Reinhard Kolb

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.

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.

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.

Kraniopharyngeom im Kindes- und Jugendalter

ZusammenfassungKraniopharyngeome sind dysontogenetische Mittellinienfehlbildungen mit Raum forderndem Charakter. 30–50% der Fälle werden im Kindes- und Jugendalter manifest und repräsentieren damit 5–10% aller intrakraniellen Tumoren im Kindesalter. Der Versuch einer kompletten Resektion unter Wahrung der optischen und hypothalamisch-hypophysären Funktion stellt die Therapie der ersten Wahl bei günstiger Lokalisation dar. Bei ungünstiger Lokalisation ist diese Therapieoption gegen eine begrenzte Resektion mit anschließender Strahlentherapie abzuwägen. Bei insgesamt hoher Überlebensrate wird die Lebensqualität der Patienten durch ophthalmologische, neuropsychiatrische und endokrine Spätfolgen beeinträchtigt. Der Adipositas infolge hypothalamischer Essstörungen kommt hierbei besondere Bedeutung zu. In einer multizentrischen Querschnittuntersuchung (n=138) zeigte die Lebensqualität keine signifikante Abhängigkeit vom intendierten oder realisierten neurochirurgischen Resektionsgrad. Im Rahmen einer multizentrischen Beobachtungsstudie (Kraniopharyngeom 2000; www.kraniopharyngeom.com) wird der Einfluss unterschiedlicher Therapiestrategien auf die Überlebensrate und die Lebensqualität von Kindern und Jugendlichen mit Kraniopharyngeom prospektiv untersucht. Aufgrund der hohen Meldebereitschaft der beteiligten Zentren ist zu hoffen, dass auch in Zukunft die Vollständigkeit der Erfassung deutlich verbessert wird.AbstractCraniopharyngiomas are benign, partly cystic epithelial tumors of the sellar region. Between 30% and 50% of the cases manifest during childhood and adolescence and represent 5–10% of all cases of intracranial tumors during childhood. The therapy of choice in patients with favourable tumor location is total microscopic resection while maintaining the visual and hypothalamic-pituitary function. In patients with unfavourable tumor location, this therapeutic strategy is subject to controversy, and consideration should be given to limited resection followed by radiation therapy. The overall survival rates are high. However, the quality of life (QoL) is substantially reduced in many survivors due to neuropsychological, ophthalmologic, and endocrine sequelae. Extreme obesity caused by eating disorders of hypothalamic origin has a major negative impact on QoL. In a cross-sectional multicenter study (n=138), QoL was not related to intended or realized degree of surgical resection. A multicenter study (Kraniopharyngeom 2000; English-language study protocol available at: www.kraniopharyngeom.com) was initiated to analyze prospectively the survival rate and QoL in newly diagnosed patients with childhood craniopharyngioma in relation to different therapeutic strategies. Based on the high rate of compliance of participating centers in Germany, Austria, and Switzerland, we hope to substantially improve the extent of epidemiologic registration of this rare disease in the near future.

Current Strategies in Diagnostics and Endocrine Treatment of Patients with Childhood Craniopharyngioma During Follow-Up – Recommendations in KRANIOPHARYNGEOM 2000

Craniopharyngiomas are rare dysontogenetic malformations. As the survival rate after craniopharyngioma diagnosed during childhood and adolescence is high, prognosis and quality of life (QoL) in survivors mainly depend on adverse late effects such as hypopituitarism and obesity. Appropriate laboratory diagnostics of endocrine deficiencies and sufficient hormonal substitution have significant impact on prognosis and QoL. In order to evaluate and standardize diagnostic and therapeutical strategies in childhood craniopharyngioma the prospective multicenter surveillance study KRANIOPHARYNGEOM 2000 was initiated for patients diagnosed with craniopharyngioma during childhood and adolescence. We are reporting on current strategies for laboratory diagnostics and endocrine substitution in patients with childhood craniopharyngioma recruited in KRANIOPHARYNGEOM 2000.

Kraniopharyngeom im Kindes- und Jugendalter@@@Childhood craniopharyngioma

ZusammenfassungKraniopharyngeome sind dysontogenetische Mittellinienfehlbildungen mit raumforderndem Charakter. Bei einer Inzidenz von 0,5–2/106/Jahr werden 30–50% der Fälle im Kindes- und Jugendalter manifest. Bei häufig langer Anamnesedauer sind Kopfschmerzen, Sehstörungen, Wachstumsstörungen und Polyurie/Polydipsie Leitsymptome der Erkrankung. Der Versuch einer operationsmikroskopisch kompletten Resektion unter Wahrung der optischen und hypothalamisch-hypophysären Funktion stellt die Therapie der ersten Wahl bei günstiger Lokalisation dar. Bei ungünstiger Lokalisation (Hypothalamusbeteiligung) wird eine begrenzte Resektion mit anschließender Strahlentherapie empfohlen. Der optimale Zeitpunkt einer Strahlentherapie nach inkompletter Resektion wird derzeit im Rahmen einer multizentrischen Studie (KRANIOPHARYNGEOM 2007) randomisiert untersucht (Bestrahlung direkt postoperativ vs. bei Progression des Tumorrests). Bei hoher Überlebensrate (92% Gesamtüberleben) wird die Lebensqualität der Patienten durch ophthalmologische, neuropsychiatrische und endokrine Spätfolgen beeinträchtigt. Der hypothalamischen Adipositas kommt hierbei besondere Bedeutung zu.AbstractCraniopharyngiomas are benign, partly cystic embryogenic malformations of the sellar region, presumably derived from Rathke pouch epithelium. With an overall incidence of 0.5–2 new cases per million population per year, 30–50% of all cases represent childhood craniopharyngioma. Typical manifestations at primary diagnosis are headache, visual disturbance, polyuria/polydipsia, growth retardation, and weight gain. The treatment of choice in patients with favorable tumor localization is total resection with the intention to maintain visual and hypothalamic–pituitary function. In patients with unfavorable tumor localization (hypothalamic involvement), a limited resection followed by radiation therapy is recommended. The appropriate time point for irradiation after incomplete resection is currently being investigated in a randomized trial (KRANIOPHARYNGEOM 2007). The overall survival rates are high (92%). However, quality of life is substantially reduced in many survivors due to sequelae. In particular, extreme obesity due to hypothalamic involvement has a major negative impact on quality of life.