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PLMD)
Accepted Manuscript Title: Outcomes of long term iron supplementation in pediatric restless leg syndrome / periodic limb movement disorder (RLS/PLMD) Author: Thomas J. Dye, Sejal V Jain, Narong Simakajornboon PII: DOI: Reference:
S1389-9457(16)00044-7 http://dx.doi.org/doi: 10.1016/j.sleep.2016.01.008 SLEEP 3001
To appear in:
Sleep Medicine
Received date: Revised date: Accepted date:
21-8-2015 26-1-2016 27-1-2016
Please cite this article as: Thomas J. Dye, Sejal V Jain, Narong Simakajornboon, Outcomes of long term iron supplementation in pediatric restless leg syndrome / periodic limb movement disorder (RLS/PLMD), Sleep Medicine (2016), http://dx.doi.org/doi: 10.1016/j.sleep.2016.01.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Outcomes of Long Term Iron Supplementation in Pediatric Restless Leg Syndrome / Periodic Limb Movement Disorder (RLS/PLMD) Thomas J. Dye, MD 1,3*, Sejal V Jain, MD 1,3, Narong Simakajornboon, MD 2,3 1. Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 2. Division of Pulmonology and Sleep Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 3. Sleep Center, Cincinnati Children’s Hospital Medical Center
* Corresponding author Thomas J Dye, MD Division of Neurology Cincinnati Children’s Hospital Medical Center 3333 Burnet Ave, MLC 2015 Cincinnati, OH 45229 Phone: 513-636-7314 Fax: 513-636-1888 Email: [email protected]
This research was partly presented at SLEEP 2014 (the 28th Annual Meeting of the Associated Professional Sleep Societies), Minneapolis, Minnesota. Dr. Thomas Dye was a recipient of the 2014 Wayne Hening Young Investigator Award from the International RLS Study Group for this research.
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Highlights:
Iron therapy is an effective treatment for pediatric RLS/PLMD. Treatment results in improvement of PLMS indices and subjective symptoms. Long term improvement is sustained in the majority of patients
Abstract: Objectives: Restless Leg Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD) are thought to center around a genetically mediated sensitivity to iron insufficiency. Previous studies have shown the effectiveness of short term iron therapy in children with low iron storages. Little is known, however, about long term iron treatment in children with RLS and PLMD. Therefore, we performed this study to assess long term effect of iron therapy in children with RLS and PLMD. Methods: A retrospective chart review was performed for children who met the following criteria: A) diagnosed as having either RLS or PLMD, B) started on iron supplementation, C) followed for more than 2 years in a sleep clinic. Baseline values for iron, ferritin, and periodic limb movements of sleep index (PLMS index) were defined in the 3 months leading up to initiation of iron therapy. Values were also computed for follow up periods of 3-6 months, 1-2 years, and >2 years. Serum iron, ferritin and PLMS index were compared between baseline and all subsequent follow-ups. Results: 105 patients met inclusion criteria. 64 were diagnosed as having PLMD alone, 7 with RLS alone, and 35 as with both RLS and PLMD. The average age was 10.2±5.3 years. Compared to the baseline (27.4±12.1 ng/ml), the average ferritin values at 3-6 months (45.62±21.2 ng/ml, p <0.001, n=34), 1-2 years (52.0±48.3 ng/ml, p<0.001, n=63), and >2 years (54.7±40.5 ng/ml, p=<0.001, n=67) were all significantly increased. Inversely, compared to baseline (21±27.0/hr, n=66), PLMS index at 3-6 months (7.5±9.5/hr p <0.05, n=11), 1-2 years (6.9±8.9/hr, p<0.001, n=29), and >2 years (10±14.5/hr, p<0.001, n=31) were all significantly decreased. No significant change in serum iron was noted at any time points. Conclusion: While retrospective in nature, this study demonstrates sustained improvement in PLM index and adequate ferritin level more than 2 years after iron therapy in our RLS/PLMD cohort with Page 2 of 20 Page 2 of 20
long term follow up. Iron therapy appears to lead long lasting improvement in children with RLS/PLMD. Keywords: restless legs syndrome; periodic limb movements; iron; ferritin; pediatric sleep medicine
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1. Introduction: Restless legs syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a sensorimotor disorder characterized by a strong, unpleasant urge to move one’s legs. RLS symptoms typically become worse at night and with rest, and are improved by movements [1, 2]. Periodic limb movements in sleep (PLMS), are periodic, repetitive, and stereotyped movements, typically involving the lower extremities [1-3]. Periodic limb movement disorder (PLMD) is characterized by periodic episodes of repetitive, highly stereotyped limb movements that occur during sleep (PLMS), in conjunction with clinical sleep disturbance or fatigue that cannot be accounted for by another primary sleep disorder or other etiology [1, 2]. RLS and PLMD are distinct, but closely related entities with a strong genetic basis. This is particularly true for the early onset phenotype seen in pediatric patients [4-7]. Recent studies have indicated that RLS is common in the pediatric population. Large population studies in the US, Europe, Turkey, and Hong Kong have shown the estimated prevalence of RLS to be 1.71 - 1.9% for school aged children and 2% - 3.6% for adolescents [8-11]. Affected patients frequently report sleep disturbances, a lack of energy, an inability to concentrate, and a negative impact on mood [12]. The pathophysiology of RLS is complex. However, a common hypothesis centers around a heritable sensitivity to iron insufficiency [13]. This is believed to cause down regulation of subcortical and spinal dopaminergic pathways [14, 15], ultimately resulting in spinal cord hyperexcitability [16, 17]. Although there is emerging literature supporting medical therapy in children with RLS and PLMD, the experience with medications such as dopaminergic medication or alpha-2-delta ligands is still limited [18]. Therefore, iron therapy offers a safer alternative treatment and is usually considered the first line of treatment. There is increasing evidence of iron therapy in management of RLS and PLMD. Low levels of serum ferritin have been associated with RLS symptoms and elevated indices of periodic limb movements of sleep (PLMS index) in pediatric patients [19, 20]. Several studies have shown the benefit of iron therapy in decreasing PLMS index and reducing RLS symptoms in children [2026] as well as adults [27]. Other studies have indicated the benefit of raising serum ferritin above 50 ng/ml [20, 21]. However, as these studies only assessed the short term effect of iron therapy, there is limited data for long term treatment efficacy of iron supplementation in the pediatric RLS and PLMD population [28]. Hence, we performed this study to evaluate the long term effect of oral iron supplementation on ferritin level, PLMS index, and improvement of clinical symptoms. 2. Methods: The primary aim of this study was to evaluate whether oral iron supplementation leads to long lasting improvement of PLMS index and clinical symptoms, and sustained serum ferritin in children with RLS and PLMD. This was a retrospective study. The study was approved by the institutional review board (IRB) at the Cincinnati Children’s Hospital Medical Center (CCHMC).
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2.1 Subjects: Following institutional IRB approval, a retrospective database was developed utilizing the de-identified medical records. Patients meeting all the following criteria were included in the database. 1) Evaluation by a sleep medicine specialist 2) Diagnosis of RLS or diagnosis of PLMD In our center, iron therapy is the first line of treatment in children with RLS/PLMD who have serum ferritin less than 50 ng/ml. We have routinely used ferrous sulfate, either solution or tablet, with dosing at 3 mg elemental iron per kg per day, based upon patient’s weight. Children who receive iron therapy will normally have iron studies every 3-6 months. Dosing is then adjusted at this point based upon response with the goal of maintaining serum ferritin levels at or above 50 ng/mL. From the database, we selected the subjects starting in 2006 who were started on iron supplementation therapy for the treatment of RLS/PLMD and who were followed for at least 2 years in our sleep clinics. Using the iron supplementation start date as a baseline we selected data from 4 time periods based upon our typical monitoring and clinical follow up schedule at the CCHMC. The first period was defined as the 3 months preceding the initiation of iron therapy. The second through fourth periods were defined as 3-6 months, 1-2 years, and more than 2 years following iron initiation, respectively. The data collected at these time points included ferritin levels, iron levels, PLMS index on polysomnography, and changes in clinical symptoms. Subjective improvement in clinical symptoms was based upon review of clinical documentation created at the time of patient follow up. As our study aimed to evaluate long term improvement, the medical records at any follow up visit more than one year after iron therapy were reviewed for subjective improvements. Daytime sleepiness was defined as daytime naps in children over the age of 5 or falling asleep at inappropriate times during daytime activities including while dressing, playing alone, playing with others, watching TV, eating meals, going to the bathroom, or attending school. 2.2 Polysomnography: Polysomnography was performed with Grass System (Grass Telefactor West Warwick, Rhode Island). Subjects were studied for up to 12 hours in a quiet dark room with an ambient temperature of 24 degrees C, in the company of their parents. Subjects went to bed at their routine bedtime. The standard pediatric EEG montage was used. The following parameters were recorded simultaneously: body position, bilateral electro-occulogram, six channel electroencephalogram (F3M2, F4M1, C3M2, C4M1, O1M2, O2M1), chin electromyogram, anterior tibialis electromyogram, tracheal microphone, electrocardiogram pulse oximetry (Maximo), thoracic and abdominal inductance plethysmography, nasal pressure transducer (Protech, Mukilteo, WA) and end-tidal CO2 (BCI, Capnochecks). Sleep stages were scored by a certified sleep technologist according to the American Academy of Sleep Medicine (AASM) guidelines [3]. AASM standard definitions were used for sleep efficiency (SE), total sleep Page 5 of 20 Page 5 of 20
time, percentages of sleep stages (N1, N2, N3, or REM %), arousals, and arousal index (AI). Periodic limb movements in sleep (PLMS) were scored according to AASM scoring rules [3], and as were defined as significant limb movement (LM) events occurring in a PLM series. The LM events were defined as having a minimum duration of 0.5 seconds, a maximum duration of 10 seconds, with a minimum amplitude increase of 8 μV above baseline on EMG. PLM series (and therefore PLMS) were scored when four or more consecutive LMs occurred and were separated by at least 5 seconds and at most 90 seconds. As per AASM rules, respiratory related LMs were not included. 2.3 Definitions: RLS and PLMD were diagnosed based on ICSD-2 criteria [1, 2]. Only those meeting definite RLS diagnosis were included. The essential criteria for RLS include an urge to move or an unpleasant sensation in legs, which is worse during rest or periods of inactivity, is partially or totally relieved by movements, and is worse during evenings or nights. For definite RLS in children, these essential criteria have to be met along with either a description in the child’s own words that is consistent with leg discomfort, or the presence of two out of three supportive criteria (including sleep disturbance, positive family history in parents or siblings with definite RLS, or PLMs with index of 5 or more on polysomnography). PLMD was defined as periodic limb movements in sleep (PLMS) on polysomnography with frequency of 5/hour or more, which caused clinically significant sleep disturbance or daytime fatigue and was not explained by any other disorder [1, 2]. 2.4 Statistical analysis: The subject characteristics were presented as mean ± standard deviation and/or percentages. The subjects were grouped together during set periods meant to mimic our typical follow up schedules (every 3-6 months). Comparisons were made between values collected at all 4 time points as well as subgroups including 2 time points. A p value of < 0.05 was considered statistically significant. Data with normal distribution (serum iron) were compared using ANOVA. Data with non-normal distribution (PLMS index and ferritin) were analyzed using the Kruskal-Wallis Test (Nonparametric ANOVA). The Mann-Whitney test was used for sub group analysis. MySQL Server and MySQL Workbench were used for data storage and retrieval, and InStat was used for statistical analysis. 3. Results: 3.1: Subject Selection: Figure 1 and Table 1 represent the flow diagram for subject selection and subject characteristics. We identified 547 patients. Of these, 328 were treated with oral ferrous sulfate and 105 of these patients were followed in a sleep medicine clinic for more than 2 years. These 105 patients formed the core subject set which we examined and was comprised of 73 males (69.5%) and 32 females (30.5%) for a male to female ratio of 2.3:1, with a mean age of 10.2 years ± 5.3 years at start of iron therapy. The mean ages of each gender was similar Page 6 of 20 Page 6 of 20
(male 9.83 years vs. female 11.10 years p = NS), as was the mean PLMS index (male 14.6/hr vs. female 13.9/hr, p = NS).
3.2 Presenting symptoms and comorbid conditions (Table 1): Sleep onset insomnia was the most common presenting complaint. Sleep maintenance insomnia, restlessness, and leg movements or jerks during sleep were also common presenting complaints. Daytime sleepiness was less commonly reported at presentation. For comorbidities, obstructive sleep apnea syndrome (OSA) and epilepsy/seizures were common comorbid medical conditions. Attention deficit hyperactivity disorder, anxiety, and depression were common comorbid behavioral and psychiatric conditions.
3.3 Diagnosis and clinical responses to iron sulfate. Table 2 represents the distribution of the RLS and PLMD in our cohort with further subset classification based upon PLMS index. Of the 105 patients who met inclusion criteria 41 (39.1%) were diagnosed with RLS and 64 (61.0%) with PLMD. Of the 41 RLS patients, 34 had a PLMS index of ≥5/hr (32.4% of total, 82.9% of RLS group) and 7 had a PLMS index of <5/hr (6.7% of total, 17.1% of RLS group). 98 patients (93.3%) were found to have a PLMS index of ≥5/hr. In term of treatment responses; of the total population, 66/105 (62.86%) demonstrated sustained subjective improvements in their symptoms after iron therapy. Of patients in our study with elevated PLMS, 62/98 (63.27%) demonstrated subjective improvement. Of patients in our study diagnosed with RLS, 32/41 (78.05%) demonstrated subjective improvement.
3.4 Laboratory results. Table 3 represents changes in serum iron, ferritin and PLMS index at various time points during 2 years after iron therapy. The mean ferritin at baseline prior to oral ferrous sulfate therapy was 27.4 ±12.1 ng/ml (n=89). It was increased to 45.6 ± 21.2 ng/ml (n=34, p < 0.001) at 3 to 6 months, 52.0±48.3 ng/ml (n=63, p < 0.001) at 1 to 2 years, and 54.7± 40.46 ng/ml (n=67, p < 0.001) at more than 2 years. There were increases of 66%, 90%, and 100%, at 3 to 6 months, 1 to 2 years and at 2 years respectively (Figure 2).
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3.5 Polysomnography Results. Table 3 and Figure 3 shows the changes in PLMS index over different time periods. PLMS index were significantly decreased at all time periods following initiation of iron therapy. The mean PLMS index at baseline prior to initiation of iron therapy was 21.0/hr. There were decreases of 64%, 67%, and 52%, at 3 to 6 months, 1 to 2 years and at > 2 years respectively.
3.6 Concurrent Medication Use. Table 4 shows the use of concurrent medications. Dopaminergic medications were used by 12.4% (n=13) of patients at any point during the follow up period. Alpha-2-delta ligands were also used by 12.4% (n=13) of patients at any point during the follow up period. However, few patients were on a dopaminergic medication (n=2, 1.9%) or alpha-2-delta ligands (n=3, 2.9%) when iron supplementation was initiated. The use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) in this population was common (36.2%); including 18.1% of patients who were on this class of medication when iron was initiated. Table 5 details the differences in PLMS index amongst subgroups based upon concurrent medication use. The subgroups include those who were on SSRI/SNRIs before and/or after iron therapy, those who were never on SSRI/SNRIs, as well as those who were never on dopaminergic medications. The improvement of PLMS index after iron therapy was noted in all groups regardless of the use of these medications.
.
4 Discussion: This is the first study to evaluate the long term effects of iron treatment on PLMS index and ferritin levels in children with RLS and PLMD. This study demonstrates sustained improvement in PLMS index and maintenance of adequate ferritin levels more than 2 years after the initiation Page 8 of 20 Page 8 of 20
of iron therapy. Sustained clinical improvement was also noted in the majority of these children. Most Children with RLS and PLMD often present with nonspecific symptoms such as sleep disturbances, insomnia, restless sleep and daytime sleepiness [29, 30]. In the current study, sleep onset and sleep maintenance insomnia, restless sleep, and leg movements during sleep were common presenting symptoms in children with RLS and PLMD. This is similar to several previous studies including two epidemiologic studies of the pediatric population [8, 9]. Our study showed that daytime sleepiness was relatively less common in children with RLS/PLMD, consistent with a previous study [8]. For comorbid conditions, we found that attention deficit hyperactivity disorder (ADHD), anxiety, and depression were common comorbid psychiatric conditions. Several studies have shown the association between RLS/PLMD and ADHD [20, 31] The prevalence of ADHD or ADHD symptoms in children with RLS and PLMD is between 18-28% [8, 20, 32-36]. The relationship between ADHD and RLS is complex and can be explained by several theories [34]. One theory is that iron deficiency may be a shared pathophysiologic mechanism for both RLS/PLMD and ADHD [37]. This could explain a high prevalence of ADHD in our population who had low iron storages and were on iron therapy. Children with RLS and PLMD have been shown to be at risk for anxiety disorder and depression [8, 38]. We found similar findings in our study. It has been speculated that sleep disruption in children with RLS and PLMD may lead to or contribute to symptoms of psychiatric disorders. While 39.1% of our patients went on to meet ICSD-2 criteria for definite RLS, the diagnosis of definite RLS was made in only 8.6% of patients at presentation. The remaining patients were first diagnosed with PLMD and then RLS at a later date. This highlights the difficulty associated with diagnosing RLS, a syndrome based almost entirely on subjective description. Although this percentage is seemingly low, Picchietti and Stevens reported a series of 18 patients who presented with various sleep complaints and eventually met criteria for definite RLS. In this series they found the average duration from onset of clinical sleep disturbance to diagnosis of RLS was 11.6 years [38]. In our population, 82.9% of patients with RLS had elevated PLMS (>5/hr). This confirmed previous studies showing high proportion of PLMS in pediatric RLS patients [4, 39]. Other sleep diagnoses were also common, specifically OSA and parasomnias. The frequency of OSA in our cohort is similar to a previous study of pediatric PLMS in which OSA was concurrently found in 46% of patients [40]. Pediatric PLMS have also been reported to emerge following the successful treatment of OSA with PAP therapy [41]. Our study confirmed an increased prevalence of parasomnias in children with RLS and PLMD as shown in other studies [29, 42]. The resolution of parasomnias after treatment of RLS and PLMD in children suggests that sleep disruption associated with RLS and PLMD may trigger or facilitate the appearance of parasomnias [42]. Further studies are needed to evaluate the relationship between RLS/PLMD and parasomnias. Diagnoses of seizures or epilepsy were also common. Further studies are Page 9 of 20 Page 9 of 20
needed to address this issue and to evaluate the effect of RLS/PLMD treatment on seizure control. Of our total population, 62.86% demonstrated subjective sustained improvements in their symptoms after starting iron therapy. Of patients in our study diagnosed with RLS, 78.05% demonstrated subjective improvement. This result is similar to our prior study of iron treatment in pediatric RLS and PLMD which demonstrated subjective improvement in 76% of patients [20]. Several studies have demonstrated improvement in RLS symptoms and reduction in PLMS index with iron therapy [20-22, 24]. However, these studies assessed only short term improvement. Our study is the first to evaluate a long term response to iron therapy. We showed a sustained decrease in the PLMS index. Compared to baseline, the PLMS index decreased 67% and 52% in PSGs done between 1 and 2 years and more than 2 years following initiation of iron therapy, respectively. This is similar to a short term study in which PLMS index decreased 52.3% 3 months after the initiation of iron therapy [20]. There are evolving evidence of the role of iron in the pathophysiology of RLS and PLMD. Dopaminergic dysfunction likely serves as the underlying basis for both RLS and PLMD [17]. As such, the utility of iron supplementation in children with RLS/PLMD is likely based upon its role in dopamine production. Iron serves as a co-factor for the conversion of L-tyrosine to L-DOPA, which is the rate limiting step in the production of catecholamines, including dopamine [43]. It has been theorized that a non-destructive dysfunction of subcortical dopaminergic pathways, via the A11 cell group, results in spinal cord excitability and ultimately the symptoms of RLS/PLMD [14, 44]. This dysfunction follows a circadian pattern [45], and demonstrates strong heritability [46], and is progressive with age [47]. The use of SSRI and SNRI in our population was relatively common; 18.1% of patients were on one of these medications at the time of iron initiation. The PLMS index of the patients on SSRI and SNRI were 37.6% higher than those who were not on these medications. This finding was not surprising as Yang et al demonstrated that the odds ratio of having a PLMS index of greater than 20 was 5.24 for patients taking venlafaxine and 5.15 patients taking a SSRI when compared to a control group in a large prospective study [48], and Vendrame et al found that 31.4% of pediatric patients receiving SSRIs had a PLMS index of ≥ 5/hr compared to 7.8% of those not receiving SSRIs [49]. This increase is likely the result of increased serotonergic action leading to a secondary decrease in dopaminergic function [50]. As summarized in a review paper by Picchietti and Winkelman, multiple population based and clinic based studies have demonstrated an increased rate of depression in adult patients with RLS and PLMS [50] and a large retrospective study by Pullen et al demonstrated concurrent mood disorder in 29.1% of children and adolescents with RLS[35]. As in our cohort, this represents a distinct clinical challenge as depression and SSRI use were both common in patients with confirmed ferritin insufficiency. One theory for this phenomenon would implicate underlying RLS or PLMD causing or exacerbating depression, which is then treated with SSRIs, ultimately leading to worsening of RLS and PLMD. However, it is encouraging that the PLMS index for children on SSRI/SNRIs improved on iron to an extent similar to that of children who were not on medication (table 5). Page 10 of 20 Page 10 of 20
For other concurrent medications, both alpha-2-delta ligands and dopaminergic medications were used in our cohort, however, they were rarely utilized prior to initiation of iron therapy (2.9% for alpha-2-delta ligands and 1.9% for dopaminergic medications).
There were several limitations to this study. First, as this was a retrospective study, it is susceptible to selection bias. Only a third of our patients with RLS or PLMD who were treated with iron therapy had 2 years follow up. Although, a significant proportion of patients simply had not yet followed long enough to be included in the study, there were many patients who dropped out at each time point which could lead to selection bias. Second, each patient did not necessarily have a lab value or PSG for each time point, so the subjects were grouped together during set periods meant to mimic our typical follow up schedules (every 3-6 months). Third, while we were able to report patients who were prescribed iron therapy, it is impossible to say whether they were taking the medication or the precise dose. However, the sustained average ferritin levels of >50, which were collected more than 2 years after the initiation of iron, suggest that the majority of patients were using the medication and that dosing was appropriate. Fourth, we included children with co-existing conditions such as OSA. Although, we excluded respiratory related limb movements, OSA treatment may potentially improve PLMS. Finally, our patient selection protocol required patients to have had a PSG at some point in their treatment. This requirement may have resulted in the exclusion of patients who had clinical RLS symptoms but didn’t have a PSG. However, we feel this to be unlikely as it is our practice to perform a PSG when RLS is suspected given the difficulty of obtaining a description of typical symptoms in children. Despite these limitations, our study of long term iron therapy for treatment of RLS/PLMD demonstrated sustained improvement in both objective and subjective measures. In conclusion, our study has demonstrated that oral iron supplementation in children and adolescents leads to sustained improvement in PLMS index, serum ferritin levels, and clinical symptoms. Given the current evidence, we believe iron therapy should be considered the first line of treatment for RLS and PLMD in children when serum ferritin is less than 50 ng/ml. Nevertheless, large scale prospective studies are still needed to confirm the efficacy of iron therapy in the long term management of children with RLS and PLMD, due to the limitations of currently available evidence.
6. Acknowledgements: This research is funded by Cincinnati Children’s Hospital Research Fund. This research was partly presented at SLEEP 2014 (the 28th Annual Meeting of the Associated Professional Sleep Societies), Minneapolis, Minnesota. Dr. Thomas Dye was a recipient of the 2014 Wayne Hening Young Investigator Award from the International RLS Study Group for this research. 7. Disclosure of conflicts of interest: The authors have nothing to disclose. Page 11 of 20 Page 11 of 20
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[21] Kryger MH, Otake K, Foerster J. Low body stores of iron and restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers. Sleep medicine. 2002;3:127-32. [22] Starn AL, Udall JN, Jr. Iron deficiency anemia, pica, and restless legs syndrome in a teenage girl. Clinical pediatrics. 2008;47:83-5. [23] Mohri I, Kato-Nishimura K, Tachibana N, Ozono K, Taniike M. Restless legs syndrome (RLS): an unrecognized cause for bedtime problems and insomnia in children. Sleep medicine. 2008;9:701-2. [24] Grim K, Lee B, Sung AY, Kotagal S. Treatment of childhood-onset restless legs syndrome and periodic limb movement disorder using intravenous iron sucrose. Sleep medicine. 2013;14:1100-4. [25] Mohri I, Kato-Nishimura K, Kagitani-Shimono K, Kimura-Ohba S, Ozono K, Tachibana N, et al. Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS). Sleep medicine. 2012;13:42932. [26] Amos LB, Grekowicz ML, Kuhn EM, Olstad JD, Collins MM, Norins NA, et al. Treatment of pediatric restless legs syndrome. Clin Pediatr (Phila). 2014;53:331-6. [27] Wang J, O'Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep medicine. 2009;10:973-5. [28] Simakajornboon N, Kheirandish-Gozal L, Sharon D, Murry L, Abraham M. A long-term follow-up study of periodic limb movement disorders in children after iron therapy. Sleep: AMER ACADEMY SLEEP MEDICINE ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA; 2006. p. A76A7. [29] Picchietti DL, Walters AS. Moderate to severe periodic limb movement disorder in childhood and adolescence. Sleep. 1999;22:297-300. [30] Walters AS, Hickey K, Maltzman J, Verrico T, Joseph D, Hening W, et al. A questionnaire study of 138 patients with restless legs syndrome: the 'Night-Walkers' survey. Neurology. 1996;46:92-5. [31] Kotagal S, Silber MH. Childhood-onset restless legs syndrome. Annals of Neurology. 2004;56:803-7. [32] Chervin RD, Archbold KH, Dillon JE, Pituch KJ, Panahi P, Dahl RE, et al. Associations between symptoms of inattention, hyperactivity, restless legs, and periodic leg movements. Sleep. 2002;25:213-8. [33] Wagner ML, Walters AS, Fisher BC. Symptoms of attention-deficit/hyperactivity disorder in adults with restless legs syndrome. Sleep. 2004;27:1499-504. [34] Cortese S, Konofal E, Lecendreux M, Arnulf I, Mouren MC, Darra F, et al. Restless legs syndrome and attention-deficit/hyperactivity disorder: a review of the literature. Sleep. 2005;28:1007-13. [35] Pullen SJ, Wall CA, Angstman ER, Munitz GE, Kotagal S. Psychiatric comorbidity in children and adolescents with restless legs syndrome: a retrospective study. J Clin Sleep Med. 2011;7:587-96. [36] Kotagal S, Silber MH. Childhood-onset restless legs syndrome. Annals of neurology. 2004;56:803-7. [37] Konofal E, Cortese S, Marchand M, Mouren MC, Arnulf I, Lecendreux M. Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children. Sleep medicine. 2007;8:711-5. [38] Picchietti DL, Stevens HE. Early manifestations of restless legs syndrome in childhood and adolescence. Sleep medicine. 2008;9:770-81. [39] Picchietti DL, Rajendran RR, Wilson MP, Picchietti MA. Pediatric restless legs syndrome and periodic limb movement disorder: parent-child pairs. Sleep medicine. 2009;10:925-31. [40] Bokkala S, Napalinga K, Pinninti N, Carvalho KS, Valencia I, Legido A, et al. Correlates of periodic limb movements of sleep in the pediatric population. Pediatric neurology. 2008;39:33-9. [41] Pai V, Khatwa U, Ramgopal S, Singh K, Fitzgerald R, Kothare SV. Prevalence of pediatric periodic leg movements of sleep after initiation of PAP therapy. Pediatric pulmonology. 2014;49:252-6. [42] Guilleminault C, Palombini L, Pelayo R, Chervin RD. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics. 2003;111:e17-25.
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[43] Clemens S, Sawchuk MA, Hochman S. Reversal of the circadian expression of tyrosine-hydroxylase but not nitric oxide synthase levels in the spinal cord of dopamine D3 receptor knockout mice. Neuroscience. 2005;133:353-7. [44] Earley CJ, Allen RP, Connor JR, Ferrucci L, Troncoso J. The dopaminergic neurons of the A11 system in RLS autopsy brains appear normal. Sleep medicine. 2009;10:1155-7. [45] Garcia-Borreguero D, Larrosa O, Granizo JJ, de la Llave Y, Hening WA. Circadian variation in neuroendocrine response to L-dopa in patients with restless legs syndrome. Sleep. 2004;27:669-73. [46] Whittom S, Dauvilliers Y, Pennestri MH, Vercauteren F, Molinari N, Petit D, et al. Age-at-onset in restless legs syndrome: a clinical and polysomnographic study. Sleep medicine. 2007;9:54-9. [47] Allen RP, Earley CJ. Defining the phenotype of the restless legs syndrome (RLS) using age-ofsymptom-onset. Sleep medicine. 2000;1:11-9. [48] Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. Biological psychiatry. 2005;58:510-4. [49] Vendrame M, Zarowski M, Loddenkemper T, Steinborn B, Kothare SV. Selective serotonin reuptake inhibitors and periodic limb movements of sleep. Pediatric neurology. 2011;45:175-7. [50] Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep. 2005;28:891-8.
Figure 1: Flow diagram for subject section and inclusion
Patients with RLS or PLMS index ≥ 5/hr (n=547) Patients not treated with iron (n=219)
Patients treated with iron (n=328)
Patients not yet followed for 2 years (n=120)
Patients with ≥ 2 years of follow up (n=105)
Patients dropped out during 2 year follow up (n=103)
Page 14 of 20 Page 14 of 20
Page 15 of 20 Page 15 of 20
Figure 2: Ferritin value for each time period. Figure 2: Ferritin value for each time period.
Ferritin 75
ng/mL
50
25
0 Baseline
*
3 to 6 Months
*
1 to 2 Years
*
> 2 Years
Ferritin levels reported in date ranges following the initiation of ferrous sulfate. * p < 0.001
Serum iron levels were not significantly different after initiation of iron supplementation. The mean iron at baseline prior to oral ferrous sulfate therapy was 74.0±39.1 µg/ml (n=62). It was 83.5±37.7 µg/ml (n=24, p > 0.05) at 3 to 6 months, 81.4±34.9 µg/ml (n=42, p > 0.05) at 1 to 2 years, and 88.2±37.6 µg/ml (n=51, p > 0.05) at > 2 years. There were increases of 13%, 10%, and 19%, at 3 to 6 months, 1 to 2 years and at 2 years respectively.
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Figure 3: PLMS index for each time period. Figure 3: PLMS index for each time period.
PLMS Index 30
25
20
15
10
5
0 Baseline
†
3 to 6 Months
*
1 to 2 Years
*
> 2 Years
PLMS, periodic limb movements of sleep. * p < 0.001, † p < 0.05
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Table 1: Subject characteristics, presenting symptoms, and co-morbid conditions Characteristic
N (%)
Age, years
10.2 ± 5.3
Gender Male
73 (69.5)
Female
32 (30.5)
38 (36.2) 32 (30.5) Presenting symptoms:
32 (30.5)
Sleep Onset Difficulties
31 (29.5)
Sleep Maintenance Difficulties
16 (15.2)
RLS symptoms*
9 (8.6)
Co-Morbid Conditions OSA
39 (37.2)
Seizure/Epilepsy
29 (27.6)
ADHD
35 (33.3)
Anxiety
24 (22.9)
Depression
17 (16.2)
Parasomnias
20 (19.1)
Data are expressed as mean ± SD or N (%). RLS, restless legs syndrome; OSA, obstructive sleep apnea; ADHD, attention deficit hyperactivity disorder. *RLS symptoms defined as those included in the ISCD-2 essential criteria.
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Table 2: Distribution of RLS and/or PLMD Disorder
N (%)
RLS
41 (39.1)
PLMS index ≥ 5/hr
98 (93.3)
PLMD
64 (61.0)
RLS with PLMS index < 5/hr
7 (6.7)
RLS with PLMS index ≥ 5/hr
34 (32.4)
Percentage RLS w/PLMS index ≥ 5/hr
82.93%
Data are expressed as N (%) or %. RLS, restless legs syndrome; PLMS index, periodic limb movement of sleep index; PLMD, periodic limb movement disorder
Table 3: Changes in ferritin and iron levels, and PLMS index at different time periods
Ferritin
Baseline Mean 27.4 ±12.1
3-6 months mean 45.6 ±21.2
Iron
74.0 ±39.1
83.5 ±37.7
PLMS Index
21.0 ±27.0 n = 66
7.5 ±9.5 n = 11
% change, p- value 66% p < 0.001 13% p > 0.05 -64% p < 0.05
1- 2 years mean 52.0 ±48.3 81.4 ±34.9 6.9 ±8.9 n = 29
% change, p- value 90% p < 0.001 10% p > 0.5 -67% p < 0.001
>2 years mean 54.7 ±40.46 88.2 ±37.6 10.0 ±14.5 n = 31
% change, p- value 100% p < 0.001 19% p > 0.05 -52% p < 0.001
Data are expressed as mean ± SD or percentage and p value. PLMS index, periodic limb movement of sleep index
Table 4: Concurrent medications Medication
At iron initiationn (%)
Anytime during the study- n (%)
Alpha-2 delta ligands
3 (2.9)
13 (12.4)
Stimulants
6 (5.7)
12 (11.4)
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SSRIs/SNRIs
19 (18.1)
38 (36.2)
Dopaminergics
2 (1.9)
13 (12.4)
Data are expressed as N (%). SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor.
Table 5: Changes in PLMS index based upon medication usage Medication
PLMS index, Pre-Iron Therapy
PLMS index, Post-Iron Therapy
% change, p- value
Not on SSRI/SNRIa On SSRI/SNRIb Never on dopaminergic medicationc
19.667 ±29.264, n = 52 25.543 ±16.444, n = 14 17.477 ±13.814, n = 57
7.34 ±11.346, n = 43 9.864 ±12.208, n = 28 5.133 ±7.018, n = 58
-63%, p < 0.0001 -61%, p = 0.0018 -71%, p < 0.0001
Data are expressed as mean, percentage change, and p value. PLMS index, periodic limb movements of sleep a index; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor. Includes b studies of patients who were not on SSRI/SNRIs at time of iron therapy initiation, or at follow up. Includes studies of patients who were on SSRI/SNRIs at time of iron therapy initiation, and those who were started on SSRI/SNRI C after intiation of iron therapy. Defined as those patients who were not on a dopaminergic medication at any point in the study
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S1389-9457(16)00044-7 http://dx.doi.org/doi: 10.1016/j.sleep.2016.01.008 SLEEP 3001
To appear in:
Sleep Medicine
Received date: Revised date: Accepted date:
21-8-2015 26-1-2016 27-1-2016
Please cite this article as: Thomas J. Dye, Sejal V Jain, Narong Simakajornboon, Outcomes of long term iron supplementation in pediatric restless leg syndrome / periodic limb movement disorder (RLS/PLMD), Sleep Medicine (2016), http://dx.doi.org/doi: 10.1016/j.sleep.2016.01.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Outcomes of Long Term Iron Supplementation in Pediatric Restless Leg Syndrome / Periodic Limb Movement Disorder (RLS/PLMD) Thomas J. Dye, MD 1,3*, Sejal V Jain, MD 1,3, Narong Simakajornboon, MD 2,3 1. Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 2. Division of Pulmonology and Sleep Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 3. Sleep Center, Cincinnati Children’s Hospital Medical Center
* Corresponding author Thomas J Dye, MD Division of Neurology Cincinnati Children’s Hospital Medical Center 3333 Burnet Ave, MLC 2015 Cincinnati, OH 45229 Phone: 513-636-7314 Fax: 513-636-1888 Email: [email protected]
This research was partly presented at SLEEP 2014 (the 28th Annual Meeting of the Associated Professional Sleep Societies), Minneapolis, Minnesota. Dr. Thomas Dye was a recipient of the 2014 Wayne Hening Young Investigator Award from the International RLS Study Group for this research.
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Highlights:
Iron therapy is an effective treatment for pediatric RLS/PLMD. Treatment results in improvement of PLMS indices and subjective symptoms. Long term improvement is sustained in the majority of patients
Abstract: Objectives: Restless Leg Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD) are thought to center around a genetically mediated sensitivity to iron insufficiency. Previous studies have shown the effectiveness of short term iron therapy in children with low iron storages. Little is known, however, about long term iron treatment in children with RLS and PLMD. Therefore, we performed this study to assess long term effect of iron therapy in children with RLS and PLMD. Methods: A retrospective chart review was performed for children who met the following criteria: A) diagnosed as having either RLS or PLMD, B) started on iron supplementation, C) followed for more than 2 years in a sleep clinic. Baseline values for iron, ferritin, and periodic limb movements of sleep index (PLMS index) were defined in the 3 months leading up to initiation of iron therapy. Values were also computed for follow up periods of 3-6 months, 1-2 years, and >2 years. Serum iron, ferritin and PLMS index were compared between baseline and all subsequent follow-ups. Results: 105 patients met inclusion criteria. 64 were diagnosed as having PLMD alone, 7 with RLS alone, and 35 as with both RLS and PLMD. The average age was 10.2±5.3 years. Compared to the baseline (27.4±12.1 ng/ml), the average ferritin values at 3-6 months (45.62±21.2 ng/ml, p <0.001, n=34), 1-2 years (52.0±48.3 ng/ml, p<0.001, n=63), and >2 years (54.7±40.5 ng/ml, p=<0.001, n=67) were all significantly increased. Inversely, compared to baseline (21±27.0/hr, n=66), PLMS index at 3-6 months (7.5±9.5/hr p <0.05, n=11), 1-2 years (6.9±8.9/hr, p<0.001, n=29), and >2 years (10±14.5/hr, p<0.001, n=31) were all significantly decreased. No significant change in serum iron was noted at any time points. Conclusion: While retrospective in nature, this study demonstrates sustained improvement in PLM index and adequate ferritin level more than 2 years after iron therapy in our RLS/PLMD cohort with Page 2 of 20 Page 2 of 20
long term follow up. Iron therapy appears to lead long lasting improvement in children with RLS/PLMD. Keywords: restless legs syndrome; periodic limb movements; iron; ferritin; pediatric sleep medicine
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1. Introduction: Restless legs syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a sensorimotor disorder characterized by a strong, unpleasant urge to move one’s legs. RLS symptoms typically become worse at night and with rest, and are improved by movements [1, 2]. Periodic limb movements in sleep (PLMS), are periodic, repetitive, and stereotyped movements, typically involving the lower extremities [1-3]. Periodic limb movement disorder (PLMD) is characterized by periodic episodes of repetitive, highly stereotyped limb movements that occur during sleep (PLMS), in conjunction with clinical sleep disturbance or fatigue that cannot be accounted for by another primary sleep disorder or other etiology [1, 2]. RLS and PLMD are distinct, but closely related entities with a strong genetic basis. This is particularly true for the early onset phenotype seen in pediatric patients [4-7]. Recent studies have indicated that RLS is common in the pediatric population. Large population studies in the US, Europe, Turkey, and Hong Kong have shown the estimated prevalence of RLS to be 1.71 - 1.9% for school aged children and 2% - 3.6% for adolescents [8-11]. Affected patients frequently report sleep disturbances, a lack of energy, an inability to concentrate, and a negative impact on mood [12]. The pathophysiology of RLS is complex. However, a common hypothesis centers around a heritable sensitivity to iron insufficiency [13]. This is believed to cause down regulation of subcortical and spinal dopaminergic pathways [14, 15], ultimately resulting in spinal cord hyperexcitability [16, 17]. Although there is emerging literature supporting medical therapy in children with RLS and PLMD, the experience with medications such as dopaminergic medication or alpha-2-delta ligands is still limited [18]. Therefore, iron therapy offers a safer alternative treatment and is usually considered the first line of treatment. There is increasing evidence of iron therapy in management of RLS and PLMD. Low levels of serum ferritin have been associated with RLS symptoms and elevated indices of periodic limb movements of sleep (PLMS index) in pediatric patients [19, 20]. Several studies have shown the benefit of iron therapy in decreasing PLMS index and reducing RLS symptoms in children [2026] as well as adults [27]. Other studies have indicated the benefit of raising serum ferritin above 50 ng/ml [20, 21]. However, as these studies only assessed the short term effect of iron therapy, there is limited data for long term treatment efficacy of iron supplementation in the pediatric RLS and PLMD population [28]. Hence, we performed this study to evaluate the long term effect of oral iron supplementation on ferritin level, PLMS index, and improvement of clinical symptoms. 2. Methods: The primary aim of this study was to evaluate whether oral iron supplementation leads to long lasting improvement of PLMS index and clinical symptoms, and sustained serum ferritin in children with RLS and PLMD. This was a retrospective study. The study was approved by the institutional review board (IRB) at the Cincinnati Children’s Hospital Medical Center (CCHMC).
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2.1 Subjects: Following institutional IRB approval, a retrospective database was developed utilizing the de-identified medical records. Patients meeting all the following criteria were included in the database. 1) Evaluation by a sleep medicine specialist 2) Diagnosis of RLS or diagnosis of PLMD In our center, iron therapy is the first line of treatment in children with RLS/PLMD who have serum ferritin less than 50 ng/ml. We have routinely used ferrous sulfate, either solution or tablet, with dosing at 3 mg elemental iron per kg per day, based upon patient’s weight. Children who receive iron therapy will normally have iron studies every 3-6 months. Dosing is then adjusted at this point based upon response with the goal of maintaining serum ferritin levels at or above 50 ng/mL. From the database, we selected the subjects starting in 2006 who were started on iron supplementation therapy for the treatment of RLS/PLMD and who were followed for at least 2 years in our sleep clinics. Using the iron supplementation start date as a baseline we selected data from 4 time periods based upon our typical monitoring and clinical follow up schedule at the CCHMC. The first period was defined as the 3 months preceding the initiation of iron therapy. The second through fourth periods were defined as 3-6 months, 1-2 years, and more than 2 years following iron initiation, respectively. The data collected at these time points included ferritin levels, iron levels, PLMS index on polysomnography, and changes in clinical symptoms. Subjective improvement in clinical symptoms was based upon review of clinical documentation created at the time of patient follow up. As our study aimed to evaluate long term improvement, the medical records at any follow up visit more than one year after iron therapy were reviewed for subjective improvements. Daytime sleepiness was defined as daytime naps in children over the age of 5 or falling asleep at inappropriate times during daytime activities including while dressing, playing alone, playing with others, watching TV, eating meals, going to the bathroom, or attending school. 2.2 Polysomnography: Polysomnography was performed with Grass System (Grass Telefactor West Warwick, Rhode Island). Subjects were studied for up to 12 hours in a quiet dark room with an ambient temperature of 24 degrees C, in the company of their parents. Subjects went to bed at their routine bedtime. The standard pediatric EEG montage was used. The following parameters were recorded simultaneously: body position, bilateral electro-occulogram, six channel electroencephalogram (F3M2, F4M1, C3M2, C4M1, O1M2, O2M1), chin electromyogram, anterior tibialis electromyogram, tracheal microphone, electrocardiogram pulse oximetry (Maximo), thoracic and abdominal inductance plethysmography, nasal pressure transducer (Protech, Mukilteo, WA) and end-tidal CO2 (BCI, Capnochecks). Sleep stages were scored by a certified sleep technologist according to the American Academy of Sleep Medicine (AASM) guidelines [3]. AASM standard definitions were used for sleep efficiency (SE), total sleep Page 5 of 20 Page 5 of 20
time, percentages of sleep stages (N1, N2, N3, or REM %), arousals, and arousal index (AI). Periodic limb movements in sleep (PLMS) were scored according to AASM scoring rules [3], and as were defined as significant limb movement (LM) events occurring in a PLM series. The LM events were defined as having a minimum duration of 0.5 seconds, a maximum duration of 10 seconds, with a minimum amplitude increase of 8 μV above baseline on EMG. PLM series (and therefore PLMS) were scored when four or more consecutive LMs occurred and were separated by at least 5 seconds and at most 90 seconds. As per AASM rules, respiratory related LMs were not included. 2.3 Definitions: RLS and PLMD were diagnosed based on ICSD-2 criteria [1, 2]. Only those meeting definite RLS diagnosis were included. The essential criteria for RLS include an urge to move or an unpleasant sensation in legs, which is worse during rest or periods of inactivity, is partially or totally relieved by movements, and is worse during evenings or nights. For definite RLS in children, these essential criteria have to be met along with either a description in the child’s own words that is consistent with leg discomfort, or the presence of two out of three supportive criteria (including sleep disturbance, positive family history in parents or siblings with definite RLS, or PLMs with index of 5 or more on polysomnography). PLMD was defined as periodic limb movements in sleep (PLMS) on polysomnography with frequency of 5/hour or more, which caused clinically significant sleep disturbance or daytime fatigue and was not explained by any other disorder [1, 2]. 2.4 Statistical analysis: The subject characteristics were presented as mean ± standard deviation and/or percentages. The subjects were grouped together during set periods meant to mimic our typical follow up schedules (every 3-6 months). Comparisons were made between values collected at all 4 time points as well as subgroups including 2 time points. A p value of < 0.05 was considered statistically significant. Data with normal distribution (serum iron) were compared using ANOVA. Data with non-normal distribution (PLMS index and ferritin) were analyzed using the Kruskal-Wallis Test (Nonparametric ANOVA). The Mann-Whitney test was used for sub group analysis. MySQL Server and MySQL Workbench were used for data storage and retrieval, and InStat was used for statistical analysis. 3. Results: 3.1: Subject Selection: Figure 1 and Table 1 represent the flow diagram for subject selection and subject characteristics. We identified 547 patients. Of these, 328 were treated with oral ferrous sulfate and 105 of these patients were followed in a sleep medicine clinic for more than 2 years. These 105 patients formed the core subject set which we examined and was comprised of 73 males (69.5%) and 32 females (30.5%) for a male to female ratio of 2.3:1, with a mean age of 10.2 years ± 5.3 years at start of iron therapy. The mean ages of each gender was similar Page 6 of 20 Page 6 of 20
(male 9.83 years vs. female 11.10 years p = NS), as was the mean PLMS index (male 14.6/hr vs. female 13.9/hr, p = NS).
3.2 Presenting symptoms and comorbid conditions (Table 1): Sleep onset insomnia was the most common presenting complaint. Sleep maintenance insomnia, restlessness, and leg movements or jerks during sleep were also common presenting complaints. Daytime sleepiness was less commonly reported at presentation. For comorbidities, obstructive sleep apnea syndrome (OSA) and epilepsy/seizures were common comorbid medical conditions. Attention deficit hyperactivity disorder, anxiety, and depression were common comorbid behavioral and psychiatric conditions.
3.3 Diagnosis and clinical responses to iron sulfate. Table 2 represents the distribution of the RLS and PLMD in our cohort with further subset classification based upon PLMS index. Of the 105 patients who met inclusion criteria 41 (39.1%) were diagnosed with RLS and 64 (61.0%) with PLMD. Of the 41 RLS patients, 34 had a PLMS index of ≥5/hr (32.4% of total, 82.9% of RLS group) and 7 had a PLMS index of <5/hr (6.7% of total, 17.1% of RLS group). 98 patients (93.3%) were found to have a PLMS index of ≥5/hr. In term of treatment responses; of the total population, 66/105 (62.86%) demonstrated sustained subjective improvements in their symptoms after iron therapy. Of patients in our study with elevated PLMS, 62/98 (63.27%) demonstrated subjective improvement. Of patients in our study diagnosed with RLS, 32/41 (78.05%) demonstrated subjective improvement.
3.4 Laboratory results. Table 3 represents changes in serum iron, ferritin and PLMS index at various time points during 2 years after iron therapy. The mean ferritin at baseline prior to oral ferrous sulfate therapy was 27.4 ±12.1 ng/ml (n=89). It was increased to 45.6 ± 21.2 ng/ml (n=34, p < 0.001) at 3 to 6 months, 52.0±48.3 ng/ml (n=63, p < 0.001) at 1 to 2 years, and 54.7± 40.46 ng/ml (n=67, p < 0.001) at more than 2 years. There were increases of 66%, 90%, and 100%, at 3 to 6 months, 1 to 2 years and at 2 years respectively (Figure 2).
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3.5 Polysomnography Results. Table 3 and Figure 3 shows the changes in PLMS index over different time periods. PLMS index were significantly decreased at all time periods following initiation of iron therapy. The mean PLMS index at baseline prior to initiation of iron therapy was 21.0/hr. There were decreases of 64%, 67%, and 52%, at 3 to 6 months, 1 to 2 years and at > 2 years respectively.
3.6 Concurrent Medication Use. Table 4 shows the use of concurrent medications. Dopaminergic medications were used by 12.4% (n=13) of patients at any point during the follow up period. Alpha-2-delta ligands were also used by 12.4% (n=13) of patients at any point during the follow up period. However, few patients were on a dopaminergic medication (n=2, 1.9%) or alpha-2-delta ligands (n=3, 2.9%) when iron supplementation was initiated. The use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) in this population was common (36.2%); including 18.1% of patients who were on this class of medication when iron was initiated. Table 5 details the differences in PLMS index amongst subgroups based upon concurrent medication use. The subgroups include those who were on SSRI/SNRIs before and/or after iron therapy, those who were never on SSRI/SNRIs, as well as those who were never on dopaminergic medications. The improvement of PLMS index after iron therapy was noted in all groups regardless of the use of these medications.
.
4 Discussion: This is the first study to evaluate the long term effects of iron treatment on PLMS index and ferritin levels in children with RLS and PLMD. This study demonstrates sustained improvement in PLMS index and maintenance of adequate ferritin levels more than 2 years after the initiation Page 8 of 20 Page 8 of 20
of iron therapy. Sustained clinical improvement was also noted in the majority of these children. Most Children with RLS and PLMD often present with nonspecific symptoms such as sleep disturbances, insomnia, restless sleep and daytime sleepiness [29, 30]. In the current study, sleep onset and sleep maintenance insomnia, restless sleep, and leg movements during sleep were common presenting symptoms in children with RLS and PLMD. This is similar to several previous studies including two epidemiologic studies of the pediatric population [8, 9]. Our study showed that daytime sleepiness was relatively less common in children with RLS/PLMD, consistent with a previous study [8]. For comorbid conditions, we found that attention deficit hyperactivity disorder (ADHD), anxiety, and depression were common comorbid psychiatric conditions. Several studies have shown the association between RLS/PLMD and ADHD [20, 31] The prevalence of ADHD or ADHD symptoms in children with RLS and PLMD is between 18-28% [8, 20, 32-36]. The relationship between ADHD and RLS is complex and can be explained by several theories [34]. One theory is that iron deficiency may be a shared pathophysiologic mechanism for both RLS/PLMD and ADHD [37]. This could explain a high prevalence of ADHD in our population who had low iron storages and were on iron therapy. Children with RLS and PLMD have been shown to be at risk for anxiety disorder and depression [8, 38]. We found similar findings in our study. It has been speculated that sleep disruption in children with RLS and PLMD may lead to or contribute to symptoms of psychiatric disorders. While 39.1% of our patients went on to meet ICSD-2 criteria for definite RLS, the diagnosis of definite RLS was made in only 8.6% of patients at presentation. The remaining patients were first diagnosed with PLMD and then RLS at a later date. This highlights the difficulty associated with diagnosing RLS, a syndrome based almost entirely on subjective description. Although this percentage is seemingly low, Picchietti and Stevens reported a series of 18 patients who presented with various sleep complaints and eventually met criteria for definite RLS. In this series they found the average duration from onset of clinical sleep disturbance to diagnosis of RLS was 11.6 years [38]. In our population, 82.9% of patients with RLS had elevated PLMS (>5/hr). This confirmed previous studies showing high proportion of PLMS in pediatric RLS patients [4, 39]. Other sleep diagnoses were also common, specifically OSA and parasomnias. The frequency of OSA in our cohort is similar to a previous study of pediatric PLMS in which OSA was concurrently found in 46% of patients [40]. Pediatric PLMS have also been reported to emerge following the successful treatment of OSA with PAP therapy [41]. Our study confirmed an increased prevalence of parasomnias in children with RLS and PLMD as shown in other studies [29, 42]. The resolution of parasomnias after treatment of RLS and PLMD in children suggests that sleep disruption associated with RLS and PLMD may trigger or facilitate the appearance of parasomnias [42]. Further studies are needed to evaluate the relationship between RLS/PLMD and parasomnias. Diagnoses of seizures or epilepsy were also common. Further studies are Page 9 of 20 Page 9 of 20
needed to address this issue and to evaluate the effect of RLS/PLMD treatment on seizure control. Of our total population, 62.86% demonstrated subjective sustained improvements in their symptoms after starting iron therapy. Of patients in our study diagnosed with RLS, 78.05% demonstrated subjective improvement. This result is similar to our prior study of iron treatment in pediatric RLS and PLMD which demonstrated subjective improvement in 76% of patients [20]. Several studies have demonstrated improvement in RLS symptoms and reduction in PLMS index with iron therapy [20-22, 24]. However, these studies assessed only short term improvement. Our study is the first to evaluate a long term response to iron therapy. We showed a sustained decrease in the PLMS index. Compared to baseline, the PLMS index decreased 67% and 52% in PSGs done between 1 and 2 years and more than 2 years following initiation of iron therapy, respectively. This is similar to a short term study in which PLMS index decreased 52.3% 3 months after the initiation of iron therapy [20]. There are evolving evidence of the role of iron in the pathophysiology of RLS and PLMD. Dopaminergic dysfunction likely serves as the underlying basis for both RLS and PLMD [17]. As such, the utility of iron supplementation in children with RLS/PLMD is likely based upon its role in dopamine production. Iron serves as a co-factor for the conversion of L-tyrosine to L-DOPA, which is the rate limiting step in the production of catecholamines, including dopamine [43]. It has been theorized that a non-destructive dysfunction of subcortical dopaminergic pathways, via the A11 cell group, results in spinal cord excitability and ultimately the symptoms of RLS/PLMD [14, 44]. This dysfunction follows a circadian pattern [45], and demonstrates strong heritability [46], and is progressive with age [47]. The use of SSRI and SNRI in our population was relatively common; 18.1% of patients were on one of these medications at the time of iron initiation. The PLMS index of the patients on SSRI and SNRI were 37.6% higher than those who were not on these medications. This finding was not surprising as Yang et al demonstrated that the odds ratio of having a PLMS index of greater than 20 was 5.24 for patients taking venlafaxine and 5.15 patients taking a SSRI when compared to a control group in a large prospective study [48], and Vendrame et al found that 31.4% of pediatric patients receiving SSRIs had a PLMS index of ≥ 5/hr compared to 7.8% of those not receiving SSRIs [49]. This increase is likely the result of increased serotonergic action leading to a secondary decrease in dopaminergic function [50]. As summarized in a review paper by Picchietti and Winkelman, multiple population based and clinic based studies have demonstrated an increased rate of depression in adult patients with RLS and PLMS [50] and a large retrospective study by Pullen et al demonstrated concurrent mood disorder in 29.1% of children and adolescents with RLS[35]. As in our cohort, this represents a distinct clinical challenge as depression and SSRI use were both common in patients with confirmed ferritin insufficiency. One theory for this phenomenon would implicate underlying RLS or PLMD causing or exacerbating depression, which is then treated with SSRIs, ultimately leading to worsening of RLS and PLMD. However, it is encouraging that the PLMS index for children on SSRI/SNRIs improved on iron to an extent similar to that of children who were not on medication (table 5). Page 10 of 20 Page 10 of 20
For other concurrent medications, both alpha-2-delta ligands and dopaminergic medications were used in our cohort, however, they were rarely utilized prior to initiation of iron therapy (2.9% for alpha-2-delta ligands and 1.9% for dopaminergic medications).
There were several limitations to this study. First, as this was a retrospective study, it is susceptible to selection bias. Only a third of our patients with RLS or PLMD who were treated with iron therapy had 2 years follow up. Although, a significant proportion of patients simply had not yet followed long enough to be included in the study, there were many patients who dropped out at each time point which could lead to selection bias. Second, each patient did not necessarily have a lab value or PSG for each time point, so the subjects were grouped together during set periods meant to mimic our typical follow up schedules (every 3-6 months). Third, while we were able to report patients who were prescribed iron therapy, it is impossible to say whether they were taking the medication or the precise dose. However, the sustained average ferritin levels of >50, which were collected more than 2 years after the initiation of iron, suggest that the majority of patients were using the medication and that dosing was appropriate. Fourth, we included children with co-existing conditions such as OSA. Although, we excluded respiratory related limb movements, OSA treatment may potentially improve PLMS. Finally, our patient selection protocol required patients to have had a PSG at some point in their treatment. This requirement may have resulted in the exclusion of patients who had clinical RLS symptoms but didn’t have a PSG. However, we feel this to be unlikely as it is our practice to perform a PSG when RLS is suspected given the difficulty of obtaining a description of typical symptoms in children. Despite these limitations, our study of long term iron therapy for treatment of RLS/PLMD demonstrated sustained improvement in both objective and subjective measures. In conclusion, our study has demonstrated that oral iron supplementation in children and adolescents leads to sustained improvement in PLMS index, serum ferritin levels, and clinical symptoms. Given the current evidence, we believe iron therapy should be considered the first line of treatment for RLS and PLMD in children when serum ferritin is less than 50 ng/ml. Nevertheless, large scale prospective studies are still needed to confirm the efficacy of iron therapy in the long term management of children with RLS and PLMD, due to the limitations of currently available evidence.
6. Acknowledgements: This research is funded by Cincinnati Children’s Hospital Research Fund. This research was partly presented at SLEEP 2014 (the 28th Annual Meeting of the Associated Professional Sleep Societies), Minneapolis, Minnesota. Dr. Thomas Dye was a recipient of the 2014 Wayne Hening Young Investigator Award from the International RLS Study Group for this research. 7. Disclosure of conflicts of interest: The authors have nothing to disclose. Page 11 of 20 Page 11 of 20
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[21] Kryger MH, Otake K, Foerster J. Low body stores of iron and restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers. Sleep medicine. 2002;3:127-32. [22] Starn AL, Udall JN, Jr. Iron deficiency anemia, pica, and restless legs syndrome in a teenage girl. Clinical pediatrics. 2008;47:83-5. [23] Mohri I, Kato-Nishimura K, Tachibana N, Ozono K, Taniike M. Restless legs syndrome (RLS): an unrecognized cause for bedtime problems and insomnia in children. Sleep medicine. 2008;9:701-2. [24] Grim K, Lee B, Sung AY, Kotagal S. Treatment of childhood-onset restless legs syndrome and periodic limb movement disorder using intravenous iron sucrose. Sleep medicine. 2013;14:1100-4. [25] Mohri I, Kato-Nishimura K, Kagitani-Shimono K, Kimura-Ohba S, Ozono K, Tachibana N, et al. Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS). Sleep medicine. 2012;13:42932. [26] Amos LB, Grekowicz ML, Kuhn EM, Olstad JD, Collins MM, Norins NA, et al. Treatment of pediatric restless legs syndrome. Clin Pediatr (Phila). 2014;53:331-6. [27] Wang J, O'Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep medicine. 2009;10:973-5. [28] Simakajornboon N, Kheirandish-Gozal L, Sharon D, Murry L, Abraham M. A long-term follow-up study of periodic limb movement disorders in children after iron therapy. Sleep: AMER ACADEMY SLEEP MEDICINE ONE WESTBROOK CORPORATE CENTER STE 920, WESTCHESTER, IL 60154 USA; 2006. p. A76A7. [29] Picchietti DL, Walters AS. Moderate to severe periodic limb movement disorder in childhood and adolescence. Sleep. 1999;22:297-300. [30] Walters AS, Hickey K, Maltzman J, Verrico T, Joseph D, Hening W, et al. A questionnaire study of 138 patients with restless legs syndrome: the 'Night-Walkers' survey. Neurology. 1996;46:92-5. [31] Kotagal S, Silber MH. Childhood-onset restless legs syndrome. Annals of Neurology. 2004;56:803-7. [32] Chervin RD, Archbold KH, Dillon JE, Pituch KJ, Panahi P, Dahl RE, et al. Associations between symptoms of inattention, hyperactivity, restless legs, and periodic leg movements. Sleep. 2002;25:213-8. [33] Wagner ML, Walters AS, Fisher BC. Symptoms of attention-deficit/hyperactivity disorder in adults with restless legs syndrome. Sleep. 2004;27:1499-504. [34] Cortese S, Konofal E, Lecendreux M, Arnulf I, Mouren MC, Darra F, et al. Restless legs syndrome and attention-deficit/hyperactivity disorder: a review of the literature. Sleep. 2005;28:1007-13. [35] Pullen SJ, Wall CA, Angstman ER, Munitz GE, Kotagal S. Psychiatric comorbidity in children and adolescents with restless legs syndrome: a retrospective study. J Clin Sleep Med. 2011;7:587-96. [36] Kotagal S, Silber MH. Childhood-onset restless legs syndrome. Annals of neurology. 2004;56:803-7. [37] Konofal E, Cortese S, Marchand M, Mouren MC, Arnulf I, Lecendreux M. Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children. Sleep medicine. 2007;8:711-5. [38] Picchietti DL, Stevens HE. Early manifestations of restless legs syndrome in childhood and adolescence. Sleep medicine. 2008;9:770-81. [39] Picchietti DL, Rajendran RR, Wilson MP, Picchietti MA. Pediatric restless legs syndrome and periodic limb movement disorder: parent-child pairs. Sleep medicine. 2009;10:925-31. [40] Bokkala S, Napalinga K, Pinninti N, Carvalho KS, Valencia I, Legido A, et al. Correlates of periodic limb movements of sleep in the pediatric population. Pediatric neurology. 2008;39:33-9. [41] Pai V, Khatwa U, Ramgopal S, Singh K, Fitzgerald R, Kothare SV. Prevalence of pediatric periodic leg movements of sleep after initiation of PAP therapy. Pediatric pulmonology. 2014;49:252-6. [42] Guilleminault C, Palombini L, Pelayo R, Chervin RD. Sleepwalking and sleep terrors in prepubertal children: what triggers them? Pediatrics. 2003;111:e17-25.
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[43] Clemens S, Sawchuk MA, Hochman S. Reversal of the circadian expression of tyrosine-hydroxylase but not nitric oxide synthase levels in the spinal cord of dopamine D3 receptor knockout mice. Neuroscience. 2005;133:353-7. [44] Earley CJ, Allen RP, Connor JR, Ferrucci L, Troncoso J. The dopaminergic neurons of the A11 system in RLS autopsy brains appear normal. Sleep medicine. 2009;10:1155-7. [45] Garcia-Borreguero D, Larrosa O, Granizo JJ, de la Llave Y, Hening WA. Circadian variation in neuroendocrine response to L-dopa in patients with restless legs syndrome. Sleep. 2004;27:669-73. [46] Whittom S, Dauvilliers Y, Pennestri MH, Vercauteren F, Molinari N, Petit D, et al. Age-at-onset in restless legs syndrome: a clinical and polysomnographic study. Sleep medicine. 2007;9:54-9. [47] Allen RP, Earley CJ. Defining the phenotype of the restless legs syndrome (RLS) using age-ofsymptom-onset. Sleep medicine. 2000;1:11-9. [48] Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. Biological psychiatry. 2005;58:510-4. [49] Vendrame M, Zarowski M, Loddenkemper T, Steinborn B, Kothare SV. Selective serotonin reuptake inhibitors and periodic limb movements of sleep. Pediatric neurology. 2011;45:175-7. [50] Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep. 2005;28:891-8.
Figure 1: Flow diagram for subject section and inclusion
Patients with RLS or PLMS index ≥ 5/hr (n=547) Patients not treated with iron (n=219)
Patients treated with iron (n=328)
Patients not yet followed for 2 years (n=120)
Patients with ≥ 2 years of follow up (n=105)
Patients dropped out during 2 year follow up (n=103)
Page 14 of 20 Page 14 of 20
Page 15 of 20 Page 15 of 20
Figure 2: Ferritin value for each time period. Figure 2: Ferritin value for each time period.
Ferritin 75
ng/mL
50
25
0 Baseline
*
3 to 6 Months
*
1 to 2 Years
*
> 2 Years
Ferritin levels reported in date ranges following the initiation of ferrous sulfate. * p < 0.001
Serum iron levels were not significantly different after initiation of iron supplementation. The mean iron at baseline prior to oral ferrous sulfate therapy was 74.0±39.1 µg/ml (n=62). It was 83.5±37.7 µg/ml (n=24, p > 0.05) at 3 to 6 months, 81.4±34.9 µg/ml (n=42, p > 0.05) at 1 to 2 years, and 88.2±37.6 µg/ml (n=51, p > 0.05) at > 2 years. There were increases of 13%, 10%, and 19%, at 3 to 6 months, 1 to 2 years and at 2 years respectively.
Page 16 of 20 Page 16 of 20
Figure 3: PLMS index for each time period. Figure 3: PLMS index for each time period.
PLMS Index 30
25
20
15
10
5
0 Baseline
†
3 to 6 Months
*
1 to 2 Years
*
> 2 Years
PLMS, periodic limb movements of sleep. * p < 0.001, † p < 0.05
Page 17 of 20 Page 17 of 20
Table 1: Subject characteristics, presenting symptoms, and co-morbid conditions Characteristic
N (%)
Age, years
10.2 ± 5.3
Gender Male
73 (69.5)
Female
32 (30.5)
38 (36.2) 32 (30.5) Presenting symptoms:
32 (30.5)
Sleep Onset Difficulties
31 (29.5)
Sleep Maintenance Difficulties
16 (15.2)
RLS symptoms*
9 (8.6)
Co-Morbid Conditions OSA
39 (37.2)
Seizure/Epilepsy
29 (27.6)
ADHD
35 (33.3)
Anxiety
24 (22.9)
Depression
17 (16.2)
Parasomnias
20 (19.1)
Data are expressed as mean ± SD or N (%). RLS, restless legs syndrome; OSA, obstructive sleep apnea; ADHD, attention deficit hyperactivity disorder. *RLS symptoms defined as those included in the ISCD-2 essential criteria.
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Table 2: Distribution of RLS and/or PLMD Disorder
N (%)
RLS
41 (39.1)
PLMS index ≥ 5/hr
98 (93.3)
PLMD
64 (61.0)
RLS with PLMS index < 5/hr
7 (6.7)
RLS with PLMS index ≥ 5/hr
34 (32.4)
Percentage RLS w/PLMS index ≥ 5/hr
82.93%
Data are expressed as N (%) or %. RLS, restless legs syndrome; PLMS index, periodic limb movement of sleep index; PLMD, periodic limb movement disorder
Table 3: Changes in ferritin and iron levels, and PLMS index at different time periods
Ferritin
Baseline Mean 27.4 ±12.1
3-6 months mean 45.6 ±21.2
Iron
74.0 ±39.1
83.5 ±37.7
PLMS Index
21.0 ±27.0 n = 66
7.5 ±9.5 n = 11
% change, p- value 66% p < 0.001 13% p > 0.05 -64% p < 0.05
1- 2 years mean 52.0 ±48.3 81.4 ±34.9 6.9 ±8.9 n = 29
% change, p- value 90% p < 0.001 10% p > 0.5 -67% p < 0.001
>2 years mean 54.7 ±40.46 88.2 ±37.6 10.0 ±14.5 n = 31
% change, p- value 100% p < 0.001 19% p > 0.05 -52% p < 0.001
Data are expressed as mean ± SD or percentage and p value. PLMS index, periodic limb movement of sleep index
Table 4: Concurrent medications Medication
At iron initiationn (%)
Anytime during the study- n (%)
Alpha-2 delta ligands
3 (2.9)
13 (12.4)
Stimulants
6 (5.7)
12 (11.4)
Page 19 of 20 Page 19 of 20
SSRIs/SNRIs
19 (18.1)
38 (36.2)
Dopaminergics
2 (1.9)
13 (12.4)
Data are expressed as N (%). SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor.
Table 5: Changes in PLMS index based upon medication usage Medication
PLMS index, Pre-Iron Therapy
PLMS index, Post-Iron Therapy
% change, p- value
Not on SSRI/SNRIa On SSRI/SNRIb Never on dopaminergic medicationc
19.667 ±29.264, n = 52 25.543 ±16.444, n = 14 17.477 ±13.814, n = 57
7.34 ±11.346, n = 43 9.864 ±12.208, n = 28 5.133 ±7.018, n = 58
-63%, p < 0.0001 -61%, p = 0.0018 -71%, p < 0.0001
Data are expressed as mean, percentage change, and p value. PLMS index, periodic limb movements of sleep a index; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor. Includes b studies of patients who were not on SSRI/SNRIs at time of iron therapy initiation, or at follow up. Includes studies of patients who were on SSRI/SNRIs at time of iron therapy initiation, and those who were started on SSRI/SNRI C after intiation of iron therapy. Defined as those patients who were not on a dopaminergic medication at any point in the study
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