Risk Factors for Hypothalamic Obesity in Patients With Adult-Onset Craniopharyngioma: A Consecutive Series of 120 Cases

ContextHypothalamic obesity (HO) is a severe complication following craniopharyngioma, but studies regarding the sequelae in adult-onset patients with craniopharyngioma are sparse.ObjectiveThe objective of the study was to describe weight changes after surgical treatment in adult-onset craniopharyngioma patients and to analyze risk factors for postoperative weight gain and HO.Subjects and MethodA retrospective analysis was conducted of 120 adult-onset patients who underwent surgery for craniopharyngioma and follow-up at the institution of the authors between January 2018 and September 2020. Clinical characteristics, anthropometric data, image features, treatment modalities, and endocrine indices were collected. Multivariable logistic regression analysis was used to identify independent risk factors for postoperative weight gain and HO.ResultsForty-nine (40.8%) patients had clinically meaningful weight gain (≥5%) in a median follow-up time of 12.0 months (range 1.0–41.0 months) after surgery. The mean postoperative weight gain in this subgroup was 17.59 ± 12.28 (%). Weight gain continued in the first year following surgery. Patients with lower preoperative BMI [OR 0.78, 95% CI (0.67–0.90), P = 0.001] and the adamantinomatous subtype [OR 3.46, 95% CI (1.02–11.76), P = 0.047] were more likely to experience postoperative weight gain ≥5%. The prevalence of HO was 19.2% preoperatively and increased to 29.2% at last follow-up postoperatively. Only preoperative BMI [OR 2.51, 95% CI (1.64–3.85), P < 0.001] was identified as an independent risk factor for postoperative HO.ConclusionsHO is a common complication in patients with adult-onset craniopharyngioma. Patients with higher preoperative BMI had a greater risk for developing HO postoperatively.

Bariatric Surgery for Hypothalamic Obesity in Craniopharyngioma Patients: A Retrospective, Matched Case-Control Study

Context Craniopharyngioma is a sellar tumor associated with high rates of pituitary deficiencies (~98%) and hypothalamic obesity (~50%). Objective To determine the efficacy regarding long-term weight loss after bariatric surgery in obese craniopharyngioma patients with hypothalamic dysfunction. Design Retrospective case control study. Setting Multicenter international study. Patients and participants Obese craniopharyngioma patients (N = 16; of which 12 women) with a history of bariatric surgery [12 Roux-en-Y gastric bypass, 4 sleeve gastrectomy; median age of 21 years (range 15-52), median follow-up 5.2 years (range 2.0-11.3)] and age/sex/surgery/BMI-matched obese controls (N = 155). Main outcome measures Weight loss and obesity-related comorbidities up to 5 years after bariatric surgery were compared and changes in hormonal replacement therapy evaluated. Results Mean weight loss at 5-year follow-up was 22.0% (95% CI 16.1, 27.8) in patients versus 29.5% (28.0, 30.9) in controls (P = 0.02), which was less after Roux-en-Y gastric bypass (22.7% [16.9, 28.5] vs. 32.0% [30.4, 33.6]; P = 0.003) but at a similar level after sleeve gastrectomy (21.7% [–1.8, 45.2] vs. 21.8% [18.2, 25.5]; P = 0.96). No major changes in endocrine replacement therapy were observed after surgery. One patient died (unknown cause). One patient had long-term absorptive problems. Conclusions Obese patients with craniopharyngioma had a substantial mean weight loss of 22% at 5-year follow-up after bariatric surgery, independent of type of bariatric surgery procedure. Weight loss was lower than in obese controls after Roux-en-Y gastric bypass. Bariatric surgery appears effective and relatively safe in the treatment of obese craniopharyngioma patients.

Multidisciplinary Approach for Hypothalamic Obesity in Children and Adolescents: A Preliminary Study

Hypothalamic obesity (HO) is delineated by an inexorable weight gain in subjects with hypothalamic disorder (congenital or acquired). The aim of the present study was to evaluate the effect of a multidisciplinary approach on weight trend and metabolic outcome in children and adolescents with hypothalamic disease who were overweight or obese. Thirteen patients (aged 8.1–16.1 years) received a personalized diet, accelerometer-based activity monitoring, and psychological assessment. Height, weight, body mass index (BMI), and serum metabolic parameters were assessed at baseline (T0) and after six months (T1). Metformin was introduced at T1 in four subjects who were then re-evaluated after six months (T2). At T1, weight gain was significantly reduced compared with T0 (0.29 ± 0.79 kg/month vs. 0.84 ± 0.55 kg/month, p = 0.03), and weight standard deviation score (SDS) and BMI SDS did not change significantly, as serum metabolic parameters. The four subjects treated with metformin showed a reduction of weight SDS and BMI SDS at T2. In conclusion, patients treated with our multidisciplinary approach showed, after 6 months, favorable results characterized by decreased weight gain and stabilization of weight SDS and BMI SDS in a condition usually characterized by inexorable weight gain. However, further analysis, larger cohorts, and longer follow-up are needed to confirm these preliminary data.

Cardiac Remodeling in Patients with Childhood-Onset Craniopharyngioma - Results of HIT-Endo and KRANIOPHARYNGEOM 2000/2007

Hypothalamic obesity caused by childhood-onset craniopharyngioma results in long-term cardiovascular morbidity. Knowledge about clinical markers and risk factors is rare. A cross-sectional study on transthoracic echocardiographic parameters was performed to determine the associations with clinical and anthropometric parameters in 36 craniopharyngioma patients recruited in HIT-Endo and KRANIOPHARYNGEOM 2000/2007. BMI correlated with the thickness of interventricular septum in diastole (IVSd) (r=0.604, p<0.001) and left ventricular posterior wall thickness in diastole (LVPWd) (r=0.460, p=0.011). In multivariate analyses on risk factors for cardiac remodeling, sex hormone replacement therapy, BMI and male gender were positively correlated with increased left ventricular internal diameter in diastole (LVIDd), R2=0.596, F=10.323, p<0.001. BMI and insulin resistance were selected as significant independent determinants of IVSd, produced R2=0.655, F=29.441, p<0.001. Due to wide range of disease duration, 17 pediatric and 19 adult patients were analyzed separately. In the adult subgroup (age at study ≥18 years), BMI correlated with IVSd (r=0.707, p=0.003), LVPWd (r=0.592, p=0.020) and LVIDd (r=0.571, p=0.026). In the pediatric subgroup (age at study <18 years), no correlation between cardiac parameters and BMI was observed. Only LVIDd correlated with disease duration (r=0.645, p<0.001). All cardiac functions were within the normal range, indicating no association with functional impairments. We conclude that cardiac remodeling in patients with childhood-onset craniopharyngioma correlated with the degree of hypothalamic obesity, disease duration, sex hormone replacement therapy, male gender and insulin resistance. As echocardiography has limited sensitivity in patients with obesity, further research on more sensitive techniques for cardiac diagnostics in craniopharyngioma patients is warranted.

Weight Loss, Improved Body Composition and Fat Distribution by Tesomet in Acquired Hypothalamic Obesity

Background: Structural damage to the hypothalamus often results in hypothalamic obesity characterized by rapid and severe weight-gain with increased risk of cardiovascular and metabolic morbidity and mortality. Currently, there are no approved or effective pharmacological treatments and conventional weight management remains largely ineffective. Objective: This RCT investigated safety and efficacy of Tesomet (co-administration of 0.5mg tesofensine and 50mg metoprolol) in hypopituitary patients with acquired hypothalamic obesity. Methods: Twenty-one (16 females) hypopituitary adults with hypothalamic obesity were randomized to Tesomet or placebo (2:1) for 24 weeks (NCT03845075). Subjects also received diet and lifestyle counselling. Primary endpoint was safety evaluated by change in heart rate, blood pressure and adverse events. Secondary endpoints included changes in anthropometric measures, body composition, corrected QT-interval and arrythmias. Results: Subjects had a median (range) age of 50 (25; 70) years and 90% had a BMI ≥30 kg/m2. Almost half (48%) had a history of craniopharyngioma, 86% had undergone pituitary/hypothalamic surgery, and 52% had irradiation therapy. All received one or more anterior pituitary hormone replacements; 52% had diabetes insipidus. In total, 18/21 subjects completed the study, one without investigational treatment. Three serious adverse events (SAE) were recorded in 2 subjects randomized to Tesomet. Adverse events were otherwise mostly mild (58%), frequently reported were sleep disturbances (62%), dry mouth (46%) and dizziness (46%), known side effects of tesofensine or metoprolol. Four subjects, two in each group, discontinued treatment. Tesomet discontinuation was secondary to anxiety (n=1) or dry mouth (n=1). No significant differences in heart rate or blood pressure were observed between the two groups. At week 24, compared to placebo (weight-loss: -0.3%), Tesomet treatment resulted in additional mean weight-loss of -6.3% (95CI [-11.3%; -1.3%], p=0.017); increase in the proportion of patients achieving >5% reduction in body weight (Tesomet 8; Placebo 1, OR 11.2 [1.0; 120.4], p=0.046); and reduction in waist circumference of -5.7cm ([-11.5; 0.1], p=0.054). Tesomet-induced weight loss was primarily correlated to a reduction in mean (SD) fat mass -5.3kg (5.3) (r2=0.9, P=0001) and to lesser extent a reduction in lean tissue mass -2.9kg (1.9) (r2=0.4, P=0.03). Treatment did not affect corrected QT-interval; mean change from placebo was -1.1ms (95CI [-16.0; 13.9], p=0.882), nor were arrythmias registered during the trial period. Conclusions: Tesomet was generally well-tolerated, did not affect heart rate, blood pressure or QTc-interval, and resulted in significant reductions in body weight compared to placebo in this cohort of hypopituitary patients with acquired hypothalamic obesity. The study was sponsored by Saniona A/S

Dextroamphetamine Treatment for Children With Hypothalamic Obesity

Introduction: Hypothalamic obesity (HO) in children can be either genetic or acquired, as a result of a suprasellar tumor or its treatment. HO, resulting from hyperphagia and/or a decreased resting energy expenditure (REE), may have devastating consequences for the child and its family. Currently, no effective drug treatment is yet available for HO. Amphetamines – commonly used in children with attention-deficit/hyperactivity disorder – are known for their stimulant effect on REE and inhibitory effect on appetite. We here present our experiences of dextroamphetamine treatment in children and adolescents with acquired or genetic HO. Methods: A retrospective cohort evaluation was performed of patients (n = 18) treated with dextroamphetamine at 2 endocrine pediatric clinics. Off-label use of dextroamphetamine was initiated in patients with progressive therapy resistant acquired HO (n = 13) and in patients with genetic obesity (n = 5). Initial treatment dosing was once or twice daily 5mg. This dose was weekly increased with 5 mg/day depending on the patient’ wellbeing and the presence of side effects, to a maximum of 0.5 mg/kg/day. Anthropometrics and REE at start and during follow-up, changes in (hyperphagic) behavior, and side effects were assessed. Results: At start of treatment, mean age was 12.8 years ± 3.4 [range 7.1–17.9] and mean REE was 69.5%± 18.5 (n = 15). At follow-up, mean treatment duration was 18.3 months ± 14.7. Ten out of eighteen children (55.6%) showed clinically relevant weight loss. In 10/13 patients with acquired HO, weight loss was observed (mean ΔBMI SDS -1.09 ± 1.00), in one patient BMI stabilization (ΔBMI SDS +0.03), and in two patients an increase in BMI SDS was seen (mean ΔBMI SDS +0.32 ± 0.05). Of nine children with acquired HO and measurement of REE before and during treatment, a mean REE increase of +15.3% ± 10.5 was observed. In three out of five patients with genetic obesity, initially weight loss was observed resulting in BMI stabilization at end of follow-up due to weight regain (mean ΔBMI SDS -0.08 ± 0.19). In these patients, no difference in REE before and during treatment was observed. In two patients an increase in BMI SDS was seen (mean ΔBMI SDS +0.29 ± 0.25). However, one patient discontinued treatment after one month, due to hypertension. Thirteen out of 18 children (72.2%) reported improvement of either their hyperphagia, energy level, and/or behavior. No serious side effects were reported. Conclusion: In children and adolescents with acquired HO, treatment with dextroamphetamine may significantly lower BMI, reduce hyperphagia and improve activity level. In genetic HO, these effects were less pronounced. Future studies in a larger cohort and with randomized controlled designs are needed to support these results.

Appetite and weight inducing and inhibiting neuroendocrine factors in Prader-Willi syndrome, Bardet-Biedl syndrome and craniopharyngioma versus anorexia nervosa

Obesity is reaching endemic state and has a major impact on health and economy. In most cases obesity is caused by life style factors. However, the risk of becoming obese differs highly between people. Individual differences in life style, genetic, and neuroendocrine factors play a role in satiety, hunger and regulation of body weight. In a small percentage of children and adults with obesity, an underlying hormonal or genetic cause can be found. The aim of this review is to present and compare data on the extreme ends of the obesity and undernutrition spectrum in patients with Prader-Willi syndrome (PWS), Bardet-Biedl syndrome (BBS), acquired hypothalamic obesity in craniopharyngioma patients, and anorexia nervosa. This may give more insight in the role of neuroendocrine factors and might give direction for future research in conditions of severe obesity and underweight.