRI antidepressants on leg movement activity and chin muscle tone during sleep in adolescents. J Clin Sleep Med. 2023;19(1):151-161.

Assessment of Executive and Cognitive Functions in Children with Restless Sleep Disorder: A Pilot Study.

Restless sleep disorder affects children and is characterized by frequent nocturnal movements, iron deficiency, and daytime symptoms such as poor school performance or behavioral problems. Although sleep parameters have been thoroughly studied and daytime sleepiness has been previously assessed, neurocognitive and executive functions have not. In this study, we evaluated neurocognitive functions in a group of 13 children diagnosed with restless sleep disorder using the National Institute of Health Toolbox (NIH toolbox). The mean age was 10.62 (S.D. 2.785). Among them, seven were male and six were female. The fully corrected T-scores (adjusted for demographic variables: age, ethnicity, and education level) showed the lowest values for the Flanker test (selective attention) and dimensional change card sorting test (cognitive flexibility and inhibitory control), with a very large effect size vs. the corresponding expected frequencies. For all the other tests, the average scores were 50; however, individual children scored low on pattern recognition and two composite scores (fluid and total). In conclusion, these data support the fact that cognitive functions are affected in children with restless sleep disorder, especially selective attention. Clinicians must recognize sleep disorders and daytime impairment in order to promptly intervene and prevent cognitive impairments.

Clinical efficacy and safety of intravenous ferric carboxymaltose treatment for restless legs symptoms and low serum ferritin in children with autism spectrum disorder.

BACKGROUND: Restless legs syndrome (RLS) may be underdiagnosed in children with autism spectrum disorder (ASD) due to difficulty expressing the symptoms in their own words. In addition, administration of oral iron may be particularly difficult in children with ASD. METHODS: This was a retrospective, open-label case series of children with ASD, restless legs (RL) symptoms, and serum ferritin <30 µg/L, who either had failed or did not tolerate oral iron, and were subsequently treated with intravenous (IV) ferric carboxymaltose (FCM). Patients received a single dose of IV FCM, 15 mg/kg up to a maximum dose of 750 mg. Data collected pre- and eight weeks post-infusion included presenting symptoms, serum ferritin, iron profile, and Clinical Global Impression Scale (CGI-Severity pre- and CGI-Improvement post-infusion). Adverse effects were assessed. RESULTS: Nineteen children, 4-11 years old (12 male, median age 6, interquartile range (IQR 4-11) were included. A definite RLS diagnosis was identified in 6 verbal children (31.6%). RL symptoms (designated probable RLS) in the 13 other children met all RLS diagnostic criteria except "improvement of symptoms with movement," which was not definitively determined. Baseline median values were: ferritin 10 µg/L (IQR 10-16), iron 66.5 µg/dL (IQR 57-96), TIBC 382 µg/dL (IQR 360-411) and transferrin saturation 19% (IQR 14-28). Median CGI-S was 4 (moderate symptoms) (IQR 3-4). At eight weeks after IV FCM, all measures were improved. Median ferritin was 68 µg/L (IQR 62.5-109, p < 0.00045). Median CGI-I was 1 (very much improved) (IQR 1-2). All children meeting definite RLS criteria improved. Three children in the probable RLS group did not improve. Children meeting the full RLS criteria had lower baseline ferritin levels than those with a probable diagnosis (9 µg/L, IQR 9-10 vs. 13 µg/L, IQR 10-16, Mann-Whitney test p < 0.045). Adverse effects included lightheadedness, gastrointestinal discomfort, fever, and headache among others. CONCLUSIONS: The majority of children (84.2%) with ASD, restless legs symptoms, and serum ferritin <30 µg/L had clinical improvement and significantly better serum iron parameters after a single IV FCM infusion. Although larger, randomized trials are needed, IV FCM appears to be a promising treatment for this subset of children with ASD.