Download Prader Willi - University of Colorado Denver

Group 10
Laparoscopic sleeve gastrectomy for management of severe obesity in Prader-Willi
Syndrome: A prospective cohort study in children and adolescents.
Calies Menard-Katcher, Logan McKenna, Michelle Rove
Background
Prader-Willi Syndrome: Prader-Willi Syndrome (PWS) is a genetic syndrome resulting from a
deletion in the paternally derived 15th chromosome (15q11-q13). It is a neurodevelopmental
disorder that affects 1:10,000-1:30,000 live births. While PWS make up the vast minority of
obese individuals, it is the most common syndromic form of obesity (1,2). Early signs of PWS in
infants consist of poor muscle tone, distinct facial features such as almond-shaped eyes, poor
sucking reflex, lack of eye coordination, and general poor responsiveness. In childhood and
adolescence, uncontrolled eating, impaired satiety, low energy expenditure, hypogonadism,
and morbid obesity characterize PWS. Primary endocrine abnormalities also co-exist that likely
relate to their appetite and metabolism, namely decreased growth hormone and increased
ghrelin, a hormone peptide that regulates appetite and plays a role in regulating metabolism.
This leads to significant comorbidities including insulin resistance, type 2 diabetes, obstructive
sleep apnea (OSA), cor pulmonale and atherscerlosis. Coexisting symptoms include dental
problems, inability to vomit, scoliosis, temperature dysregulation, high pain threshold, seizures,
sensory impairment, obsessive compulsive disorder, and autistic behaviors (2).
Weight Loss Management: Clinical management is directed at controlling weight gain and
preventing subsequent comorbidities. Standard of care aims to minimize weight gain through
restriction and close supervision of food intake. It is critical for these patients to maintain a
strict meal plan, prevent binge eating, and encourage regular daily activity. Some have even
gone as far as putting locks on cabinets and trash cans in order to prevent patients from binge
eating. Medications that aim to curb weight gain either targeting the endocrine abnormalities
or behavior control have shown mixed results and are not part of standard care. For example,
growth hormone treatment, used to treat growth hormone deficiency in PWS, does not affect
appetite or weight gain (2).
Weight Loss Surgery: Bariatric surgery procedures such as roux-en-Y gastric bypass are
increasingly used to manage adult obesity. Currently, the three major weight loss surgeries are
laparoscopic band surgery, sleeve gastrectomy, and gastric bypass. Laparoscopic band surgery
has a very low mortality and complication rate (2.4%), but equivalently has lower weight loss
outcomes (about 20% of pre-surgical weight) than the other two surgeries. Sleeve gastrectomy
has a slightly higher mortality (0.1%) and complication rate (6.3%), along with a higher weight
loss outcome (about 25% of pre-surgical weight). Gastric bypass tends to have the highest
weight loss outcome (about 30% of pre-surgical weight), but has the highest mortality (0.2%)
and complication rate (10%) of the three surgeries (3). Weight loss from these surgeries has
been found to be durable for decades and results in significantly improved over-all mortality
(4). But perhaps most importantly, weight loss surgery has been shown to be effective in
treating the sequelae of obesity, particulary diabetes mellitus and OSA. This is particularly true
for the roux-en-Y gastric bypass procedure, with one study showing that 42% or patients were
essentially cured of their diabetes with HgA1c measurements within goal range on no diabetic
medications (5).
Due to the excellent results in adults, weight loss surgery has been attempted in
children and adolecents with Prader-Willi syndrome with mixed results. A 2008 review noted
that several studies showed an increased complication and mortality rate in this patient
population, suggesting that patients with Prader-Willi syndrome were a higher risk population
(6). It should be noted, however, that most of these studies are somewhat dated, and that most
patients in the review underwent a bilio-pancreatic diversion, an incredibly morbid procedure
that is rarely performed in the modern weight loss surgery era. None of the patient underwent
more modern interventions such as the laparoscopic band procedure or sleeve gastrectomy.
Laparoscopic Sleeve Gastrectomy (LSG) in PWS: Laparoscopic Sleeve Gastrectomy (LSG) is a
novel intervention for Prader-Willi syndrome. The first study of LSG in PWS reported on one
Chinese female patient with PWS and type two diabetes (T2DM). After a 15 month follow up
period the patient had lost 26.2 kg (94.2 kg to 68 kg), BMI of 46.7 to 33.7, and was in remission
from T2DM (7). The second study looked at ghrelin levels and weight loss after LSG and gastric
mini-bypass (LMGBP) in 3 Chinese patients (8). Two of the patients had LSG and one had
LMGBP. At 24 month follow up the patients had an average weight loss of 13.4 kg, average BMI
reduction of 11.8, and an average ghrelin level reduction of 614.4 pg/ml. There were no major
peri-operative complications or mortality, but the LMGBP patient had an iron deficiency even
while on an iron supplement. These studies provided preliminary data to suggest modern
weight loss surgery may provide weight loss, BMI reduction, and improvement in other
secondary outcomes in this patient population without the risk seen previously.
Alqahtani et al have since published the first convenience cohort study of LSG in PWS
patients comparing 24 PWS patients to non-PWS patients who underwent LSG.(9) Groups were
similar in age range, gender, and BMI. The study indicated that LSG results in a loss of 60%
excess weight in both Prader-Willi and non Prader-willi children. Post-operatively 81.8% of all
Prader-Willi patients co-morbidities including OSA, diabetes, dyslipidemia and hypertension,
were in complete remission. It suggests that modern weight loss surgery may have comparable
risk in the PWS population as it does in the general weight loss surgery population and may
improve outcomes for children and adolescents with PWS.
We therefore propose to design a prospective cohort study of LSG in children and
adolescents in the United States to test the hypothesis that LSG will decrease BMI and improve
co-morbidities compared to current standard of care, medical weight loss management, and
have a tolerable safety and risk profile in this at risk population.
Synopsis of Proposed Study
Study Population:
In this study, we will include subjects with PWS as defined by the revised Holm et al criteria for
diagnosis of PWS (10). The diagnosis will be further confirmed by genetic evaluation with DNA
methylation analysis on chromosome 15. Inclusion criteria include: Age 11 to 18 years of age,
extreme obesity (BMI>40), and must have at least one serious obesity related comorbidity
including T2DM, OSA, dyslidipemia, hypertriglyceridemia, or hypertension. Both genders and all
race/ethnicities are eligible. Potential subjects must have completed an intake appointment
with the multidisciplinary Children’s Hospital of Colorado (CHCO) Prader-Willi clinic, specified
below. Exclusion criteria include: Having received growth hormone in the past 3 months,
diagnosis of pituitary, thyroid or adrenal gland dysfunction, history of poor compliance or
follow-up, plan to relocated in the next 12 months, or have undergone a prior surgical weight
loss procedure.
Study Treatments:
Pre-enrollment: Patients will undergo an initial evaluation by a multidisciplinary team including
pediatric endocrinologists, gastroenterologists, geneticists, behavioral and developmental
specialists, bariatric surgeons, dieticians, nurses, psychologists, social workers, and health
educators. All potential subjects will undergo six months of maximal medical weight loss
therapy as determined by the multidisciplinary treatment team. If unable to lose 10% of excess
body weight, surgery will be discussed in the multidisciplinary team setting and offered as a
treatment option to the family and patient.
Surgical treatment: Patients consenting for weight loss surgery will undergo surgical treatment
with LSG. LSG will be performed according the pediatric bariatric surgery pathway at CHCO
bariatric surgery program. Subjects not consenting for weight loss surgery will continue with
intensive but standard of care medical management through the Prader Willi Clinic at CHCO.
Follow up will be performed at 2 weeks, 3 months, 6 months, 9 months, 12 months, and then
annually thereafter. For patients that do not choose to undergo surgery, follow up will occur at
the same time frame except for the 2-week post-operative check.
Study Measurements:
At the time of enrollment within one month of surgery, subjects will have the following
assessments: anthropometrics including height and weight, blood pressure, polysomnography,
phlebotomy for tests including CBC, CMP, lipid panel, fasting glucose plasma level, oral glucose
tolerance test, HgbA1c, and baseline ghrelin. Serum will be saved for future analysis and
additional secondary studies. These measurements will be repeated at defined intervals
postoperatively (See Table).
Anthropometrics: Weight measures will be obtained to the nearest .1 kg using calibrated
electronic scales and height measures will be obtained to the nearest .1 cm using standing
stadiometers. Adiposity will be assessed by BMI and BMI z score, the change in those 2
variables from baseline, as well as %BMI change. Percent excess weight loss will be calculated
as: (Baseline weight – follow-up weight) / (Baseline weight – weight corresponding to 85th
percentile for age and gender on CDC weight for age growth chart). Percent total weight loss
will be calculated as: (Baseline weight – follow-up weight) / Baseline weight.
Obstructive sleep apnea: OSA will be evaluated by polysomnography and defined as a score of
15 or greater on the Apnea Hypoxia Index which is determined by the number of apneic or
hypoxic events per hour of sleep.
Lipids and cholesterol: Dyslipidemia will be measured by fasting serum levels and defined as
LDL>190, total cholesterol >240, or HDL <40 mg/dL. Trygliceride levels will be measured fasting
and hypertriglyceridemia will be defined as levels >200 mg/dL.
Diabetes Mellitus: DM type 2 will be defined by fasting serum plasma level (>126 mg/dL ab),
oral glucose tolerance test (OGT) (>200 mg/dL abnormal), or hgb A1c (>6.5% abnormal). Prediabetes will be defined as fasting serum plasma level (100-125 mg/dL), oral glucose tolerance
test (140-200 mg/dL), or hgb A1c (5.7-6.4%).
Blood pressure: BP will be measured by sphygmomanometer and hypertension defined as >99 th
percentile systolic or diastolic blood pressure based on height and gender.
Ghrelin: Fasting ghrelin levels (pg/mL) will be measured at baseline and annually thereafter.
This is an exploratory aim; therefore normative values are not defined for the purposes of this
study.
Visit Table
Visit (months post op)
Study
Ht, Wt, BMI
Blood Pressure
CBC, CMP,
lipids,
triglyceride,
ghrelin, HgbA1c,
Fasting Insulin
OGT
Polysomnograp
hy
PreOP
X
X
3
6
9
12
24
36
48
60
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Statistical Design:
This study will be a prospective observational cohort study with a continuous superiority
probability model for our primary endpoint. Patients will be followed for 5 years. The primary
endpoint will be reduction in BMI at 12 months (follow-up BMI – base-line BMI). Secondary
endpoints will include: 1) post-operative complication rate (including post-operative bleeding,
infection, need for further procedures (further operations or upper endoscopy), pneumonia,
UTI, thromboembolic event); 2) reduction in BMI at 60 months, 3) proportion of patient with
resolution of T2DM, hypertension, dyslipidemia, obstructive sleep apnea, or
hypertriglyceridemia; and 4) nutritional deficiency. We calculate that in order to show an
improvement in mean BMI of 12 kg/m^2 or greater with 97.5% confidence, we will need to
accrue 11 patients per treatment group. This is based on results from Alqahtani et al (9) where
they demonstrated a BMI reduction of 12 kg/m2 with a standard deviation of the differences to
be 7kg/m2.
(1.96 + 1.96) * SE = 12
3.92 * SE = 12
2
2
3.92 * √(7 /N + 7 /N) = 12
2
2
(3.92/12) * (2 * 7 ) = N
Planning for a 10% loss to follow up rate as seen in the Alqahtani et al. study and in line with
the local experience we plan to recruit 13 patients per arm. Given that CHCO is the only clinic
in the western United States dedicated to this rare disorder and we see on average 100 patients
per year between 11 and 18 years of age, we anticipate we will be able to accrue a sufficient
number of patients within three years. For our primary outcome, we will analyze mean BMI
change at 12-month follow for the surgical and non-surgical group. Results will be presented as
the mean and standard deviation. Significance will be assessed by the two-sample t-test. In
addition we will compared the mean rate of increase in BMI over the duration of the study (the
slope) using the two-sample t-test. Secondary endpoints will be summarized as the percent
positive and analyzed using Fisher’s exact test. All tests will be two-tailed tests and a P-value of
<0.05 will be considered significant.
Study Implementation and Conduct:
Recruitment and Retention Plan: Potential participants will be identified by their care providers
in the multidisciplinary team at the CHCO Prader-Willi Clinic. To encourage retention of
subjects, subjects but not their parents, will receive a ten dollar target gift card at each followup visit and birthday cards will be sent at each patient’s birthday thanking them for their
participation in the study.
Procedures for Blinding: Due to the nature of our study, there will be no randomization or
blinding of the patients or caregivers. However, the statistician will be blinded to the identified
groups during analysis.
Procedures for Minimizing Missing Data: In order to maximize retention, follow-up visits will be
scheduled in advance and reminder phone calls will be made. Intensive evaluations such as
polysomnography will be evaluated every 2 years to help with compliance. After the first year,
six month follow-up calls will be done to minimize loss of follow-up, subjects will be thanked for
their participation and asked to updated the research and/or clinical team with any plans for
relocation and any questions or concerns. This will enable alternate arrangements to be made
for annual evaluations.
References
1. "Prader-Willi Syndrome." Mayo Clinic. Mayo Foundation for Medical Education and
Research, 17 Apr. 2014. Web. 4 Nov. 2015.
2. Griggs, J., Sinnayah, P., Mathai, M.L.,Prader-Willi syndrome: From genetics to behaviour,
with special focus on appetite treatments, Neuroscience and Biobehavioral Reviews
(2015), http://dx.doi.org/10.1016/j.neubiorev.2015.10.003
3. Longitudinal Assessment of Bariatric Surgery (LABS) Consortium, Flum DR, Belle SH, King
WC, et al. Perioperative safety in the longitudinal assessment of bariatric surgery. N
Engl J Med. 2009 Jul 30;361(5):445-54.
4. Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial - a
prospective controlled intervention study of bariatric surgery. J Intern Med. 2013
Mar;273(3):219-34.
5. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical
therapy in obese patients with diabetes. N Engl J Med. 2012 Apr 26;366(17):1567-76.
6. Scheimann AO, Butler MG, Gourash L, et al. Critical analysis of bariatric procedures in
Prader-Willi syndrome. J Pediatr Gastroenterol Nutr. 2008 Jan;46(1):80-3.
7. Yu H, Di J, Jia W. Laparoscopic sleeve gastrectomy in Chinese female patient with
Prader-Willi syndrome and diabetes. Surg Obes Relat Dis. 2013 Mar-Apr;9(2):e25-7. doi:
10.1016/j.soard.2012.07.009. Epub 2012 Aug 1. PubMed PMID: 22951076.\
8. Fong AK, Wong SK, Lam CC, Ng EK. Ghrelin level and weight loss after laparoscopic
sleeve gastrectomy and gastric mini-bypass for Prader-Willi syndrome in Chinese. Obes
Surg. 2012 Nov;22(11):1742-5. doi: 10.1007/s11695-012-0725-x. PubMed PMID:
22923339.
9. Alqahtani, et al. Laparoscopic sleeve gastrectomy in children and adolescents with
Prader-Willi syndrome: a matched-control study. Surg Obes Relat Dis. 2015 Jul 22.
10. Holm VA,CassidySB,ButlerMG,etal.Prader-Willi syndrome: consensus diagnostic criteria.
Pediatrics 1993;91(2):398–402.