- Email: [email protected]
BioEnterics Intragastric Balloon for the treatment of pathologic obesity in Prader–Willi patients
METABOLIC DISORDERS
BioEnterics Intragastric Balloon for the treatment of pathologic obesity in PradereWilli patients
body weight is mandatory to reduce the risk of cardiorespiratory and metabolic complications. The aim of the present study was to assess the risks and benefits of the BioEnterics Intragastric Balloon (BIB) for the treatment of morbid obesity in patients with PWS. Twenty-one BIBs were positioned in 12 patients with PWS (4 male and 8 female) aged from 8.1 to 30.1 years, and were removed after 8 (SD) 1.4 (range 5e10) months. Auxological, clinical and nutritional evaluations were performed every 2 months. Variations in body composition were analysed by dual-energy X-ray absorptiometry (DEXA). One patient (aged 28.5 years and with a body mass index [BMI] of 59.3 kg/m2) died 22 days after BIB positioning because of gastric perforation. In another individual (26.2 years, BMI 57.6 kg/m2), the BIB was surgically removed after 25 days because of symptoms suggesting gastric perforation (which was not confirmed). The remaining 10 patients showed a significant decrease of BMI ( p ¼ 0.005) and of fat tissue as measured by DEXA ( p ¼ 0.012). No significant modifications in bone mineral density occurred, but a slight loss in lean body mass ( p ¼ 0.036) was documented. In five patients, BIB treatment was repeated more than once. This study shows that when noninvasive pharmacological therapies fail, BIB may be effective to control body weight in PWS patients with morbid obesity, particularly when treatment is started in early childhood. However, careful clinical follow-up and close collaboration with parents are crucial to avoid severe complications, which can be caused by persisting unrestrained food intake.
Francesco De Peppo Ottavio Adorisio Berardino Melissa Vincenzo Abate Micaela Germani Antonio Crino` Gabriele Di Giorgio Franco Schiavi Massimo Rivosecchi
Abstract Obesity in PradereWilli syndrome (PWS) is progressive, severe and resistant to dietary, pharmacological and behavioural treatment. A reduction in
Keywords body mass index; intragastric balloon; obesity; PradereWilli syndrome
PradereWilli syndrome (PWS) is the most common genetic cause of obesity and is due to a paternally derived deletion of the q11e13 region or to a maternal uniparental disomy of chromosome 15.1 It occurs in approximately 1 in 15 000e25 000 live births.2 The earlyonset childhood hyperphagia characteristic of the syndrome very often leads to precocious morbid obesity. The exact aetiology of the excessive appetite and lack of satiety in these patients is unknown, but it seems to have a hypothalamic origin.3 The first step among the various therapeutic options currently available consists of combining a low-calorie diet with changes in lifestyle. In most cases, conventional treatment, based on behavioural and dietary approaches, has been proven to be inadequate to obtain substantial and prolonged weight loss.4 A self-imposed food intake restriction is often impossible to obtain in these patients. Surgery must be reserved for those patients in whom medical treatment has been unsuccessful. The BioEnterics Intragastric Balloon (BIB) is an endoscopic device for a temporary nonsurgical and non-pharmaceutical treatment of morbid obesity5; it is a restrictive device whose application is totally reversible and repeatable. The BIB is a smooth silicone elastic balloon with a self-sealing radio-opaque valve, designed to remain in the gastric cavity for a period of 6 months. The BIB has also been recommended as a preliminary treatment in order to reduce life-threatening co-morbidities and the risks of bariatric surgery, especially in extremely obese patients.6 BIBs are used in adults not only to obtain weight loss for obese patients, but also as a means to reduce risk factors associated with obesity prior to bariatric surgery.7 The aim of the study was to assess the risks and benefits of using the BIB in the treatment of morbid obesity in paediatric and adolescent patients with PWS.
Francesco De Peppo MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Ottavio Adorisio MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Berardino Melissa MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Vincenzo Abate MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Micaela Germani MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Antonio Crino` MD is Endocrinologist at Paediatric and Autoimmune Endocrine Diseases Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Gabriele Di Giorgio MD is Endocrinologist at Paediatric and Autoimmune Endocrine Diseases Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Franco Schiavi MD is Anesthesiologist at Anaesthesiology Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Massimo Rivosecchi MD is Head of Peadiatric Surgery Department, IRCCS at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy.
PAEDIATRICS AND CHILD HEALTH 19:S1
S38
Ó 2009 Elsevier Ltd. All rights reserved.
METABOLIC DISORDERS
device (ASA Benelux, Turnhot, Belgium) after a mean of 8 1.41 (range 5e10) months. In two patients the treatment was repeated twice, and in another three patients three times (one of these still being on treatment with the fourth balloon). There was a free interval of 12.2 7.7 (range 3e25) months between any two consecutive treatments. Paired comparisons of weight, BMI, %BWE and body composition before and after treatment were carried out using the Wilcoxon signed-rank test. A value p < 0.05 was used as the critical value to determine statistical significance. Data were expressed as mean standard deviation and ranges. The analysis was performed using the statistical software Stata, version 9.0 (StataCorp, TX, USA).
Materials and methods The study group included 12 individuals with PWS (4 male and 8 female) who were admitted to our Paediatric Surgery Unit from March 2002 to July 2007. Twenty-eight BIBs (Inamed, Santa Barbara, CA, USA) were used in these 12 patients aged from 8 to 30.1 (mean age 18.7 [SD] 7.07) years. The diagnosis of PWS was made according to the Holm and Cassidy criteria8 and confirmed by genetic analysis using the methylation test and/or fluorescence in situ hybridisation for chromosome 15. Preoperative co-morbidities were diagnosed in six patients (50%). Three patients were affected by type 2 diabetes mellitus, and one by both type 2 diabetes mellitus and hypertension. The fifth presented with subclinical hypothyroidism, and the sixth, a 10-year-old boy suffering from severe scoliosis, required tracheostomy for respiratory failure at the age of 5. The preoperative mean BMI was 50.1 8.39 (range 39.3e 62.1) kg/m2, the mean weight 105.40 17.3 (range 63e150) kg, the mean height 145.8 10.0 (range 134e163) cm and the mean body weight excess percentage (%BWE) 123.4 48.8% (range 69.4e244.0%). All these patients underwent cardiological evaluation, a barium meal, hepatic ultrasound, psychological evaluation, endocrinological assessment and dual-energy X-ray absorptiometry (DEXA). Exclusion criteria for BIB treatment were: BMI less than 30 kg/m2, BMI between 30 and 35 kg/m2 without co-morbidities, oesophagitis (above grade 1), hiatus hernia (more than 5 cm), chronic steroid therapy, use of non-steroidal anti-inflammatory drugs or anticoagulants, an active peptic ulcer or its previous complications, previous gastrointestinal resection, structural abnormalities of the gastrointestinal tract, lesions considered at risk of bleeding and problems precluding safe endoscopy. Informed consent was obtained from the patients’ parents. Under general anaesthesia with orotracheal intubation or heavy sedation with propofol, a BIB was positioned in the gastric cavity following routine oesophagogastroscopy to exclude the presence of any contraindications. After positioning in the gastric fundus, the BIB was inflated under endoscopic vision with a mean of 547.72 51.44 (range 510e640) ml of saline; 10 ml of methylene blue solution was added in order to allow early detection of a balloon rupture by colouring the patient’s urine and faeces. Once able to tolerate fluids by mouth, the patients were discharged with a restricted-calorie food intake (700e1000 kcal). At discharge, a proton pump inhibitor was prescribed (lansoprazole 60 mg per day for 2 weeks followed by 30 mg per day for the duration of treatment) associated with sucralfate (1e2 g twice a day as required) and antiemetics (ondansetron 4e8 mg per day if required). Auxological, clinical and nutritional evaluations were performed before the treatment and then every 2 months until BIB removal. Body composition was evaluated by DEXA before insertion and immediately after BIB removal, using Delphi W (S/ N 70400) and Hologic QDR 11.2 (2001) software to calculate lumbar spine bone mineral density (also expressed as T-score and Z-score), fat mass (kg), fat percentage and lean mass (kg). Under general anaesthesia with orotracheal intubation, the BIB was endoscopically removed using a specially designed
PAEDIATRICS AND CHILD HEALTH 19:S1
Results BIB positioning was uncomplicated in all cases, with a mean procedure duration of 14 5 minutes. The immediate postoperative period was uneventful, and all the patients were discharged within 48 hours. Antiemetic drugs, which are usually used in the first postoperative period in simple obesity, were required, as a single dose, in only two of our patients. The patients’ preoperative auxological characteristics, weight and BMI variations are shown in Table 1. The use of BIB was uncomplicated in 15 out of 21 procedures (71.4%). In addition to the major complications mentioned above, we observed one case (T.K.) of acute gaseous gastric distension (Figure 1) due to ingestion of 500 ml of a fizzy drink (absolutely forbidden according to our protocol) that was resolved by nasogastric tube insertion. In the same patient, a balloon rupture occurred 9 months after the positioning of his third BIB, which was easily removed by endoscopy. Another patient suffered from chronic gastric food impaction (Figure 2) with abdominal tenderness and pain, requiring a prolonged abstinence from solid food and intravenous therapy with erythromycin (30 mg/kg per day) used as a prokinetic.9 Minor complications, in the form of recurrent diarrhoea with aerophagy and halitosis, were observed in this last patient. Overall, the 10 patients (age 17 6.4 years; 4 male and 6 female) who continued treatment according to the protocol had an average treatment period of 8 1.4 (range 5e10) months and showed a significant clinical improvement on all main body weight indices (Table 2) with a percentage of excess weight loss of 24.3 17.4%. DEXA analysis of body composition showed
The study population Number of patients
12
Genetic analysis Age (years) Sex (m:f ) Height (SDS) Body mass index (kg/m2) Body mass index (SDS)
8Del-3UPD 18.7 7.07 4:8 1.64 2.5 50.1 8.39 12.8 3.57
Range 8.0e30.1 5.08e2.28 39.1e60.9 7.7e22
Table 1
S39
Ó 2009 Elsevier Ltd. All rights reserved.
METABOLIC DISORDERS
Body composition before and 6 months after insertion of a BioEnterics Intragastric Balloon (BIB) Patients with Pradere Willi syndrome (n [ 9)
Before BIB insertion
At BIB removal
p
Body mass index (kg/m2) Body mass index (SDS) % Fat Fat tissue (g) Lean mass (g) Bone mineral density (g/cm2)
50.39 8.39 12.96 3.9 52.9 1.7 52 202 12 616 46 251 8 172 0.98 0.12
41.5 9.8 9.28 2.6 49.1 5.3 45 785 14 070 44 600 7 593 0.99 0.12
0.0002 0.005 0.017 0.003 ns ns
ns, not significant.
Table 2
87 to 70.3 kg and from 44.6 to 33.7 kg/m2, respectively; another patient, a 9.4-year-old boy, lost 25.4 kg, reducing his BMI from 39.1 to 24.9 kg/m2. An evident reduction of the characteristic spasmodic food search was reported by almost all the patients’ families but only during the first 3e4 months of treatment. In the five patients who underwent multiple treatments, an excellent result was obtained in the two younger ones. The first was treated for the first time at the age of 8.1 when his BMI was 44.6 kg/m2; more than 5 years later, he started his fourth treatment (still ongoing) with a BMI of 36 kg/m2. The second patient had his first treatment at the age of 9.4 years with a starting BMI of 39.1 kg/m2; 3 years later, at the end of his second treatment, his BMI was 23.6 kg/m2. In the remaining three cases, BMI stabilisation was obtained during a mean treatment period of 3.5 1.6 (range 2.4e5.4) years. A 12.4-year-old boy (P.D.M.) was treated three times in about 3 years: his starting BMI was 39.3 kg/m2, while at the end of the third treatment period, it had slightly increased to 40.2 kg/m2. At the age of 17.5, he underwent a biliopancreatic diversion due to his inadequate compliance with dietetic rules. In the two oldest patients (20.6 and 30.1 years respectively), only a slight reduction in BMI was obtained with their first balloon, and BMI stabilisation was observed during the subsequent treatments. During the free intervals or after treatment interruption, BMI tended to increase in every patient. One female patient (M.L.) died 22 days after BIB positioning due to gastric perforation. Her first postoperative period was uneventful and, according to the protocol in force at the time, she started a solid diet 15 days after BIB positioning. Five days later, she developed halitosis and sporadic regurgitation, but unfortunately these symptoms were not immediately reported by her parents. After two additional days, she was admitted to our hospital with acute abdominal pain and haematic vomiting. Following radiographic evidence of free air in the abdomen, an emergency laparotomy was attempted. She died during the anaesthetic induction because of irreversible cardiorespiratory failure. At autopsy, we found a large volume of food remnants filling the abdominal cavity, and a large amount of undigested vegetables filling the stomach, as well as massive gastric fundal necrosis.
Figure 1 Posteroanterior abdominal X-ray showing acute gaseous gastric distension due to the ingestion of 500ml of a fizzy drink.
a significant reduction in fat tissue ( p ¼ 0.012) with no considerable loss of bone mineral density and only a slight loss in lean mass ( p ¼ 0.036; Table 2). An improvement in co-morbidities was observed in all patients with type 2 diabetes mellitus, allowing a reduction in pharmacological dosage. In our series, BMI reduction seems to be higher in young patients: the 8.1-year-old child reduced his weight and BMI from
Figure 2 Posteroanterior abdominal X-ray showing chronic gastric food impaction.
PAEDIATRICS AND CHILD HEALTH 19:S1
S40
Ó 2009 Elsevier Ltd. All rights reserved.
METABOLIC DISORDERS
One month later, a second female patient (P.G.) developed, 25 days after BIB insertion and about 10 days after starting a solid diet, a similar clinical picture with nausea and abdominal pain. A gastric perforation was suspected after abdominal X-ray: the emergency laparotomy revealed a giant gastric fitobezoar without any gastric perforation. Since the endoscopical removal of the balloon failed due to the huge quantity of undigested vegetables, a gastrostomy was necessary to void the gastric cavity and to remove the balloon.
designed dietary protocol. Lack of compliance, due to severe behavioural problems and/or intellectual disability, may expose these patients to the risk of excessive or uncontrolled food and/ or drink intake. The consequent acute or chronic gastric distension, together with the almost totally absent emetic reflex, may lead to a delayed diagnosis of gastric perforation. The delayed gastric emptying typical of BIB positioning may play a role in reducing hunger, especially during the first month of treatment. In patients with PWS, in whom it seems to be more marked and persistent, it may contribute to gastric food impaction, and is also seen in the subsequent months of treatment. There are dangerous features typical of PWS that warrant the adoption of a specific postoperative management protocol including: a semi-liquid diet for at least 30 days after positioning the BIB, which should be started again if any gastrointestinal symptoms arise; because of the delayed gastric emptying, the careful dicing of vegetables into very small pieces to avoid the risk of developing a phytobezoar and chronic gastric distension; mandatory close collaboration between the family/patient and the medical team; alerting of the patient’s general practitioner, schoolteachers and any other caregiver; mandatory prompt clinical examination and radiological study if any gastrointestinal symptom occurs. To our knowledge, this is the first reported experience of BIB use in patients with PWS. In these subjects, the BIB may represent an alternative treatment for body weight control when other pharmacological or dietary approaches have failed. Being totally reversible and repeatable, the BIB procedure can be used more than once, bringing paediatric patients to adult age while maintaining a BMI as close as possible to normal values, therefore reducing the risk of co-morbidities. In older individuals with PWS, the BIB can be useful as a preliminary treatment to reduce the risks of a definitive bariatric surgical procedure, such as biliopancreatic diversion. A specific postoperative management protocol must be adopted in these patients in order to decrease the BIB complication rate, even though the peculiar characteristics of PWS patients preclude the possibility of achieving the very low morbidity rate observed for patients with primary obesity.
Discussion Obesity associated with PWS is likely to be progressive and severe, with a BMI over 40, and is almost always resistant to dietary, pharmacological and behavioural treatments. In these patients, a drastic reduction in body weight is mandatory to reduce the risk of cardiorespiratory and metabolic complications and to improve life expectancy. During the last three decades, several bariatric surgical techniques have been applied to treat morbid obesity in patients with PWS, including truncal vagotomy,10 jejunoileal bypass,11 vertical banded gastroplasty,12 adjustable silicone gastric banding,13 gastric bypass14 and biliopancreatic diversion.15,16 However, a higher morbidity and mortality rate has been reported in these patients compared with those with simple obesity.17 Endoscopic treatment of morbid obesity with an intragastric balloon has been tested, both on its own and in combination with other treatments, in adults with simple obesity.10 In a large multicentric study, Genco et al. showed that the use of a BIB induced a significant reduction in BMI and an improvement of co-morbidities. A complication rate of 2.8% (70 out of 2515 patients) was observed, with five cases of gastric perforation (0.19%) leading to two deaths (0.08%). In the long-term followup, a success rate of 20% was reported.10 However, there are no published data regarding the use of this technique in individuals with PWS. Our study showed that, in patients with PWS, BIB positioning induced reduced eating due to a feeling of satiety during the first months of treatment. A significant weight loss, an average BMI decrease of about 6 points, a reduction of mean %BWE from 123 to 93, together with a significant reduction in fat tissue and only a slight loss in lean mass were observed. An improvement of co-morbidities was observed in all patients by the end of treatment, although in some cases it was only temporary. In our series, younger patients appeared to benefit from treatment more than older ones, suggesting that early treatment may produce better results and minimise complications; however, the small sample size does not allow for any firm conclusion. In the subset of patients treated more than once, we obtained positive results in the two youngest, with a substantial BMI reduction maintained during a treatment period of about 3 years. In one patient, we were able to maintain a satisfactory BMI control until the age of 17, when he underwent a successful biliopancreatic diversion. In our study, the use of BIB was associated with a complication rate of 6 out of 21 procedures (28.6%). The standard dietary BIB protocol needs to be modified in PWS patients in order to reduce the risk of adverse events; in fact, all major complications observed occurred as a consequence of the lack of a specifically
PAEDIATRICS AND CHILD HEALTH 19:S1
Conflict of interest None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. A
REFERENCES 1 Goldstone AP. PradereWilli syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab 2004; 15: 12e20. 2 Whittington JE, Holand AJ, Webb T, et al. Population prevalence and estimated birth incidence and mortality rate for people with Pradere Willi syndrome in one UK Health Region. J Med Genet 2001; 38: 792e8.
S41
Ó 2009 Elsevier Ltd. All rights reserved.
METABOLIC DISORDERS
3 Burman P, Ritzen EM, Lindgren AC. Endocrine dysfunction in Pradere Willi syndrome: a review with special reference to GH. Endocr Rev 2001; 22: 787e99. 4 Butler MG. Management of obesity in PradereWilli syndrome. Nat Clin Pract Endocrinol Metab 2006; 2: 592e3. 5 Nieben OG, Harboe H. Intragastric balloon as an artificial bezoar for treatment of obesity. Lancet 1982; 1: 198e9. 6 Doldi SB, Micheletto G, Perrini MN, et al. Intragastric balloon: another option for treatment of obesity and morbid obesity. Hepatogastroenterology 2004; 51: 294e7. 7 Roman S, Napoleon B, Mion F, et al. Intragastric balloon for ‘‘nonmorbid’’ obesity: a retrospective evaluation of tolerance and efficacy. Obes Surg 2004; 14: 539e44. 8 Holm VA, Cassidy SB, Buter MG, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993; 91: 398e402. 9 Curry JI, Lander TD, Stringer MD. Review article: erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001; 15: 595e603. 10 Touquet VL, Ward MW, Clark CG. Obesity surgery in a patient with PradereWilli syndrome. Br J Surg 1983; 70: 180e6.
PAEDIATRICS AND CHILD HEALTH 19:S1
11 Smith R, Kouvalainen K. Jejunoileal bypass for morbidly obese adolescents. Acta Paediatr Scand 1975;(Suppl): 62e3. 12 Dousei T, Miyata M, Izukura M, et al. Long term follow up of gastroplasty in a patient with PradereWilli syndrome. Obes Surg 1992; 2: 189e93. 13 Mason EE, Scott DH, Doherty C, et al. Vertical banded gastroplasty in the severely obese under age twenty-one. Obes Surg 1995; 5: 23e33. 14 Chelala E, Cadiere GB, Favretti F, et al. Conversion and complication in 185 laparoscopic adjustable silicone gastric banding cases. Surg Endosc 1997; 11: 268e71. 15 Kobayashi J, Kodama M, Yamazaki K, et al. Gastric bypass in a Japanese man with PradereWilli syndrome and morbid obesity. Obes Surg 2003; 13: 803e5. 16 Laurent-Jaccard A, Hofstetter JR, Saegesser F, et al. Long-term result of treatment of PradereWilli syndrome by Scopinaro’s biliopancreatic diversion. Study of three cases and the effect of dextrofenfluramine on the postoperative evolution. Obes Surg 1991; 1: 83e7. 17 Marinari GM, Camerini G, Novelli GB, et al. Outcome of biliopancreatic diversion in subjects with PradereWilli syndrome. Obes Surg 2001; 11: 491e5.
S42
Ó 2009 Elsevier Ltd. All rights reserved.
BioEnterics Intragastric Balloon for the treatment of pathologic obesity in PradereWilli patients
body weight is mandatory to reduce the risk of cardiorespiratory and metabolic complications. The aim of the present study was to assess the risks and benefits of the BioEnterics Intragastric Balloon (BIB) for the treatment of morbid obesity in patients with PWS. Twenty-one BIBs were positioned in 12 patients with PWS (4 male and 8 female) aged from 8.1 to 30.1 years, and were removed after 8 (SD) 1.4 (range 5e10) months. Auxological, clinical and nutritional evaluations were performed every 2 months. Variations in body composition were analysed by dual-energy X-ray absorptiometry (DEXA). One patient (aged 28.5 years and with a body mass index [BMI] of 59.3 kg/m2) died 22 days after BIB positioning because of gastric perforation. In another individual (26.2 years, BMI 57.6 kg/m2), the BIB was surgically removed after 25 days because of symptoms suggesting gastric perforation (which was not confirmed). The remaining 10 patients showed a significant decrease of BMI ( p ¼ 0.005) and of fat tissue as measured by DEXA ( p ¼ 0.012). No significant modifications in bone mineral density occurred, but a slight loss in lean body mass ( p ¼ 0.036) was documented. In five patients, BIB treatment was repeated more than once. This study shows that when noninvasive pharmacological therapies fail, BIB may be effective to control body weight in PWS patients with morbid obesity, particularly when treatment is started in early childhood. However, careful clinical follow-up and close collaboration with parents are crucial to avoid severe complications, which can be caused by persisting unrestrained food intake.
Francesco De Peppo Ottavio Adorisio Berardino Melissa Vincenzo Abate Micaela Germani Antonio Crino` Gabriele Di Giorgio Franco Schiavi Massimo Rivosecchi
Abstract Obesity in PradereWilli syndrome (PWS) is progressive, severe and resistant to dietary, pharmacological and behavioural treatment. A reduction in
Keywords body mass index; intragastric balloon; obesity; PradereWilli syndrome
PradereWilli syndrome (PWS) is the most common genetic cause of obesity and is due to a paternally derived deletion of the q11e13 region or to a maternal uniparental disomy of chromosome 15.1 It occurs in approximately 1 in 15 000e25 000 live births.2 The earlyonset childhood hyperphagia characteristic of the syndrome very often leads to precocious morbid obesity. The exact aetiology of the excessive appetite and lack of satiety in these patients is unknown, but it seems to have a hypothalamic origin.3 The first step among the various therapeutic options currently available consists of combining a low-calorie diet with changes in lifestyle. In most cases, conventional treatment, based on behavioural and dietary approaches, has been proven to be inadequate to obtain substantial and prolonged weight loss.4 A self-imposed food intake restriction is often impossible to obtain in these patients. Surgery must be reserved for those patients in whom medical treatment has been unsuccessful. The BioEnterics Intragastric Balloon (BIB) is an endoscopic device for a temporary nonsurgical and non-pharmaceutical treatment of morbid obesity5; it is a restrictive device whose application is totally reversible and repeatable. The BIB is a smooth silicone elastic balloon with a self-sealing radio-opaque valve, designed to remain in the gastric cavity for a period of 6 months. The BIB has also been recommended as a preliminary treatment in order to reduce life-threatening co-morbidities and the risks of bariatric surgery, especially in extremely obese patients.6 BIBs are used in adults not only to obtain weight loss for obese patients, but also as a means to reduce risk factors associated with obesity prior to bariatric surgery.7 The aim of the study was to assess the risks and benefits of using the BIB in the treatment of morbid obesity in paediatric and adolescent patients with PWS.
Francesco De Peppo MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Ottavio Adorisio MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Berardino Melissa MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Vincenzo Abate MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Micaela Germani MD is Pediatric Surgeons at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Antonio Crino` MD is Endocrinologist at Paediatric and Autoimmune Endocrine Diseases Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Gabriele Di Giorgio MD is Endocrinologist at Paediatric and Autoimmune Endocrine Diseases Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Franco Schiavi MD is Anesthesiologist at Anaesthesiology Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy. Massimo Rivosecchi MD is Head of Peadiatric Surgery Department, IRCCS at Paediatric Surgery Unit, Bambino Gesu` Children’s Hospital Research Institute, Palidoro, Rome, Italy.
PAEDIATRICS AND CHILD HEALTH 19:S1
S38
Ó 2009 Elsevier Ltd. All rights reserved.
METABOLIC DISORDERS
device (ASA Benelux, Turnhot, Belgium) after a mean of 8 1.41 (range 5e10) months. In two patients the treatment was repeated twice, and in another three patients three times (one of these still being on treatment with the fourth balloon). There was a free interval of 12.2 7.7 (range 3e25) months between any two consecutive treatments. Paired comparisons of weight, BMI, %BWE and body composition before and after treatment were carried out using the Wilcoxon signed-rank test. A value p < 0.05 was used as the critical value to determine statistical significance. Data were expressed as mean standard deviation and ranges. The analysis was performed using the statistical software Stata, version 9.0 (StataCorp, TX, USA).
Materials and methods The study group included 12 individuals with PWS (4 male and 8 female) who were admitted to our Paediatric Surgery Unit from March 2002 to July 2007. Twenty-eight BIBs (Inamed, Santa Barbara, CA, USA) were used in these 12 patients aged from 8 to 30.1 (mean age 18.7 [SD] 7.07) years. The diagnosis of PWS was made according to the Holm and Cassidy criteria8 and confirmed by genetic analysis using the methylation test and/or fluorescence in situ hybridisation for chromosome 15. Preoperative co-morbidities were diagnosed in six patients (50%). Three patients were affected by type 2 diabetes mellitus, and one by both type 2 diabetes mellitus and hypertension. The fifth presented with subclinical hypothyroidism, and the sixth, a 10-year-old boy suffering from severe scoliosis, required tracheostomy for respiratory failure at the age of 5. The preoperative mean BMI was 50.1 8.39 (range 39.3e 62.1) kg/m2, the mean weight 105.40 17.3 (range 63e150) kg, the mean height 145.8 10.0 (range 134e163) cm and the mean body weight excess percentage (%BWE) 123.4 48.8% (range 69.4e244.0%). All these patients underwent cardiological evaluation, a barium meal, hepatic ultrasound, psychological evaluation, endocrinological assessment and dual-energy X-ray absorptiometry (DEXA). Exclusion criteria for BIB treatment were: BMI less than 30 kg/m2, BMI between 30 and 35 kg/m2 without co-morbidities, oesophagitis (above grade 1), hiatus hernia (more than 5 cm), chronic steroid therapy, use of non-steroidal anti-inflammatory drugs or anticoagulants, an active peptic ulcer or its previous complications, previous gastrointestinal resection, structural abnormalities of the gastrointestinal tract, lesions considered at risk of bleeding and problems precluding safe endoscopy. Informed consent was obtained from the patients’ parents. Under general anaesthesia with orotracheal intubation or heavy sedation with propofol, a BIB was positioned in the gastric cavity following routine oesophagogastroscopy to exclude the presence of any contraindications. After positioning in the gastric fundus, the BIB was inflated under endoscopic vision with a mean of 547.72 51.44 (range 510e640) ml of saline; 10 ml of methylene blue solution was added in order to allow early detection of a balloon rupture by colouring the patient’s urine and faeces. Once able to tolerate fluids by mouth, the patients were discharged with a restricted-calorie food intake (700e1000 kcal). At discharge, a proton pump inhibitor was prescribed (lansoprazole 60 mg per day for 2 weeks followed by 30 mg per day for the duration of treatment) associated with sucralfate (1e2 g twice a day as required) and antiemetics (ondansetron 4e8 mg per day if required). Auxological, clinical and nutritional evaluations were performed before the treatment and then every 2 months until BIB removal. Body composition was evaluated by DEXA before insertion and immediately after BIB removal, using Delphi W (S/ N 70400) and Hologic QDR 11.2 (2001) software to calculate lumbar spine bone mineral density (also expressed as T-score and Z-score), fat mass (kg), fat percentage and lean mass (kg). Under general anaesthesia with orotracheal intubation, the BIB was endoscopically removed using a specially designed
PAEDIATRICS AND CHILD HEALTH 19:S1
Results BIB positioning was uncomplicated in all cases, with a mean procedure duration of 14 5 minutes. The immediate postoperative period was uneventful, and all the patients were discharged within 48 hours. Antiemetic drugs, which are usually used in the first postoperative period in simple obesity, were required, as a single dose, in only two of our patients. The patients’ preoperative auxological characteristics, weight and BMI variations are shown in Table 1. The use of BIB was uncomplicated in 15 out of 21 procedures (71.4%). In addition to the major complications mentioned above, we observed one case (T.K.) of acute gaseous gastric distension (Figure 1) due to ingestion of 500 ml of a fizzy drink (absolutely forbidden according to our protocol) that was resolved by nasogastric tube insertion. In the same patient, a balloon rupture occurred 9 months after the positioning of his third BIB, which was easily removed by endoscopy. Another patient suffered from chronic gastric food impaction (Figure 2) with abdominal tenderness and pain, requiring a prolonged abstinence from solid food and intravenous therapy with erythromycin (30 mg/kg per day) used as a prokinetic.9 Minor complications, in the form of recurrent diarrhoea with aerophagy and halitosis, were observed in this last patient. Overall, the 10 patients (age 17 6.4 years; 4 male and 6 female) who continued treatment according to the protocol had an average treatment period of 8 1.4 (range 5e10) months and showed a significant clinical improvement on all main body weight indices (Table 2) with a percentage of excess weight loss of 24.3 17.4%. DEXA analysis of body composition showed
The study population Number of patients
12
Genetic analysis Age (years) Sex (m:f ) Height (SDS) Body mass index (kg/m2) Body mass index (SDS)
8Del-3UPD 18.7 7.07 4:8 1.64 2.5 50.1 8.39 12.8 3.57
Range 8.0e30.1 5.08e2.28 39.1e60.9 7.7e22
Table 1
S39
Ó 2009 Elsevier Ltd. All rights reserved.
METABOLIC DISORDERS
Body composition before and 6 months after insertion of a BioEnterics Intragastric Balloon (BIB) Patients with Pradere Willi syndrome (n [ 9)
Before BIB insertion
At BIB removal
p
Body mass index (kg/m2) Body mass index (SDS) % Fat Fat tissue (g) Lean mass (g) Bone mineral density (g/cm2)
50.39 8.39 12.96 3.9 52.9 1.7 52 202 12 616 46 251 8 172 0.98 0.12
41.5 9.8 9.28 2.6 49.1 5.3 45 785 14 070 44 600 7 593 0.99 0.12
0.0002 0.005 0.017 0.003 ns ns
ns, not significant.
Table 2
87 to 70.3 kg and from 44.6 to 33.7 kg/m2, respectively; another patient, a 9.4-year-old boy, lost 25.4 kg, reducing his BMI from 39.1 to 24.9 kg/m2. An evident reduction of the characteristic spasmodic food search was reported by almost all the patients’ families but only during the first 3e4 months of treatment. In the five patients who underwent multiple treatments, an excellent result was obtained in the two younger ones. The first was treated for the first time at the age of 8.1 when his BMI was 44.6 kg/m2; more than 5 years later, he started his fourth treatment (still ongoing) with a BMI of 36 kg/m2. The second patient had his first treatment at the age of 9.4 years with a starting BMI of 39.1 kg/m2; 3 years later, at the end of his second treatment, his BMI was 23.6 kg/m2. In the remaining three cases, BMI stabilisation was obtained during a mean treatment period of 3.5 1.6 (range 2.4e5.4) years. A 12.4-year-old boy (P.D.M.) was treated three times in about 3 years: his starting BMI was 39.3 kg/m2, while at the end of the third treatment period, it had slightly increased to 40.2 kg/m2. At the age of 17.5, he underwent a biliopancreatic diversion due to his inadequate compliance with dietetic rules. In the two oldest patients (20.6 and 30.1 years respectively), only a slight reduction in BMI was obtained with their first balloon, and BMI stabilisation was observed during the subsequent treatments. During the free intervals or after treatment interruption, BMI tended to increase in every patient. One female patient (M.L.) died 22 days after BIB positioning due to gastric perforation. Her first postoperative period was uneventful and, according to the protocol in force at the time, she started a solid diet 15 days after BIB positioning. Five days later, she developed halitosis and sporadic regurgitation, but unfortunately these symptoms were not immediately reported by her parents. After two additional days, she was admitted to our hospital with acute abdominal pain and haematic vomiting. Following radiographic evidence of free air in the abdomen, an emergency laparotomy was attempted. She died during the anaesthetic induction because of irreversible cardiorespiratory failure. At autopsy, we found a large volume of food remnants filling the abdominal cavity, and a large amount of undigested vegetables filling the stomach, as well as massive gastric fundal necrosis.
Figure 1 Posteroanterior abdominal X-ray showing acute gaseous gastric distension due to the ingestion of 500ml of a fizzy drink.
a significant reduction in fat tissue ( p ¼ 0.012) with no considerable loss of bone mineral density and only a slight loss in lean mass ( p ¼ 0.036; Table 2). An improvement in co-morbidities was observed in all patients with type 2 diabetes mellitus, allowing a reduction in pharmacological dosage. In our series, BMI reduction seems to be higher in young patients: the 8.1-year-old child reduced his weight and BMI from
Figure 2 Posteroanterior abdominal X-ray showing chronic gastric food impaction.
PAEDIATRICS AND CHILD HEALTH 19:S1
S40
Ó 2009 Elsevier Ltd. All rights reserved.
METABOLIC DISORDERS
One month later, a second female patient (P.G.) developed, 25 days after BIB insertion and about 10 days after starting a solid diet, a similar clinical picture with nausea and abdominal pain. A gastric perforation was suspected after abdominal X-ray: the emergency laparotomy revealed a giant gastric fitobezoar without any gastric perforation. Since the endoscopical removal of the balloon failed due to the huge quantity of undigested vegetables, a gastrostomy was necessary to void the gastric cavity and to remove the balloon.
designed dietary protocol. Lack of compliance, due to severe behavioural problems and/or intellectual disability, may expose these patients to the risk of excessive or uncontrolled food and/ or drink intake. The consequent acute or chronic gastric distension, together with the almost totally absent emetic reflex, may lead to a delayed diagnosis of gastric perforation. The delayed gastric emptying typical of BIB positioning may play a role in reducing hunger, especially during the first month of treatment. In patients with PWS, in whom it seems to be more marked and persistent, it may contribute to gastric food impaction, and is also seen in the subsequent months of treatment. There are dangerous features typical of PWS that warrant the adoption of a specific postoperative management protocol including: a semi-liquid diet for at least 30 days after positioning the BIB, which should be started again if any gastrointestinal symptoms arise; because of the delayed gastric emptying, the careful dicing of vegetables into very small pieces to avoid the risk of developing a phytobezoar and chronic gastric distension; mandatory close collaboration between the family/patient and the medical team; alerting of the patient’s general practitioner, schoolteachers and any other caregiver; mandatory prompt clinical examination and radiological study if any gastrointestinal symptom occurs. To our knowledge, this is the first reported experience of BIB use in patients with PWS. In these subjects, the BIB may represent an alternative treatment for body weight control when other pharmacological or dietary approaches have failed. Being totally reversible and repeatable, the BIB procedure can be used more than once, bringing paediatric patients to adult age while maintaining a BMI as close as possible to normal values, therefore reducing the risk of co-morbidities. In older individuals with PWS, the BIB can be useful as a preliminary treatment to reduce the risks of a definitive bariatric surgical procedure, such as biliopancreatic diversion. A specific postoperative management protocol must be adopted in these patients in order to decrease the BIB complication rate, even though the peculiar characteristics of PWS patients preclude the possibility of achieving the very low morbidity rate observed for patients with primary obesity.
Discussion Obesity associated with PWS is likely to be progressive and severe, with a BMI over 40, and is almost always resistant to dietary, pharmacological and behavioural treatments. In these patients, a drastic reduction in body weight is mandatory to reduce the risk of cardiorespiratory and metabolic complications and to improve life expectancy. During the last three decades, several bariatric surgical techniques have been applied to treat morbid obesity in patients with PWS, including truncal vagotomy,10 jejunoileal bypass,11 vertical banded gastroplasty,12 adjustable silicone gastric banding,13 gastric bypass14 and biliopancreatic diversion.15,16 However, a higher morbidity and mortality rate has been reported in these patients compared with those with simple obesity.17 Endoscopic treatment of morbid obesity with an intragastric balloon has been tested, both on its own and in combination with other treatments, in adults with simple obesity.10 In a large multicentric study, Genco et al. showed that the use of a BIB induced a significant reduction in BMI and an improvement of co-morbidities. A complication rate of 2.8% (70 out of 2515 patients) was observed, with five cases of gastric perforation (0.19%) leading to two deaths (0.08%). In the long-term followup, a success rate of 20% was reported.10 However, there are no published data regarding the use of this technique in individuals with PWS. Our study showed that, in patients with PWS, BIB positioning induced reduced eating due to a feeling of satiety during the first months of treatment. A significant weight loss, an average BMI decrease of about 6 points, a reduction of mean %BWE from 123 to 93, together with a significant reduction in fat tissue and only a slight loss in lean mass were observed. An improvement of co-morbidities was observed in all patients by the end of treatment, although in some cases it was only temporary. In our series, younger patients appeared to benefit from treatment more than older ones, suggesting that early treatment may produce better results and minimise complications; however, the small sample size does not allow for any firm conclusion. In the subset of patients treated more than once, we obtained positive results in the two youngest, with a substantial BMI reduction maintained during a treatment period of about 3 years. In one patient, we were able to maintain a satisfactory BMI control until the age of 17, when he underwent a successful biliopancreatic diversion. In our study, the use of BIB was associated with a complication rate of 6 out of 21 procedures (28.6%). The standard dietary BIB protocol needs to be modified in PWS patients in order to reduce the risk of adverse events; in fact, all major complications observed occurred as a consequence of the lack of a specifically
PAEDIATRICS AND CHILD HEALTH 19:S1
Conflict of interest None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. A
REFERENCES 1 Goldstone AP. PradereWilli syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab 2004; 15: 12e20. 2 Whittington JE, Holand AJ, Webb T, et al. Population prevalence and estimated birth incidence and mortality rate for people with Pradere Willi syndrome in one UK Health Region. J Med Genet 2001; 38: 792e8.
S41
Ó 2009 Elsevier Ltd. All rights reserved.
METABOLIC DISORDERS
3 Burman P, Ritzen EM, Lindgren AC. Endocrine dysfunction in Pradere Willi syndrome: a review with special reference to GH. Endocr Rev 2001; 22: 787e99. 4 Butler MG. Management of obesity in PradereWilli syndrome. Nat Clin Pract Endocrinol Metab 2006; 2: 592e3. 5 Nieben OG, Harboe H. Intragastric balloon as an artificial bezoar for treatment of obesity. Lancet 1982; 1: 198e9. 6 Doldi SB, Micheletto G, Perrini MN, et al. Intragastric balloon: another option for treatment of obesity and morbid obesity. Hepatogastroenterology 2004; 51: 294e7. 7 Roman S, Napoleon B, Mion F, et al. Intragastric balloon for ‘‘nonmorbid’’ obesity: a retrospective evaluation of tolerance and efficacy. Obes Surg 2004; 14: 539e44. 8 Holm VA, Cassidy SB, Buter MG, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993; 91: 398e402. 9 Curry JI, Lander TD, Stringer MD. Review article: erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001; 15: 595e603. 10 Touquet VL, Ward MW, Clark CG. Obesity surgery in a patient with PradereWilli syndrome. Br J Surg 1983; 70: 180e6.
PAEDIATRICS AND CHILD HEALTH 19:S1
11 Smith R, Kouvalainen K. Jejunoileal bypass for morbidly obese adolescents. Acta Paediatr Scand 1975;(Suppl): 62e3. 12 Dousei T, Miyata M, Izukura M, et al. Long term follow up of gastroplasty in a patient with PradereWilli syndrome. Obes Surg 1992; 2: 189e93. 13 Mason EE, Scott DH, Doherty C, et al. Vertical banded gastroplasty in the severely obese under age twenty-one. Obes Surg 1995; 5: 23e33. 14 Chelala E, Cadiere GB, Favretti F, et al. Conversion and complication in 185 laparoscopic adjustable silicone gastric banding cases. Surg Endosc 1997; 11: 268e71. 15 Kobayashi J, Kodama M, Yamazaki K, et al. Gastric bypass in a Japanese man with PradereWilli syndrome and morbid obesity. Obes Surg 2003; 13: 803e5. 16 Laurent-Jaccard A, Hofstetter JR, Saegesser F, et al. Long-term result of treatment of PradereWilli syndrome by Scopinaro’s biliopancreatic diversion. Study of three cases and the effect of dextrofenfluramine on the postoperative evolution. Obes Surg 1991; 1: 83e7. 17 Marinari GM, Camerini G, Novelli GB, et al. Outcome of biliopancreatic diversion in subjects with PradereWilli syndrome. Obes Surg 2001; 11: 491e5.
S42
Ó 2009 Elsevier Ltd. All rights reserved.