Ursel Gebhardt

Melatonin Treatment in Obese Patients with Childhood Craniopharyngioma and Increased Daytime Sleepiness

Craniopharyngioma is a rare dysontogenetic benign tumor. Patients frequently suffer from endocrine deficiencies, sleep disturbances and obesity due to pituitary and hypothalamic lesions. A self-assessment daytime sleepiness questionnaire (German version of the Epworth Sleepiness Scale [ESS]) was used to evaluate 79 patients with childhood craniopharyngioma. Because hypothalamic lesions may explain daytime sleepiness in craniopharyngioma patients, salivary melatonin and cortisol concentrations were examined in severely obese (BMI≥4SD) and non severely obese (BMI<4SD) craniopharyngioma patients (n=79), patients with hypothalamic pilocytic astrocytoma (n=19), and control subjects (n=30). Using a general linear model procedure analyzing the influence of BMI and tumor diagnosis on diurnal salivary melatonin we found that morning salivary melatonin levels were related to BMI (F test: p-value=0.004) and tumor diagnosis (F-test: p-value=0.032). Also for nighttime salivary melatonin levels significant relations with BMI (p-value in F-test: <0.001) and tumor diagnosis (p-value in F-test: 0.025) were detectable. Melatonin concentrations in saliva of craniopharyngioma patients collected at nighttime or in the morning showed a negative correlation (Spearman’s rho: −0.42; p=0.001; Spearman’s rho: −0.31; p=0.020) with the patient’s ESS score. Severely obese craniopharyngioma patients and severely obese hypothalamic tumor patients had similar patterns of melatonin secretion. Differences in terms of diurnal salivary cortisol concentrations were not detectable when patient groups and controls were compared. As decreased nocturnal melatonin levels were associated with increased daytime sleepiness, BMI and hypothalamic tumor diagnosis, we initiated an experimental melatonin substitution in 10 adult obese patients (5f/5m) with childhood craniopharyngioma. In all 10 patients with childhood craniopharyngioma the degree of daytime sleepiness significantly improved based on activity diaries, ESS, self assessment questionnaires and actimetry. We speculate that hypothalamic lesions might be responsible for both obesity and daytime sleepiness. As first experiences with experimental melatonin substitution were promising, further randomized double-blinded studies on the beneficial effects of melatonin substitution on daytime sleepiness and weight control in these patients are warranted.

Reduced Sympathetic Metabolites in Urine of Obese Patients With Craniopharyngioma

Severe obesity is a major problem in patients suffering from craniopharyngioma (CP), a benign tumor located in pituitary and hypothalamic regions. In this study, the hypothesis that hypothalamic damage leads to a reduction in overall sympathetic tone was tested. Catecholamines, as well as their metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA), markers of catecholamine turnover, were measured in morning voided urine of 109 patients participating in a German pediatric CP study, and their physical activity was analyzed using a questionnaire. HVA and VMA results were compared with age-matched HVA and VMA in urine of patients proven to not have a catecholamine-secreting tumor. Patients with the most severe obesity displayed the lowest urine HVA and VMA values. Patients with hypothalamic CP had 3.2-fold higher BMI values (p < 0.0001), lower HVA (0.72-fold, p < 0.001), and VMA (0.84-fold, p < 0.01) values, and significantly lower activity scores than those without hypothalamic involvement, but their epinephrine- and norepinephrine/creatinine ratios were not significantly different, possibly due to low levels. The low HVA and VMA values suggest decreased sympathetic outflow contributing to reduced physical activity and severe obesity, especially in patients with a hypothalamic tumor. In further studies investigating treatment options for hypothalamic obesity, disturbed sympathetic tone should be considered.

Survival, hypothalamic obesity, and neuropsychological/psychosocial status after childhood-onset craniopharyngioma: newly reported long-term outcomes

BACKGROUND Quality of life (QoL) and long-term prognosis are frequently, and often severely, impaired in craniopharyngioma (CP) patients. Knowledge of risk factors for long-term outcome is important for optimization of treatment. METHODS Overall survival (OS) and progression-free survival (PFS), body mass index (BMI), neuropsychological status (EORTCQLQ-C30, MFI-20), and psychosocial status were analyzed in 261 patients with childhood-onset CP diagnosed before 2000 and longitudinally observed in HIT-Endo. RESULTS Twenty-year OS was lower (P = .006) in CP with hypothalamic involvement (HI) (n = 132; 0.84 ± 0.04) when compared with CP without HI (n = 82; 0.95 ± 0.04). OS was not related to degree of resection, sex, age at diagnosis, or year of diagnosis (before/after 1990). PFS (n = 168; 0.58 ± 0.05) was lower in younger patients (<5 y at diagnosis) (n = 30; 0.39 ± 0.10) compared with patients aged 5-10 years (n = 66; 0.52 ± 0.08) and older than 10 years (n = 72; 0.77 ± 0.06) at diagnosis. PFS was not associated with HI, degree of resection, or sex. HI led to severe weight gain during the first 8-12 years of follow-up (median BMI increase: +4.59SD) compared with no HI (median increase: +1.20SD) (P = .00). During >12 years of follow-up, patients with HI presented no further increase in BMI. QoL in CP patients with HI was impaired by obesity, physical fatigue, reduced motivation, dyspnea, diarrhea, and nonoptimal psychosocial development. CONCLUSIONS OS and QoL are impaired by HI in long-term survivors of CP. HI is associated with severe obesity, which plateaus after 12 years. OS/PFS are not related to degree of resection, but gross-total resection should be avoided in cases of HI to prevent further hypothalamic damage, which exacerbates sequelae.

Xanthogranuloma, Rathke's Cyst, and Childhood Craniopharyngioma: Results of Prospective Multinational Studies of Children and Adolescents with Rare Sellar Malformations

CONTEXT Craniopharyngioma (CP), Rathkes cyst (RC), and xanthogranuloma (XG) are closely related rare sellar masses. Treatment strategies in children lack consensus. OBJECTIVE Our objective was to study clinical manifestations and treatment-related outcome in RC, XG, and CP patients. DESIGN We conducted a multicenter surveillance trial. PATIENTS Inclusion criteria were 1) histological diagnosis of CP, XG, or RC and 2) diagnosis at age of 18 yr or less. A total of 117 CP, 14 XG (2001-2006), and 14 RC (1996-2006) were recruited. MAIN OUTCOME Overall survival (OS), event-free survival (EFS), and quality of life (QoL) were evaluated. RESULTS The 5-yr OS rates were 1.00 ± 0.00 in RC and XG and 0.97 ± 0.02 in CP. The 5-yr EFS rates were 0.85 ± 0.10 in RC, 1.00 ± 0.00 in XG, and 0.50 ± 0.05 in CP. Surgical resection of XG results in complete remission without recurrence. Recurrences occur in RC (14%) and CR (59%) but can be efficiently treated by irradiation, reoperation, and/or intracystic treatment. Severe hypothalamic sequelae such as obesity and others affecting QoL are predominant in CP due to presurgical involvement (59%) and postsurgical lesions (44%) of posterior hypothalamic structures. Centers with lower neurosurgery patient load use more radical surgical approaches to treat CP, resulting in higher rates of obesity and reduced QoL. Despite 46% anterior hypothalamic involvement, severe obesity is not encountered in XG. CONCLUSIONS Treatment of choice in XG and RC is radical surgery. In CP involving hypothalamic structures, less radical surgical approaches preserving hypothalamic integrity are recommended. Due to frequent relapses, regular imaging during follow-up is recommended for CP and RC. Treatment of patients with sellar masses should be confined to experienced multidisciplinary teams.

Analyses of treatment variables for patients with childhood craniopharyngioma--results of the multicenter prospective trial KRANIOPHARYNGEOM 2000 after three years of follow-up.

Background: Controversies surround various treatment variables for patients with childhood craniopharyngioma such as growth hormone (GH) replacement, which some believe can exacerbate recurrence/progression. We prospectively assessed the risk of tumor recurrence/progression in survivors of childhood craniopharyngioma. Methods: Multivariable analyses of risk factors (age at diagnosis, degree of resection, irradiation, GH treatment and gender) and descriptive analyses of overall survival (OS) and event-free survival (EFS) rates were performed in 117 patients, recruited prospectively and evaluated after 3 years of follow-up in the German, Austrian and Swiss multicenter trial KRANIOPHARYNGEOM 2000. Results: We observed a 3-year OS of 0.97 and a 3-year EFS of 0.46, indicating high recurrence rates after complete resection (CR) (n = 47; 3-year-EFS: 0.64) and high progression rates after incomplete resection (IR) (n = 64; 3-year EFS: 0.31). The risk of an event decreased by 80% after CR compared to IR (hazard ratio = 0.20; p < 0.001). Irradiation had protective effects on EFS: irradiated patients had an 88% lower risk of recurrence/progression compared to patients without/before irradiation (hazard ratio = 0.12; p < 0.001). GH treatment had no impact on 3-year EFS rates. Conclusions: Tumor recurrences/progressions are frequent and occur early after initial treatment of childhood craniopharyngioma. A radical resection preserving the integrity of hypothalamic structures appears optimal at original diagnosis. Irradiation was efficient in preventing recurrences/progressions. GH treatment had no impact on the low 3-year EFS observed in our study. However, further conclusions on the influence of GH on recurrence rates have to be refined to long-term follow-up studies of patients with childhood craniopharyngioma.

Appetite‐Regulating Hormone Changes in Patients With Craniopharyngioma

Patients with craniopharyngioma (CP), an embryological tumor located in the hypothalamic and/or pituitary region, often suffer from uncontrolled eating and severe obesity. We aimed to compare peripherally secreted hormones involved in controlling food intake in normal weight and obese children and adolescents with CP vs. controls. Plasma insulin, glucose, total ghrelin, and peptide‐YY (PYY) levels were assessed under fasting conditions as well as 60 min after liquid mixed meal in four groups: Normal weight (n = 12) and obese (n = 15) CP patients, and 12 normal weight and 15 obese otherwise healthy BMI‐, gender‐ and age‐matched controls. Homeostasis model assessment of insulin resistance (HOMAIR), as well as quantitative insulin sensitivity check index (QUICKI) were calculated. Obese CP subjects had significantly higher HOMAIR, higher baseline and postmeal insulin but lower ghrelin levels, weaker postmeal changes for PYY, and lower QUICKI compared to obese controls. QUICKI data from all CP patients correlated positively with ghrelin and PYY % postmeal changes (ghrelin: r = 0.38, P = 0.023; PYY r = 0.40, P = 0.017) and negatively with standard deviation score‐BMI (SDS‐BMI: r = −0.49, P = 0.002). Tumor growth of 87% obese and 58% of normal weight CP patients affected the hypothalamic area which was associated with higher SDS‐BMI and weaker % postmeal ghrelin changes (P = 0.014) compared to CP patients without hypothalamic tumor involvement. Blunted postmeal ghrelin and PYY responses in obese CP subjects are likely due to their higher degree of insulin resistance and lower insulin sensitivity compared to matched obese controls. Thus, insulin resistance in CP patients seems to affect eating behavior by affecting meal responses of gut peptides.

Changes of peripheral α-melanocyte–stimulating hormone in childhood obesity

Relationships of blood circulating melanocortins to childhood obesity are not well established. We evaluated serum alpha-melanocyte-stimulating hormone (alpha-MSH) in lean children and different study groups of childhood obesity. We examined serum alpha-MSH in 52 otherwise healthy children with childhood obesity (Ob; mean age, 11 years; 32 girls/20 boys), 27 normal-weight children of same age, 7 additional obese patients with reduced melanocortin-4 receptor function (MC4Rmut), and 22 patients with craniopharyngioma (CP). Fasting serum alpha-MSH and leptin were measured by radioimmunoassay. Serum alpha-MSH was also evaluated 1 hour after 500-kcal liquid meal (CP and Ob) and at the end of 1-year lifestyle intervention in 24 Ob patients. The alpha-MSH levels were similar in obese vs lean children but significantly lower in CP (P < .001) and significantly higher (P < .05) in MC4Rmut patients compared with Ob. One hour after liquid meal, alpha-MSH increased in patients with Ob but not with CP. After 1 year, alpha-MSH levels increased significantly in the successful weight reduction Ob subgroup despite unchanged cortisol levels. The alpha-MSH changes correlated to weight status changes (r = 0.67, P = .0003) but not to changes of cortisol, insulin, or homeostasis model assessment of insulin resistance index. Persistently low alpha-MSH levels in CP patients are suspected to be due to pituitary or hypothalamic damage. High peripheral levels in MC4Rmut carriers indicate up-regulation of alpha-MSH. Changes of weight status are associated with changes of peripheral alpha-MSH.

Functional capacity and body mass index in patients with sellar masses—cross-sectional study on 403 patients diagnosed during childhood and adolescence

RationaleWe analyzed the impact of tumour localization and histology on functional capacity (FC) and body mass index (BMI) in children with sellar masses.MethodsFC was evaluated using the ability scale Fertigkeitenskala Münster–Heidelberg in 403 children and adolescents with sellar masses (276 craniopharyngioma, 14 germinoma, 21 optic/chiasmatic glioma, 40 hypothalamic glioma, 13 cysts of Rathke’s cleft and 39 other sellar masses). Besides tumour localization, the influence of gender, irradiation and age at diagnosis and at evaluation on FC and BMI was analyzed. General linear models with explanatory influential variables were built.ResultsIn multivariate analysis, only age at diagnosis (p<0.001) and hypothalamic involvement (p=0.005) had relevant impact on FC. The second model showed BMI at diagnosis (p<0,001), hypothalamic involvement (p<0.001) and craniopharyngioma (p=0,004) to influence BMI at the latest evaluation.ConclusionWe conclude that hypothalamic involvement and young age at diagnosis had major impact on FC and BMI and should be considered as risk factors for impaired rehabilitation.

Brain-derived neurotrophic factor and its relation to leptin in obese children before and after weight loss

OBJECTIVE Brain-derived neurotrophic factor (BDNF) is a regulator of energy homeostasis and food intake through hypothalamic signaling. Currently, data regarding BDNF in children with obesity are lacking. We evaluated serum BDNF concentrations in obese children, both before and after lifestyle intervention, in reference to those of lean children. METHODS A total of 90 (24 normal weight; 66 obese) children were studied utilizing a cross-sectional clinical outpatient study design. In addition, longitudinal data analysis was performed in 30 obese children participating in a lifestyle intervention for one year. RESULTS Fasting serum BDNF concentrations were higher in obese vs. normal weight children (BDNF 20.3±1.0 vs. 12.5±1.7 ng/mL, respectively, mean±SEM, p<0.001) and correlated significantly to BMI standard deviation score (r=0.426, p<0.001), and leptin (r=0.414, p<0.01). BDNF concentrations were not regulated in response to food, 60 min after ingestion of a liquid test meal. After one year lifestyle intervention, delta BDNF correlated significantly to delta leptin (r=0.475, p<0.01), but not to changes of insulin resistance index HOMA-IR, systolic and diastolic blood pressure, HDL, LDL, and triglycerides. In a multiple stepwise linear regression adjusted for pubertal stage, age, sex, and BMI, delta BDNF correlated significantly (p<0.05) to delta leptin and delta triceps skinfold and in tendency to delta subscapularis skinfold thickness (p=0.050). CONCLUSIONS Our results in children do not indicate a significant relationship between BDNF and insulin resistance or cardiovascular risk factors. However, the correlation between changes of BDNF and changes of leptin suggests a relationship between BDNF and fat mass.

Eating behavior, weight problems and eating disorders in 101 long-term survivors of childhood-onset craniopharyngioma

Abstract Background: As a result of hypothalamic involvement and/or treatment-related hypothalamic damage, up to 75% of childhood craniopharyngioma patients develop hypothalamic obesity. Methods: Eating behavior was analyzed in 101 survivors of childhood craniopharyngioma, recruited from 1980 to 2001 in the HIT-Endo multicenter study, and in 85 body mass index (BMI)-matched healthy controls using the Inventory for Eating Behavior and Weight Problems (IEG) and the Inventory for Eating Disorders (ESI). Results: Severely obese patients (BMI>8 SD; n=9) presented with pathological eating behavior, more weight problems, and eating disorders, as compared to obese (BMI 3–8 SD; n=44) and normal or overweight patients (BMI<3 SD; n=48). Craniopharyngioma patients with different degrees of obesity showed similar or even less pathological findings as compared to BMI-matched normal controls. Conclusion: Severe obesity is associated with pathological eating behavior/disorders in craniopharyngioma patients. As these disorders are not disease-specific, risk factors for hypothalamic obesity should be the focus of further craniopharyngioma research.