Altered endocannabinoid-dynamics in craniopharyngioma patients and their association with HPA-axis disturbances.

OBJECTIVE: Patients with craniopharyngioma (CP) frequently suffer from morbid obesity. Endocannabinoids (ECs) are involved in weight gain and rewarding behavior but have not been investigated in this context. DESIGN: Cross-sectional single-center study. METHODS: Eighteen patients with CP and 16 age- and sex-matched controls were included. Differences in endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and endocannabinoid-like molecules (oleoyl ethanolamide (OEA), palmitoylethanolamide (PEA), and arachidonic acid (AA) were measured at baseline and following endurance exercise. We further explored ECs-dynamics in relation to markers of HPA-axis activity (ACTH, cortisol, copeptin) and hypothalamic damage. RESULTS: Under resting conditions, independent of differences in BMI, 2-AG levels were more than twice as high in CP patients compared to controls. In contrast, 2-AG and OEA level increased in response to exercise in controls but not in CP patients, while AEA levels decreased in controls. As expected, exercise increased ACTH and copeptin levels in controls only. In a mixed model analysis across time and group, HPA measures did not provide additional information for explaining differences in 2-AG levels. However, AEA levels were negatively influenced by ACTH and copeptin levels, while OEA levels were negatively predicted by copeptin levels only. There were no significant differences in endocannabinoids depending on hypothalamic involvement. CONCLUSION: Patients with CP show signs of a dysregulated endocannabinoid system under resting conditions as well as following exercise in comparison to healthy controls. Increased 2-AG levels under resting conditions and the missing response to physical activity could contribute to the metabolic phenotype of CP patients.

Craniopharyngioma treatment: an updated summary of important clinicopathological concepts.

INTRODUCTION: Craniopharyngiomas (CPs) are benign histological tumors that may develop at different positions along the hypothalamic-pituitary axis. Their close, heterogenous relationship to the hypothalamus makes surgical removal challenging even though this remains the primary treatment strategy. AREAS COVERED: This article presents a critical overview of the pathological and clinical concepts regarding CPs that should be considered when planning treatment. Thus, we have performed a comprehensive review of detailed CP reports published between 1839 and 2020. EXPERT OPINION: CP surgery should pursue maximal tumor resection while minimizing the risk of injuring the hypothalamus. Therefore, surgical strategies should be individualized for each patient. Accurate assessment of presenting symptoms and preoperative MRI has proven useful to predict the type of CP-hypothalamus relationship that will be found during surgery. CPs with dense and extensive adhesions to the hypothalamus should be highly suspected when MRI shows the hypothalamus positioned around the mid-third of the tumor and an amputated upper portion of the pituitary stalk. Symptoms related to functional impairment of the infundibulo-tuberal area of the third ventricle floor, such as obesity/hyperphagia, Fröhlich's syndrome, diabetes insipidus, and/or somnolence, also indicate risky CP-hypothalamic adhesions. In these cases, limited tumor removal is strongly advocated followed by radiation therapy.

Eating behaviour and oxytocin in patients with childhood-onset craniopharyngioma and different grades of hypothalamic involvement.

BACKGROUND: Patients with childhood-onset craniopharyngioma (CP) often suffer from tumour or treatment-related hypothalamic lesions (HL). These lesions may alter production of oxytocin, which plays a major role in the regulation of eating behaviour and body composition. OBJECTIVE: In CP with different degrees of HL, we investigated associations between HL, eating behaviour/eating attitudes, and oxytocin saliva concentrations (OSC). METHODS: In a cross-sectional case-control study on 34 CP and 73 healthy controls, OSC were measured before, and 60 minutes after breakfast by immunoassay. Eating behaviour, attitudes, and habits were assessed by standardized questionnaires. RESULTS: CP with anterior + posterior HL presented with more adverse eating behaviours/symptoms of eating disorders than CP without HL, CP with anterior HL, and controls. Eating behaviour in CP with anterior HL was similar to controls, except for their tendency towards high dietary restraints. Decreases in postprandial compared with fasting OSC were associated with adverse eating behaviour in CP and controls and with higher BMI in CP. CONCLUSIONS: CP with anterior HL and CP with anterior + posterior HL present with distinct patterns of eating behaviour. Reduced postprandial compared with fasting OSC is associated with weight problems in CP and with adverse eating behaviour and symptoms of eating disorders in both CP and controls.

Craniopharyngiomas Primarily Involving the Hypothalamus: A Model of Neurosurgical Lesions to Elucidate the Neurobiological Basis of Psychiatric Disorders.

OBJECTIVE: This study provides a systematic review and meta-analysis of psychiatric disorders caused by craniopharyngiomas and the hypothalamic alterations underlying these symptoms. METHODS: We investigated a collection of 210 craniopharyngiomas reported from 1823 to 2017 providing detailed clinical and pathologic information about psychiatric disturbances, including 10 of our own series, and compared the hypothalamic damage in this cohort with the present in a control cohort of 105 cases without psychiatric symptoms. RESULTS: Psychiatric disorders occurred predominantly in patients with craniopharyngiomas developing primarily at the infundibulotuberal region (45%) or entirely within the third ventricle (30%), mostly affecting adult patients (61%; P < 0.001). Most tumors without psychic symptoms developed beneath the third ventricle floor (53.5%; P < 0.001), in young patients (57%; P < 0.001). Psychiatric disturbances were classified in 6 major categories: 1) Korsakoff-like memory deficits, 66%; 2) behavior/personality changes, 48.5%; 3) impaired emotional expression/control, 42%; 4) cognitive impairments, 40%; 5) mood alterations, 32%; and 6) psychotic symptoms, 22%. None of these categories was associated with hydrocephalus. Severe memory deficits occurred with damage of the mammillary bodies (P < 0.001). Mood disorders occurred with compression/invasion of the third ventricle floor and/or walls (P < 0.012). Coexistence of other hypothalamic symptoms such as temperature/metabolic dysregulation or sleepiness favored the emergence of psychotic disorders (P < 0.008). Postoperative psychiatric outcome was better in strictly intraventricular craniopharyngiomas than in other topographies (P < 0.001). A multivariate model including the hypothalamic structures involved, age, hydrocephalus, and hypothalamic symptoms predicts the appearance of psychiatric disorders in 81% of patients. CONCLUSIONS: Craniopharyngiomas primarily involving the hypothalamus represent a neurobiological model of psychiatric and behavioral disorders.

Polysomnographic findings in craniopharyngioma patients.

PURPOSE: The purpose of this study is to evaluate whether damage to the hypothalamus due to craniopharyngioma or consequent surgery may involve the sleep-wake regulatory system, resulting in sleep disturbances and sleepiness. METHODS: Seven craniopharyngioma patients and 10 healthy controls were evaluated with sleep questionnaires including the Epworth Sleepiness Scale, polysomnography, and a multiple sleep latency test (MSLT). Five patients and eight controls had lumbar puncture performed to determine hypocretin-1 levels. RESULTS: Patients tended to feel sleepier than control individuals of the same age (p = 0.09). No subjects had symptoms of hypnagogic hallucinations, sleep paralyses, or cataplexies. Four patients and one control had periodic leg movements (PLMs). One patient had fragmented sleep pattern, rapid eye movement (REM) sleep without atonia, and PLMs. One patient had short sleep periods during the daytime. Four patients had fragmented sleep pattern. With the MSLT, four patients and two controls had mean sleep latency of < 8 min. One patient and three controls had sudden onset of REM sleep in 2/5 and 3/5 sleep periods, respectively. All subjects showed normal hypocretin-1 levels. Four patients had electrophysiological findings indicative of central hypersomnia including one patient meeting the criteria of narcolepsy. CONCLUSION: The sleep-wake regulatory system may be involved in craniopharyngioma patients.

Site and type of craniopharyngiomas impact differently on 24-hour circadian rhythms and surgical outcome. A neurophysiological evaluation.

This study aimed to quantify 24h body core temperature (BcT°) and sleep-wake cycle rhythm alterations in craniopharyngioma (CP) patients and to identify markers related to the postsurgical outcomes. Ten consecutive CP patients underwent neuroradiological, endocrinological and ophthalmological evaluations, 24h BcT° and sleep-wake cycle recordings before and after endoscopic endonasal surgery. The sample included four women and six men. Nocturnal sleep efficiency was pathologically reduced in eight patients before surgery. Seven out of ten patients presented one to three daytime naps. 24h BcT° rhythm was pathological in six out of ten cases. Post-surgery sleep efficiency normalized in four out of eight patients, whereas nine out of ten patients presented with two to six longer daytime naps. Diurnal naps were mainly present in patients showing pre-operative involvement of the third ventricle floor. 24h BcT° remained pathological in only one out of six cases, returned to normal in two and improved in three. 24h BcT° rhythm improved more in papillary CPs than in adamantomatous CPs. Our data confirmed that both CP and surgery frequently disrupt the sleep-wake cycle and BcT° rhythms. Tumour location and histotype may be related to a worse postsurgical outcome. Therefore, in-depth investigation including circadian monitoring is crucial for surgical outcome.

Risk-adapted treatment and follow-up management in childhood-onset craniopharyngioma.

Craniopharyngiomas are rare embryonic malformations of the sellar/parasellar region with low histological grade. Here, we review findings on the diagnosis, treatment, clinical course, follow-up, and prognosis of craniopharyngioma patients. Clinical manifestations develop from increased intracranial pressure, anterior visual pathway damage, and hypothalamic/pituitary deficiencies. If the tumor is favorably localized (no anatomical involvement with the hypothalamic and optical structures) therapy of choice is complete resection, meticulously performed to preserve hypothalamic and optic functions. In patients with unfavorable tumor involvement, optimal therapy is limited hypothalamus-sparing surgical strategy, followed by judicious irradiation dosage to minimize recurrences and progression. Surgical lesions and/or anatomical involvement of posterior hypothalamic areas result in serious sequelae, mainly hypothalamic syndrome. Craniopharyngioma is a chronic disease and must be managed as such, providing ongoing care of pediatric and adult patients by experienced multidisciplinary teams in the context of multicenter trials.

The infundibulo-tuberal syndrome caused by craniopharyngiomas: clinicopathological evidence from an historical French cohort (1705-1973).

PURPOSE: Infundibulo-tuberal syndrome groups endocrine, metabolic and behavioral disturbances caused by lesions involving the upper neurohypophysis (median eminence) and adjacent basal hypothalamus (tuber cinereum). It was originally described by Henri Claude and Jean Lhermitte in 1917, in a patient with a craniopharyngioma. This study investigates the clinical, pathological and surgical evidence verifying the infundibulo-tuberal syndrome caused by craniopharyngiomas (CPs). METHODS: A systematic retrospective review of craniopharyngiomas reported in French literature between 1705 and 1973 was conducted. A total of 128 well described reports providing a comprehensive clinical and pathological description of the tumors were selected. This series represents the historical French cohort of CPs reported in the pre-CT/MRI era. RESULTS: Three major syndromes caused by CPs were categorized: pituitary syndrome (35%), infundibulo-tuberal syndrome (52%) and hypothalamic syndrome (49%). CP topography was significantly related to the type of syndrome described (p < 0.001). Infundibulo-tuberal syndrome occurred in CPs which replaced or invaded the third ventricle floor. In contrast, the majority of sellar/suprasellar CPs growing below the third ventricle showed a pituitary syndrome (82%). Cases with hypothalamic syndrome were characterized by anatomical integrity of the pituitary gland and stalk (p = 0.033) and occurred predominantly in adults older than 41 years old (p < 0.005). Among infundibulo-tuberal symptoms, abnormal somnolence was not related with the presence of hydrocephalus. All squamous-papillary CPs presented psychiatric disturbances (p < 0.001). CONCLUSION: This historical CP cohort evidences a clinical-topographical correlation between the patient's type of syndrome and the anatomical structures involved by the tumor along the hypophysial-hypothalamic axis.

Nutritional and endocrinologic evaluation of patients with craniopharyngioma.

BACKGROUND & AIMS: Lesions of hypothalamus or adjacent brain structures by the craniopharyngioma (CP) and/or its treatment, as well as changes in orexigenic and anorexigenic hormones, are possible pathogenic factors for the obesity observed in CP patients. This study assessed anthropometric measurements, food intake, and biochemical markers of CP patients. METHODS: Weight, height, skinfold thicknesses, circumferences, body composition, food intake evaluation, basal glucose, lipids, insulin, ghrelin, PYY, and HOMA-IR calculation were obtained from CP children (n = 10, 4F, aged 12 ± 4.2yr) and CP adults (n = 27,13F aged 42 ± 13 yr) and from 32 gender and age matched controls. RESULTS: Overweight/obesity was observed in 51.4% of the patients at the diagnosis and increased to 86.5% at the time of the study. Obesity was more frequent in patients with grade 2 hypothalamic involvement. Most anthropometric measurements were similar in patients and controls. Caloric intake was lower in CP adults, without difference between children. Lipid intake was higher in CP patients. Carbohydrate and protein intakes were lower in CP children, with no difference between adult groups. There were no differences in micronutrients intake as well as in insulin and PYY levels, and HOMA-IR between patients and controls. HDL-c was lower in CP adults and ghrelin higher in CP children. CONCLUSIONS: There is a high rate of overweight/obesity in CP patients at the diagnosis and throughout the follow-up period. Obesity was associated with degree of hypothalamic involvement but not with caloric intake. Obesity and a lipid rich diet may have contributed to the dyslipidemia observed in CP patients.

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.

Impaired aerobic exercise adaptation in children and adolescents with craniopharyngioma is associated with hypothalamic involvement.

OBJECTIVE: Many patients treated for craniopharyngioma (CP) complain of a relative incapacity for physical activity. Whether this is due to an objective decrease in adaptation to exercise is unclear. We assessed exercise tolerance in children with surgically treated CP and appropriate pituitary hormone replacement therapy compared with healthy controls and we examined the potential relationships with hypothalamic involvement, GH replacement, and the catecholamine deficiency frequently observed in these subjects. DESIGN AND METHODS: Seventeen subjects (12 males and five females) with CP and 22 healthy controls (14 males and eight females) aged 15.3±2.5 years (7.3-18 years) underwent a standardized cycle ergometer test. Maximum aerobic capacity was expressed as the ratio of VO(2max) to fat-free mass (VO(2max)/FFM), a measure independent of age and fat mass in children. RESULTS: VO(2max)/FFM was 20% lower in children with CP compared with controls (P<0.05), even after adjustment for gender. Children with hypothalamic involvement (n=10) had a higher percentage of fat mass (P<0.05) than those without hypothalamic involvement (n=7) and lower VO(2max)/FFM (P<0.05), whereas children without hypothalamic involvement had VO(2max)/FFM close to that of controls (P>0.05). GH treatment was associated with a significant positive effect on aerobic capacity (P<0.05) only in the absence of hypothalamic involvement. No relationship was found between exercise capacity parameters and daily urine epinephrine excretion or epinephrine peak response to insulin-induced hypoglycemia. CONCLUSIONS: Children with CP have a decrease in aerobic capacity mainly related to hypothalamic involvement. The hypothalamic factors altering aerobic capacity remain to be determined.

Deep brain stimulation for treatment of hemichorea-hemiballism after craniopharyngioma resection: long-term follow-up.

Hemichorea-hemiballism is a rare movement disorder that has various causes. In treatment-resistant cases, both thalamic and pallidal functional procedures have been shown to yield beneficial results. Until now it has not been clarified whether the thalamus or the pallidum would yield a superior outcome. After resection of a craniopharyngioma in this patient at the age of 49 years, hemichorea-hemiballism developed, with a latency of several weeks. Because the patient was greatly impaired by the movement disorder, she underwent implantation of deep brain stimulation (DBS) electrodes in the thalamic ventralis intermedius nucleus and the posteroventral lateral globus pallidus internus. Although both pallidal and thalamic stimulation could suppress the movement disorder, the voltage needed was clearly less with thalamic than with pallidal stimulation. At the last available follow-up 25 months postoperatively, complete subsidence of hemichorea-hemiballism was achieved with long-term thalamic stimulation. Long-term DBS therapy is an efficient treatment modality for refractory hemichorea-hemiballism in the long run (> 2 years). A bifocal (thalamic and pallidal) target paradigm allowed selection of the optimal stimulation site. Thalamic DBS was more favorable with regard to energy consumption.

Hypothalamic involvement and insufficient sex steroid supplementation are associated with low bone mineral density in women with childhood onset craniopharyngioma.

CONTEXT: Data on bone mineral density (BMD) are lacking in adults with childhood onset (CO)-craniopharyngioma (CP) with hypothalamic damage from the tumor. In patients with CO GH deficiency, BMD increases during GH treatment. OBJECTIVE: The aims were to evaluate BMD in adults with CO-CPs on complete hormone replacement, including long-term GH and to evaluate the impact of hypothalamic damage on these measures. DESIGN AND PARTICIPANTS: BMD (dual-energy X-ray absorptiometry), markers of bone turn over, physical activity and calcium intake were assessed in 39 CO-CP adults (20 women), with a median age of 28 (17-57) years, in comparison with matched population controls. RESULTS: Late puberty induction was recorded in both genders, but reduced androgen levels in females only. Only CP women had lower BMD (P=0.03) at L2-L4, and reduced Z-scores at femoral neck (P=0.004) and L2-L4 (P=0.004). Both genders had increased serum leptin levels (P=0.001), which significantly correlated negatively with BMD at L2-L4 (P=0.003; r=-0.5) and 45% of CP women had Z-score levels ≤-2.0 s.d. Furthermore, 75% of those with a Z-score ≤-2.0 s.d. had hypothalamic involvement by the tumor. Calcium intake (P=0.008) and physical activity (P=0.007) levels were reduced in CP men only. Levels of ostecalcin and crossLaps were increased in CP men only. CONCLUSIONS: Despite continuous GH therapy, low BMD was recorded in CO-CP females. Insufficient estrogen and androgen supplementation during adolescence was the main cause, but hypothalamic involvement with consequent leptin resistance was also strongly associated with low BMD in both genders.

Delayed ghrelin suppression following oral glucose tolerance test in children and adolescents with hypothalamic injury secondary to craniopharyngioma compared with obese controls.

Ghrelin, released from the stomach, acts at the hypothalamus and is associated with initiation of food intake. We hypothesised that patients with craniopharyngioma and hypothalamic obesity (CRHO) would have ghrelin abnormalities. Fifteen CRHO patients and 15 BMI-matched controls underwent oral glucose tolerance test with dynamic ghrelin measurement. From 0-30 minutes, ghrelin (pg/ml) decreased less (43.4 ? 38.8 vs. 70.8 ? 35.8, p < 0.05) and insulin (pmol/l) increased more (1 669.2 ? 861.7 vs. 1 049.1 ? 560.4, p = 0.04) in CRHO compared with controls, respectively. Insulin area-under-the-curve was a weak negative predictor of the 0?30 minutes ghrelin decrease (r(2) = 0.29, p = 0.02). Delayed ghrelin suppression may contribute to obesity in CRHO.

The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children.

INTRODUCTION: In this study, we have investigated the role of leptin, soluble leptin receptor(sOb-R), resistin, and insulin secretory dynamics in the development of hypothalamic obesity. MATERIALS AND METHODS: Children who had hypothalamo-pituitary tumor were divided into two groups. First group included obese-overweight (hypothalamic obese = HOB group, n = 23) and second group included non-obese children (hypothalamic non-obese = HNOB group, n = 16). Exogenously obese-overweight children (OB group, n = 22) were included as controls. Basal and second-hour serum glucose and insulin in oral glucose tolerance test (OGTT), basal serum leptin, sOb-R, resistin levels, and homeostasis model assessment (HOMA) indexes were compared between the groups. RESULTS: Age, sex, and pubertal status were similar in study groups. Median and interquartile ranges of body mass index (BMI) z scores were similar in HOB and OB groups (2.0 (1.5-2.1) and 2.1 (1.8-2.3), respectively). Serum leptin levels corrected for BMI were highest and total leptin/sOb-R ratios (free leptin index (FLI)) tended to be higher in HOB than HNOB and OB groups, indicating leptin resistance (leptin/BMI, 4.0 (1.6-5.2), 1.5 (0.8-3.1), and 2.5 (1.8-3.5); FLI, 2.0 (0.8-3.5), 0.6 (0.3-1.2), and 1.5 (1-2.3) in HOB, HNOB, and OB groups; respectively). Serum resistin levels were similar in groups (2.6 (1.9-3.1), 2.8 (1.7-3.4), and 3.0 (2.2-3.5) ng/ml in HOB, HNOB, and OB groups, respectively). Basal serum glucose, basal and second-hour insulin levels in OGTT, and HOMA index were higher in OB group than the HOB and HNOB groups, indicating insulin resistance in simple obesity; however, increment of insulin to same glycemic load in OGTT was highest in the HOB group indicating insulin dysregulation (p < 0.05). CONCLUSION: Hypothalamic obesity seems to be related to both dysregulated afferent (leptin) and efferent (insulin) neural outputs through the autonomic nervous system resulting in energy storage as fat.

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.

Functional capacity, obesity and hypothalamic involvement: cross-sectional study on 212 patients with childhood craniopharyngioma.

The aim of this study was to analyze the impact of hypothalamic involvement of craniopharyngioma on functional capacity (FC) and obesity in 212 patients with childhood craniopharyngioma. FC could be evaluated using an ability scale (Fertigkeitenskala Münster-Heidelberg [FMH]) in 174 patients with childhood craniopharyngioma. Obesity was quantified in 212 patients at the time of diagnosis and at the time of latest evaluation by body mass index SDS [BMI]. The influence of hypothalamic tumor involvement on FC and BMI was analyzed. Patients with hypothalamic involvement (n = 125) presented with higher BMI SDS at the time of diagnosis (p = 0.001) and at latest follow-up evaluation (p < 0.001). FC as measured by FMH percentiles was lower (p < 0.001) in patients with hypothalamic involvement when compared with patients without hypothalamic involvement. FC negatively correlated (p < 0.001) with BMI SDS (Spearman's Rho = -0.40) only in patients with hypothalamic involvement whereas no correlation between FC and BMI SDS was found in patients without hypothalamic involvement. We conclude that hypothalamic involvement of childhood craniopharyngioma had major impact on FC in survivors. Obesity resulted in impaired FC of patients with hypothalamic involvement. BMI at diagnosis was a sensitive parameter to identify patients at risk of severe obesity. Further analysis on this issue is performed in the prospective, multicenter surveillance study on children and adolescents with craniopharyngioma (KRANIOPHARYNGEOM 2000).

Sympathoadrenal counterregulation in patients with hypothalamic craniopharyngioma.

In humans, the role of hypothalamic centers for activation of counterregulatory release of catecholamines and glucagon during hypoglycemia is unclear. To address this question, we investigated the counterregulatory response to acute insulin-induced hypoglycemia of glucagon, epinephrine, and norepinephrine in eight patients who had undergone transcranial surgery for a craniopharyngioma extending to the hypothalamic region. We compared the patients' responses with those of four patients suffering from hypopituitarism and of six healthy subjects. After the i.v. injection of 0.1 U of human insulin per kg of body weight in the patients or 0.15 U in healthy subjects, the plasma glucose concentrations decreased to similar minimum levels within 30 min in all three groups. All subjects recovered spontaneously from hypoglycemia within 2 h. In five of eight craniopharyngioma patients, only a small counterregulatory rise in plasma epinephrine (< or =2-fold) and norepinephrine could be observed (P < 0.05 for epinephrine and P = 0.22 for norepinephrine vs. healthy controls). During hypoglycemia, virtually no adrenergic symptoms (tremor, heart pounding, and anxiety) were reported by these five patients, and changes in the heart rate were diminished. In three craniopharyngioma patients, the counterregulatory increase in catecholamines was unimpaired, adrenergic symptoms were reported and a rise in heart rate was observed during hypoglycemia. In all craniopharyngioma patients, the counterregulatory glucagon response to hypoglycemia was preserved and orthostasis increased both catecholamines and the heart rate similar to in the patients with hypopituitarism as well as in the healthy controls. Our results demonstrate selective impairment of counterregulatory sympathoadrenal activation in patients who had undergone surgery for a craniopharyngioma extending to the hypothalamic region. This strongly suggests the involvement of hypothalamic centers in hypoglycemia-induced activation of the sympathoadrenal axis in humans. It remains unclear as to whether hypoglycemia-induced glucagon secretion is also controlled by the hypothalamus. However, a common hypothalamic center controlling both counterregulatory catecholamine and glucagon release is unlikely, and sympathoadrenal activation is not required for hypoglycemia-induced glucagon secretion in humans.