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abstract ARTICLE These results open perspectives for early treatment in neurodevelopment diseases with feeding problems.

The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader Willi Syndrome Maïthé Tauber, MD, a, b, c Kader Boulanouar, PhD, d Gwenaelle Diene, MD, a, e Sophie Çabal-Berthoumieu, MD,
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The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader Willi Syndrome Maïthé Tauber, MD, a, b, c Kader Boulanouar, PhD, d Gwenaelle Diene, MD, a, e Sophie Çabal-Berthoumieu, MD, a, f Virginie Ehlinger, MS, e Pascale Fichaux-Bourin, MD, a Catherine Molinas, MS, a, b, c Sandy Faye, PhD, a, b Marion Valette, PhD, a, b Jeanne Pourrinet, MS, a Catie Cessans, MD, a Sylvie Viaux-Sauvelon, MD, g Céline Bascoul, MD, f Antoine Guedeney, MD, h Patric Delhanty, PhD, i Vincent Geenen, PhD, j Henri Martens, PhD, j Françoise Muscatelli, PhD, k David Cohen, MD, g, l Angèle Consoli, MD, g, m Pierre Payoux, MD, d Catherine Arnaud, MD, e, n Jean-Pierre Salles, MDa, b, c BACKGROUND AND OBJECTIVES: Patients with Prader Willi syndrome (PWS) display poor feeding and social skills as infants and fewer hypothalamic oxytocin (OXT)-producing neurons were documented in adults. Animal data demonstrated that early treatment with OXT restores sucking after birth. Our aim is to reproduce these data in infants with PWS. METHODS: We conducted a phase 2 escalating dose study of a short course (7 days) of intranasal OXT administration. We enrolled 18 infants with PWS under 6 months old (6 infants in each step) who received 4 IU of OXT either every other day, daily, or twice daily. We investigated the tolerance and the effects on feeding and social skills and changes in circulating ghrelin and brain connectivity by functional MRI. RESULTS: No adverse events were reported. No dose effect was observed. Sucking assessed by the Neonatal Oral-Motor Scale was abnormal in all infants at baseline and normalized in 88% after treatment. The scores of Neonatal Oral-Motor Scale and videofluoroscopy of swallowing significantly decreased from 16 to 9 (P .001) and from 18 to 12.5 (P .001), respectively. Significant improvements in Clinical Global Impression scale scores, social withdrawal behavior, and mother infant interactions were observed. We documented a significant increase in acylated ghrelin and connectivity of the right superior orbitofrontal network that correlated with changes in sucking and behavior. CONCLUSIONS: OXT is well tolerated in infants with PWS and improves feeding and social skills. These results open perspectives for early treatment in neurodevelopment diseases with feeding problems. abstract a Unité d Endocrinologie, Obésité, Maladies Osseuses, Génétique et Gynécologie Médicale. Centre de Référence du Syndrome de Prader-Willi, b Axe Pédiatrique du Centre d'investigation Clinique 9302/Intitut National de la Santé Et de la Recherche Médicale, and f Service de Psychiatrie de l'enfant et de l'adolescent, Hôpital des Enfants, Toulouse, France; c Institut National de la Santé Et de la Recherche Médicale Unité 1043, Centre de Physiopathologie de Toulouse Purpan, Université Paul Sabatier, Toulouse, France; d Toulouse NeuroImaging Center, Université de Toulouse, Institut National de la Santé Et de la Recherche Médicale, Université Paul Sabatier, Toulouse, France; e Institut National de la Santé Et de la Recherche Médicale, Unité Mixte de Recherche 1027, Université Toulouse III, Hôpital Paule de Viguier, Toulouse, France; g Service de Psychiatrie de l'enfant et de l'adolescent, la Pitié Salpêtrière, Paris, France; h Service de Psychiatrie de l Enfant et de l Adolescent, Hôpital Bichat-Claude Bernard, Paris, France; i Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; j Grappe Interdisciplinaire de Génoprotéomique Appliquée-I3-Immunoendocrinologie, Université de Liège, Sart Tilman, Liege, Belgium; k Institut de Neurobiologie de la Méditerranée, Institut de la Santé Et de la Recherche Médicale Unité 901, Marseille, France; l Centre National de la Recherche Sscientifique, Unité Mixte de Recherche 7222, Institut des Systèmes Intelligents et de Robotiques, and m Groupe de Recherches Cliniques Abord dimensionnel des épisodes psychotiques de l enfant et de l adolescent, Université Pierre et Marie Curie, Paris France; and n Unité de Soutien méthodologique à la recherche, CHU Toulouse, Toulouse, France WHAT S KNOWN ON THIS SUBJECT: In a Prader Willi syndrome mouse model early oxytocin administration can strongly modify the course of the disease with short- and long-term effects on feeding and socials skills. There are no data of oxytocin effects in human infants. WHAT THIS STUDY ADDS: We report that 7-day intranasal oxytocin administration in infants with Prader Willi syndrome is well tolerated and improves sucking/swallowing, social skills, and mother infant interactions. Changes in brain connectivity of superior orbitofrontal cortex correlate with clinical improvements. To cite: Tauber M, Boulanouar K, Diene G, et al. The Use of Oxytocin to Improve Feeding and Social Skills in Infants With Prader Willi Syndrome. Pediatrics. 2017;139(2):e PEDIATRICS Volume 139, number 2, February 2017 :e ARTICLE TABLE 1 Clinical Characteristics of the Population at Birth and at Trial Inclusion Whole Population (n = 18) Oxytocin (OXT) is a neuropeptide that plays an important role in modulating social interactions and mother infant bonding. 1 3 Quantitative neuroanatomical studies of postmortem human hypothalamic tissue from patients with Prader Willi syndrome (PWS) have demonstrated a reduced number and volume of OXT neurons in the paraventricular nucleus in comparison with controls. 4 Similarly, an alteration in the OXT system was described in PWS mouse models. 5 Interestingly, a single OXT injection before the first 5 hours of life rescued 100% of the newborn Magel2 knock-out (KO) mice from early death by restoring normal sucking activity. 5 The Magel2 KO mouse is now considered a mouse model for PWS and autism spectrum disorder (ASD) because truncated mutations Step 1 Step 2 Step 3 4 IU OXT 4 IU OXT 4 IU OXT Every Other Day Every Day Twice Daily (n = 6) (n = 6) (n = 6) Boy 10 (56%) Girl 8 (44%) Genetic diagnosis Deletion 6 (33%) Uniparental disomy 10 (56%) Imprinting defect 2 (11%) At birth Term (wk) 39 (30;42) Prematurity ( 37 wk) 4 (22%) Caesarean delivery 11 (61%) Apgar 1 min 8.5 (3;10) Apgar 5 min 9.5 (5;10) Weight (SD) a 1.2 ( 2.5;0.2) Length (SD) a 1.1 ( 3.0;0.9) Head circumference (SD) a 0.2 ( 2.8;2.4) Tube feeding, n (%) 16 (89%) At inclusion Age (mo) 3.9 (0.8;5.7) Weight (SD) a 1.4 ( 2.7;0.5) Length (SD) a 0.0 ( 2.3;0.1) HC (SD) a 0.3 ( 1.4;2.4) BMI (SD) a 1.3 ( 2.7;0.6) Tube feeding b 5 (28%) Results are presented as median (minimum;maximum) or n = (%) (Whole Population column) and as median or n ( Step1, 2, or 3 columns). Age is expressed as corrected age in premature babies. HC, head circumference; a SD scores at birth were calculated according to Usher and McLean 9. SD scores at inclusion were calculated according to World Health Organization standards depending on sex and corrected age. b Age of infants still on tube feeding at inclusion: 1 and 1.8 months (step 3), 3.5 months (step 2), 5.3 months (step 3) and 6 mo (step 1). For the 11 infants who stopped NGT before inclusion, median duration of NGT was 1.5 months, ranging from 0.9 to 5.1 months. in the Magel2 gene have been reported in some patients with ASD. 6 Restricted production of mature OXT despite normal prohormone production was detected specifically in the hypothalamus of the Magel2 KO pups. Altogether, these data suggest that OXT is involved in the pathophysiology of PWS and ASD. PWS is a rare genetic disease caused by the lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13 due to a deletion of chromosome 15q11-q13, maternal uniparental disomy, or an imprinting defect. 7 This complex neurodevelopmental disease comprises several nutritional phases. 7, 8 From birth to 9 months, infants with PWS display severe hypotonia, poor interactions, and anorexic behavior with poor suck that may cause life-threatening complications like aspiration. Breast feeding is impossible in most cases and nasogastric tube feeding (NGT) is started at birth in 80% of the infants to ensure normal weight gain. Genetic diagnosis, which is now made in the first months of life, 7 offers a unique opportunity for early treatment with OXT. In this study, we report the results of a proof-ofconcept phase 2 study of a short course of intranasal OXT (7 days) in 18 infants with PWS 6 months of age on safety, feeding, and social skills, ghrelin levels, and brain connectivity. METHODS Patients Eighteen infants with a genetic diagnosis of PWS were recruited and hospitalized in our French reference center for PWS. A detailed description of the population is shown in Table 1. 9 Study Protocol This proof-of-concept, monocentric phase 2 escalating dose study was divided into 3 steps of 7 days of OXT treatment (Syntocinon), each step recruiting 6 consecutive infants 6 months old. The flowchart and a diagram summarizing the time course of the study are shown in Fig 1 A and B, respectively. The study protocol has been registered at www. clinicaltrials. gov (identifier NCT ) and was approved by the Research Ethics Committee of the Hospital of Toulouse. The complete study protocol is available at www. chu- toulouse. fr/- documentsdisponibles- #art7101. Written informed consent was provided by the parents. Evaluation of Tolerance Each infant was examined daily by the team pediatrician, and blood pressure and heart rate 2 TAUBER et al were monitored 3 times per day and for 2 hours after each OXT administration. An electrocardiogram was performed before and 5 min after each OXT administration. Biological parameters, glucose, potassium, sodium, and osmolality were assessed every 2 days. Diuresis and urinary density were monitored daily. After discharge, tolerance was evaluated by the parents with a standardized daily case report form and the local pediatrician in concert with the study team until the end of the study at day 30. Evaluation of Oral Feeding Skills Sucking and swallowing were evaluated before the first and after the last OXT administration. All evaluations were performed by the same speech language pathologist (SLP) with expertise in PWS. We used the Neonatal Oral-Motor Assessment Scale (NOMAS) (Supplemental Table 4). 10 Scores can vary between 8 and 28, with a score 10 defining a near-normal sucking pattern ( Fig 2A). We also calculated the percentage of infants with a score 10 versus a score 10. A score 10 corresponds to a normal or nearnormal sucking pattern without severe or life threatening respiratory complications. The same day, a dynamic videofluoroscopy of swallowing was performed by the same SLP and scored with a grid of 9 relevant items used in routine practice (Supplemental Table 5). Videofluoroscopy was normal if the score was 11, and the maximum abnormal score was 29. Finally, evaluations of behavior before and during feeding by using a Clinical Global Impression (CGI) scale (see Supplemental Table 6) were performed by the same team SLP concomitantly with the clinical scoring of sucking/swallowing. FIGURE 1 A, Flowchart of Study. B, Diagram summarizing the time course of the study. Blind Evaluation of Social Skills In addition, we assessed social withdrawal behavior and mother infant interactions using the Alarm Distress Baby (ADBB) Scale and the validated Coding Interactive Behavior (CIB) Scale, respectively The ADBB and CIB Scales were scored in a blinded manner on videos of feeding taken before and after OXT administration by 2 experts who did not participate in either designing the protocol or conducting the trial. The ADBB Scale is a composite scale comprising 8 items with a score 5 indicating normal behavior. 11 For the CIB Scale, each of the 42 items was rated from 1 (a little) to 5 (a lot) and grouped into 5 composites. In addition, according to the infant s age, 26 specific infant items based on Brazelton s Neonatal Behavioral Assessment Scale 13 were rated and grouped into 2 additional composites (see Methods section in the Supplemental Information). Psychoanalytic infant observation PEDIATRICS Volume 139, number 2, February FIGURE 2 Evaluation of sucking/swallowing. A, NOMAS scores before (N = 18) and after the last OXT administration (N = 17). Score 10 defining a near-normal sucking pattern is represented as a dotted line. B, Scores of videofluoroscopy of swallowing before (N = 18) and after the last OXT administration (N = 16); P values refer to the whole group. was performed with the parents consent by a psychologist trained in E Bick s method before the first and after the last OXT administration at the hospital. 14 During these observations, the psychologist provided parental support and highlighted the infant s skills with the parents. Sampling and Hormone Assays Blood sampling was performed every 2 days after a minimum of 3 hours of fasting. The samples were drawn into EDTA tubes with antiprotease 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (Sigma- Aldrich, St Louis, MO) at a concentration of 2 mg/ml for the ghrelin and OXT measurements. Samples were stored at 20 C before the measurements were performed and were assayed not longer than 6 months after collection. Measurements of acylated (AG) and unacylated ghrelin (UAG) and OXT in blood were performed as described. 15 Brain Connectivity Analysis During Resting State Using Functional MRI The brain connectivity is defined as the temporal correlation of neuronal activity as evidenced by blood oxygen level dependant (BOLD) signal of anatomically separated brain regions. With resting-state functional MRI (rs-fmri), it is possible to investigate the whole brain. 16 Regions are said to be functionally connected if they demonstrate synchronous BOLD fluctuations at rest and then form a network. There are multiple resting-state networks that pertain to different brain functions that can be detected from the time-series scans. Independent Component Analysis (ICA)-based methods 17 are the most commonly used and display high level of consistency. 18 To investigate the effect of OXT on brain connectivity, we scanned 17 of 18 infants at rest without sedation before and on the seventh day after the first OXT administration. We applied ICA (Group ICA fmri Toolbox [GIFT], mialab. mrn. org/ 4 TAUBER et al software/ gift/, Version 4.0a) 18 to find a set of statistically independent spatial components. This group analysis allowed us to identify important networks and then provide the associated map for each subject and each condition where the value in each voxel is a z score measure of the pixel connectivity to the network (see Methods in Supplemental Information). Long-term Observational Data Although clinical follow-up was not part of the phase 2 trial, we routinely followed 16 of the 18 children for 2 to 3 years and compared them with 16 age-matched untreated children with PWS also followed in our reference center. Statistical Analysis Data are presented for the whole population and for each dose step. The continuous variables were expressed as medians and ranges and the categorical data as numbers and percentages. Continuous variables before and after treatment were compared by using Wilcoxon signed rank tests in the whole population and in each dose step. The score changes were compared between dose steps by using Kruskall Wallis ranking tests when significant evolution was observed in the whole study group. Changes in the connectivity z score before and after OXT treatment were measured with a paired t test Correlations between connectivity z score changes in rs-fmri and changes in the oral feeding scales (NOMAS, videofluoroscopy) and behavior changes (CGI, ADBB, CIB) were estimated for the whole sample by the Kendall τ-b coefficient. Comparative analyses of long-term data between early OXT-treated infants and age-matched untreated infants were conducted by using Mann Whitney or χ 2 tests. Data analysis was performed with Stata version 11.2 software (Stata Corp, College Station, TX). P values.05 were considered statistically significant. RESULTS Tolerance We observed no adverse event in relation to OXT for any of the parameters specifically surveyed and no other event occurred during the 7 days of OXT administration and up to day 30. Overall, the tolerance to OXT was excellent, with no cardiovascular or antidiuretic arginine vasopressin like effects. Plasma OXT levels were highly variable before and after OXT administration and did not significantly change in each step (data not shown). Effect of OXT on Oral Skills The NOMAS score significantly improved after treatment for the whole group, with a change in the median score from 16 to 9 (P .001). At baseline, the score varied widely from 11 to 24 with no infant having a normal score. After OXT treatment, 8 infants (47%) reached a score of 8, which is strictly normal and 15 (88%) had a score 10, meaning that they displayed a near-normal sucking pattern ( Fig 2A). Only 2 patients included in step 1 did not normalize their score after treatment. Overall, the changes in NOMAS scores did not differ between the 3 dose steps (P =.504). The scores of videofluoroscopy of swallowing significantly improved after treatment for the whole group from a median value of 18 to 12.5 (P .001) and in each dose step (see Fig 2B). At baseline, 13 infants out of 16 displayed pharyngeal stasis that can drive inhalation, whereas only 2 infants displayed it after OXT treatment. Improvement was obvious as is shown in the videofluoroscopy of swallowing before and after OXT of 1 infant (see Supplemental Video 1 and 2). No significant difference according to dose step (P =.588) was found. Effect on Behavior and Social Skills As shown in Fig 3A, the CGI score significantly improved after treatment from a median score of 3 to 6 before feeding (P =.001) and from 0 to 3.5 during feeding (P =.001) in the whole group. At baseline, the median ADBB score was 6.5, with 62% of the infants with an ADBB score 5 (value of normal score, 5). The median score significantly improved for the whole group from 6.5 to 3.5 (P =.005), with a normal score in 81% of infants after OXT treatment ( Fig 3B). We observed significant improvements on 4 of the 8 items: facial expression, from a median score of 1.0 to 0.0 (P =.005); eye contact, from 1.0 to 0.5 (P =.043); general level of activity, from 1.0 to 0.0 (P =.028); and relationships, from 1.0 to 0.0 (P =.006) ( Fig 3C). For the total ADBB score as well as for these 4 items, the observed changes did not significantly differ between the 3 steps. Figure 3D shows the changes in composites of the CIB scale for the whole group. We observed significant improvements after treatment on 4 out of 7 composites: parental sensitivity, from a median score of 2.47 to 3.08 (P =.033); dyadic reciprocity, 2.43 to 2.75 (P =.009); child social engagement, 1.91 to 2.50 (P =.001); and child state, 2.40 to 3.20 (P =.002). These significant changes did not differ between the 3 steps. Infants observations revealed an improvement in the parents interrelations with the baby in gaze, holding, and handling. Effect of OXT on Circulating Ghrelin In PWS infants, AG levels significantly increased between baseline and, respectively, 2 days (from 189 to 307 pg/ml, P =.037) and 4 days (from 189 to 370 pg/ml, P =.044) after the first OXT administration ( Fig 4A). No significant changes were observed PEDIATRICS Volume 139, number 2, February mean change calculated over all the voxels in this area for each subject was correlated with the changes in NOMAS (τ-b = 0.396), the CIB child social engagement composite (τ-b = 0.555), and the CIB child state composite (τ-b = 0.535) ( Fig 5C). Long-term Observational Data Collected During Routine Follow-up As shown in Table 2, we observed no significant differences in height, weight, BMI, or body composition at a median age of 26.5 months (range, 13 to 35 months), thus documenting the excellent long-term tolerance of early OXT treatment. Although we did not observe a difference in the age at walking between
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