History before diagnosis in childhood craniopharyngioma: associations with initial presentation and long-term prognosis.

OBJECTIVE: Childhood craniopharyngiomas (CP) are often diagnosed after a long duration of history (DOH). Tumor size, hypothalamic involvement (HI), and obesity are associated with reduced overall survival (OS) and functional capacity (FC). The effect of DOH and specific symptoms in history on presentation at initial diagnosis and long-term prognosis are unknown. DESIGN: Retrospective analysis of patients' records and prospective longitudinal follow-up. METHODS: Histories of 411 CP patients recruited in HIT Endo, KRANIOPHARYNGEOM 2000 were retrospectively evaluated for DOH, symptoms, and characteristics. The effect of specific manifestations and DOH on clinical presentation and tumor characteristics at time of initial CP diagnosis and long-term outcome were analyzed. Main outcome measures were 10-year OS and progression-free survival (PFS), FC, and BMI during longitudinal follow-up. RESULTS: Median DOH was 6 months (range: 0.1-108 months) and correlated with age at diagnosis. Tumor size, HI, degree of resection, and BMI at diagnosis were not related to DOH. In multivariate analysis adjusted for age at diagnosis, only hydrocephalus was found to have a relevant influence on DOH. Visual and neurological deficits were associated with larger initial tumor size and impaired 10-year OS. Weight gain and growth failure were observed with longest DOH. PFS and FC were not related to any specific symptom. Endocrine deficits at diagnosis were associated with long DOH. CONCLUSIONS: CP is frequently diagnosed after long DOH, especially in older children. However, DOH was not associated with tumor size, HI, survival, or FC. Visual and neurological deficits necessitate rapid diagnostic workup.

Nonalcoholic fatty liver disease and fatigue in long-term survivors of childhood-onset craniopharyngioma.

OBJECTIVE: Hypothalamic obesity in childhood craniopharyngioma (CP) patients carries a high risk for development of metabolic syndrome. In metabolic syndrome, the development of nonalcoholic fatty liver disease (NAFLD) is known. The aim of this study is to detect the risk for NAFLD in childhood-onset CP. DESIGN: This cross-sectional study included liver computed tomography (CT); ultrasound analysis of abdomen; measurements of serum parameters, height, weight and body composition; and daily medication of patients with childhood-onset CP. METHODS: A total of 384 patients recruited in trials HIT Endo and KRANIOPHARYNGEOM 2000 were analyzed. Ninety-four survivors were included by fulfilling the criteria of proven hypothalamic involvement (HI), a minimum time interval of 5 years between diagnosis and study, and a minimum age of 18 years at the time of evaluation. A total of 19 patients agreed to participate. To quantify the degree of steatosis hepatis, analyses of liver density were performed once by non-contrasted CT of liver sections. RESULTS: NAFLD occurs in about 50% of CP patients with HI and is associated with elevated liver enzymes and homeostasis model assessment index. BMI is not an effective predictive factor but body fat mass measured by near-infrared spectroscopy (NIRS) is. Over half of CP patients (60%) with NAFLD are treated with stimulating agents, with risk of hepatic side effects. CONCLUSIONS: NAFLD is a major adverse late effect in childhood-onset CP. NIRS rather than BMI should be used to measure body composition and predict NAFLD. Stimulating agents for treatment of fatigue and daytime sleepiness in CP should be prescribed judiciously.

Remote effects of hypothalamic lesions in the prefrontal cortex of craniopharygioma patients.

Albeit histologically low grade (WHO I(o)) brain tumors, craniopharyngiomas and/or their surgical removal frequently affect the hypothalamus, amongst other brain regions at risk. Due to rich hypothalamic connections with prefrontal and limbic regions, hypothalamic injury may adversely affect neural substrates of emotion processing and higher cognitive control, including memory and executive functions. The current study is the first to investigate the consequences of hypothalamic involvement on neural substrates of emotional and cognitive functioning. Ten patients with childhood craniopharyngioma and known hypothalamic involvement and fifteen age- and intelligence matched control subjects (median age: 17.8 and 17.3 yrs.) were studied with functional magnetic resonance imaging and an emotional face recognition task. During encoding, participants were asked to classify neutral and emotional faces. In a subsequent recognition phase, participants had to recognize these old faces within a set of new faces. Behavioral performance was comparable between patients and controls. Neural activity revealed, however, differential recruitment of fronto-limbic brain regions during recognition. Patients exhibited an abnormal pattern of task-induced activation and deactivation in the anterior and posterior rostral medial prefrontal cortex and a higher functional coupling between anterior rostral medial prefrontal cortex and the thalamus. Additionally, we found a higher reactivity in the patients' amygdala to emotional relative to neutral faces when compared to healthy controls. Our data provide first evidence that hypothalamic damage impacts neural correlates of memory retrieval in medial prefrontal cortex, indicating a less efficient use of an area involved in executive control processes. We propose that the deactivation failure in the patients' anterior rostral medial prefrontal cortex is related to an increased coupling with the thalamus and reflects a reduced efficiency to flexibly adapt to task demands.

Post-operative hypothalamic lesions and obesity in childhood craniopharyngioma: results of the multinational prospective trial KRANIOPHARYNGEOM 2000 after 3-year follow-up.

BACKGROUND: Hypothalamic obesity has major impact on prognosis and quality of life (QoL) in childhood craniopharyngioma. PATIENTS AND METHODS: For this study, 120 patients were prospectively recruited during 2001 and 2007 and evaluated after 3 years of follow-up (KRANIOPHARYNGEOM 2000). Body mass index (BMI) and QoL at diagnosis and 36 months after diagnosis were analysed based on the reference assessment of tumour localisation and post-surgical hypothalamic lesions. Treatment was analysed based on the neurosurgical strategy of 50 participating neurosurgical centres, the centre size based on the patient load. RESULTS: BMI SDS at diagnosis was similar in patients with or without hypothalamic involvement. Surgical lesions of anterior and posterior hypothalamic areas were associated with higher increase in BMI SDS during 36 months post-diagnosis compared with patients without or only anterior lesion (+1.8 BMISD, P=0.033, +2.1 BMISD; P=0.011), negative impact on QoL in patients with posterior hypothalamic lesions. Surgical strategies varied among the 50 neurosurgical centres (three large-sized, 24 middle-sized and 23 small-sized centres). Patients treated in small-sized centres presented with a higher rate of hypothalamic involvement compared with those treated in the middle- and large-sized centres. Treatment in large-sized centres was less radical, and the rates of complete resection and hypothalamic surgical lesions were lower in large-sized centres than those of the middle- and small-sized centres. However, a multivariable analysis showed that pre-operative hypothalamic involvement was the only independent risk factor for severe obesity (P=0.002). CONCLUSIONS: Radical neurosurgical strategies leading to posterior hypothalamic lesions are not recommended due to the potential to exacerbate hypothalamic obesity and impaired QoL. Treatment should be confined to experienced multidisciplinary teams.

Longitudinal study on quality of life in 102 survivors of childhood craniopharyngioma.

OBJECTS: We longitudinally analysed functional capacity and quality of life (QoL) in 102 patients with a childhood craniopharyngioma during follow-up. METHODS: The Fertigkeitenskala Münster-Heidelberg (FMH) ability scale was used for QoL assessment. Multivariate analysis evaluated FMH scores at various time points, examining hypothalamus involvement (HI), body mass index (BMI), degree of resection, tumour progression, relapse and irradiation. RESULTS AND CONCLUSION: Patients without HI (n=60) self-assessed higher QoL at baseline (p=0.001) and follow-up (p<0.001) than patients with HI (n=42). Only patients without HI evaluated at baseline >12 months after diagnosis showed longitudinal improvement in FMH scores (p=0.040). Rates of incomplete resection and irradiation were higher (p=0.070 and p=0.002 respectively) in patients with HI. In multivariate analysis, only HI, tumour relapse, progression, baseline FMH score, and time between diagnosis and baseline evaluation had independent impact on QoL. HI, tumour progression, and relapse had long-term QoL affects-most notably, severe obesity.

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

RATIONALE: We analyzed the impact of tumour localization and histology on functional capacity (FC) and body mass index (BMI) in children with sellar masses. METHODS: FC 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. RESULTS: In 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. CONCLUSION: We 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.

Longitudinal study on growth and body mass index before and after diagnosis of childhood craniopharyngioma.

We analyzed whether childhood craniopharyngioma predisposes to obesity and growth impairment. Height/length, body mass index (BMI), and hypothalamic involvement were evaluated in 90 patients at standardized ages and time points before, after, and at the time of diagnosis. Relevant decreases in height sd score (SDS) started at 10-12 months of age and persisted until diagnosis of childhood craniopharyngioma. Relevant increases in BMI SDS were detectable between 4 and 5 yr of age. Postoperative BMI SDS (yr 1-6) had a weak positive correlation with BMI SDS at the time of diagnosis. In linear regression analysis, hypothalamic tumor involvement (P < 0.001), ponderal index at birth (P = 0.014), and BMI SDS at age 6-7 months (P = 0.029) and at age 5 yr (P < 0.001) had relevant and independent impacts on the development of obesity. Patients with hypothalamic involvement (n = 48) presented lower ponderal index and BMI SDS at birth and higher BMI SDS at the time of diagnosis (P < 0.001) as well as during annual follow-up (P < 0.001) compared with patients without hypothalamic involvement (n = 42). From childhood (3.5-4 yr) to the time of diagnosis, growth rates were reduced for patients with hypothalamic tumor involvement. Patients without hypothalamic involvement presented reduced growth rates in early infancy (age 10-12 months) that persisted until diagnosis. We conclude that reduced growth rates occur quite early in history; BMI SDS increases occur later and are predictive of obesity. Hypothalamic involvement is the major risk factor for obesity in patients with childhood craniopharyngioma.