Children with low grade glioma (LGG) may present with, or develop, elevated concentrations of insulin‐like growth factor 1 (IGF‐1). The prevalence, pathophysiology, or its possible clinical effects ...are poorly understood. Our aim was to evaluate the prevalence of such elevated IGF‐1 concentrations and to describe its association with linear growth, body mass index (BMI), pituitary outcome, and tumor behavior in a large retrospective national cohort. From a nationwide retrospective cohort of pediatric brain tumor survivors diagnosed between 2002 and 2012, tumor, treatment, endocrine, and auxological data of children with LGG were collected (n = 358). Prevalence and risk factors for elevated IGF‐1 concentrations, as well as the association between having elevated IGF‐1 concentrations and receiving tumor treatment, were explored. IGF‐1 concentrations had only been measured in 45.5% of cases (n = 163/358). In 18.4% of 163 children with available IGF‐1 measurements, IGF‐1 concentrations were found elevated. No association was described between having an elevated IGF‐1 concentration and tumor behavior or height SDS at last moment of follow‐up. Multivariate logistic regression identified posterior pituitary disorder (OR 6.14 95% CI: 2.21–17.09) and BMI SDS at follow‐up (OR 1.56 95% CI: 1.09–2.20) to be significantly associated with elevated IGF‐1 concentrations. In this retrospective cohort of children with LGG, IGF‐1 was found elevated in 18.4% of children with available IGF‐1 measurements. Elevated IGF‐1 seems to be related to hypothalamic dysfunction worsening over time. Larger prospective cohort studies are needed.
Elevated IGF‐1 concentration (> +2 SDS) was found in 18.4% of childhood low grade glioma and seems to be related to hypothalamic dysfunction (BMI and posterior pituitary disorder) worsening over time.
Objective: Hypothalamic obesity (HO) in children after treatment for a tumor in the suprasellar region has severe implications. Previous studies have shown various effects of glucagon-like peptide-1 ...(GLP-1) receptor agonist in acquired HO, but in adults only. We present our experience of GLP-1 receptor agonist (exenatide) treatment during a 1-year period on body mass index (BMI) in children with acquired HO. Patients and Methods: Children with severe weight gain after treatment for suprasellar tumor were given 2 mg exenatide weekly for a 12-month period. All had undergone previous dietary intervention. BMI standard deviation score (SDS), weight change, and adverse effects were assessed. Results: Five children with a mean age of 15.4 years (range 13–18) and a mean follow-up time of 8.4 years (mean age of 7.0 years at the time of brain tumor diagnosis) were treated with GLP-1 receptor agonist. After 1 year, BMI SDS or absolute weight had not changed significantly compared to the period without treatment (BMI SDS change +0.005, 95% CI –0.07 to 0.08, p = 0.89, and absolute weight change +1.5 kg, 95% CI –0.08 to 3.1, p = 0.061). Only 1 patient experienced weight loss after 1 year (–5.4 kg, BMI SDS –0.33). All patients experienced mild side effects, such as injection pain or nausea, and 2 patients stopped treatment upon their own request after 8 and 11 months, respectively. Conclusions: In this small cohort, we found little effect of GLP-1 receptor agonist in the treatment for acquired HO. Future research should focus on the prevention of HO or, if prevention is not possible, on alternative, individualized interventions.
Although childhood-onset craniopharyngioma is a low-grade intracranial tumor with excellent prognosis in terms of overall survival, survivors may suffer from devastating consequences caused by ...hypothalamic damage. Disease- or treatment-related hypothalamic damage leads to disturbed hunger-satiety and thirst feelings, decreased energy expenditure, behavioral problems, disturbances of circadian rhythm, temperature dysregulation, and pituitary dysfunction. These children are at great risk for developing the metabolic syndrome and comorbidities leading to premature mortality. In this chapter, we shall discuss hypothalamic-pituitary morbidity and outcome of childhood-onset craniopharyngioma patients and future perspectives for improvement.
Hypothalamic obesity (HO) in children has severe health consequences. Lifestyle interventions are mostly insufficient and currently no drug treatment is approved for children with HO. Amphetamines ...are known for their stimulant side-effect on resting energy expenditure (REE) and suppressing of appetite. Earlier case series have shown positive effects of amphetamines on weight in children with acquired HO. We present our experiences with dextroamphetamine treatment in the, up to now, largest cohort of children with HO.
A retrospective cohort evaluation was performed of children with HO treated with dextroamphetamine at two academic endocrine pediatric clinics. Off-label use of dextroamphetamine was initiated in patients with progressive, therapy-resistant acquired or congenital HO. Anthropometrics, REE, self-reported (hyperphagic) behavior and energy level, and side effects were assessed at start and during treatment.
Nineteen patients with a mean age of 12.3 ± 4.0 years had been treated with dextroamphetamine. In two patients, ΔBMI SDS could not be evaluated due to short treatment duration or the simultaneous start of extensive lifestyle treatment. Mean treatment duration of the 17 evaluated patients was 23.7 ± 12.7 months. Fourteen patients (
= 10 with acquired HO,
= 4 with congenital HO) responded by BMI decline or BMI stabilization (mean ΔBMI SDS of -0.6 ± 0.8, after a mean period of 22.4 ± 10.5 months). In three patients, BMI SDS increased (mean ΔBMI SDS of +0.5 ± 0.1, after a mean period of 29.7 ± 22.6 months). In 11 responders, measured REE divided by predicted REE increased with +8.9%. Thirteen patients (68.4%) reported decreased hyperphagia, improvement of energy level and/or behavior during treatment. Two patients developed hypertension during treatment, which resulted in dosage adjustment or discontinuation of treatment. Twelve children continued treatment at last moment of follow-up.
In addition to supportive lifestyle interventions, dextroamphetamine treatment may improve BMI in children with HO. Furthermore, dextroamphetamines have the potential to decrease hyperphagia and improve resting energy expenditure, behavior, and energy level. In patients with acquired HO, these effects seem to be more pronounced when compared to patients with congenital HO. Future studies are needed to support these results.
Hypothalamic dysfunction may result in morbid obesity as a consequence of decreased energy expenditure, decreased feelings of satiety, and increased fat storage. In patients with hypothalamic ...dysfunction, neurobehavioral dysfunction is also often present. Currently, no effective treatment has been found for hypothalamic obesity (HO). We hypothesize that deep brain stimulation (DBS) may be an effective treatment for patients with hypothalamic dysfunction, aiming to treat HO as well as the neurobehavioral dysfunction.
A systematic search was conducted in the PubMed, EMBASE and Cochrane Library databases for studies published until May 2022 reporting on DBS for the treatment of HO.
Three studies met the predetermined inclusion criteria, with in total six patients treated with DBS for HO, of which five patients with Prader-Willi syndrome (PWS) and one patient with HO after treatment for craniopharyngioma (CP). Targets of DBS included the lateral hypothalamic area (LHA) and the nucleus accumbens (NAcc). In patients with PWS, LHA-DBS was associated with a mean increase of Body Mass Index (BMI) (+5.8%), with no change in hormonal levels, results of blood workup, sleep, or neuropsychological evaluation. In the patient with CP, NAcc-DBS was associated with a decrease in BMI (−8.7%) and a subjective increase in mental health, energy and willingness to act, and no feeling of increased appetite. No objective measurements on neurobehavioral function were reported. No severe adverse events were reported in these cases. Mild to moderate adverse events included hypomanic symptoms and infection. All patients with a described follow-up period (n = 5) were able to sustain the treatment for at least 6 months with few interruptions.
There is limited research reporting on DBS for HO. The effectiveness differed across studies and the evidence is limited. Although there may be potential for DBS treatment in the severe-refractory condition of HO in patients with CP, more research is needed for target selection and evaluation of effectiveness.
Abstract
The optimal neurosurgical strategy for pediatric craniopharyngiomas is on debate with shifts from gross total resection to limited resections in combination with local radiotherapy. The most ...relevant question underlying this ongoing discussion is how to prevent additional surgical morbidity to the hypothalamus. Limited neurosurgical resection in combination with local radiotherapy has been proved a safe alternative to gross total resection concerning tumor control. Pre-operative anatomical grading of hypothalamic involvement has been proposed by Puget et al using MRI discriminating between no hypothalamic involvement (grade 0), hypothalamic displacement (grade 1), and hypothalamic disruption (grade 2). Subsequently, post-operative hypothalamic damage can also be assessed on post-op MRI by the grading of the Vile et al in no discernable damage (grade 0), abnormality of floor of third ventricle (grade 1), or damaged or deficient floor of third ventricle (grade 2). Three questions remain to be settled: 1. How to define pre-operatively the extent of resection 2. How to realize per-operatively the intended limited resection, and three. How to determine post-operatively the (additional) surgical damage to the hypothalamus. We retrospectively evaluated a series of 25 children with craniopharyngioma being resected in our center from June 2018 until January 2022, with pre- and post-operative grading of hypothalamic involvement. In total 11 patients were downgraded on the post-operative compared to the pre-operative scale; either by 1 grade (n=6) or by 2 grades (n=5). These findings illustrate that the preoperative grading score does not always represent the actual hypothalamic involvement. This complicates the definition of limited surgery pre-operatively and illustrates the importance of both how to integrate per-operative findings in the realization of the intended limited resection and how to evaluate hypothalamic damage caused by tumor growth versus neurosurgical intervention. A more detailed treatment algorithm will be discussed.
Hypothalamic syndrome (HS) in childhood is a rare condition. Its epidemiology is not well known because incidence and prevalence are related to very rare underlying diseases. In addition, different ...criteria for the syndrome are used across studies. Recognizing the HS may be difficult, due to its rareness and variety of symptoms. Having diagnostic criteria for signs and symptoms of hypothalamic dysfunction may aid in early recognition and diagnosis, in the reporting and understanding of its etiology, in predicting its course and its management. We aimed to define diagnostic criteria for hypothalamic dysfunction and a score for the presence of HS in childhood.
Diagnostic criteria for hypothalamic dysfunction were developed and subdivided into hyperphagia, hypophagia, body mass index, behavioral problems, sleep disorders, temperature regulation disorders, pituitary dysfunction, radiological hypothalamic assessment, and presence/suspicion of a hypothalamic genetic syndrome. Subsequently, the scoring system was tested in a retrospective cohort of 120 patients at risk for hypothalamic dysfunction.
A score for presence of HS was developed. Using this new hypothalamic score, in total 52.5% were scored as having HS. Of these patients, 76.7% were diagnosed with pituitary dysfunction, 32.5% with hyperphagia, 40% with sleep disorders, and 14.2% with temperature dysregulation. For several criteria, clinical data was missing in more than 50% of cases.
The here proposed diagnostic criteria for hypothalamic dysfunction and score for presence of HS may be used for care purposes and to aid in early recognition. Also it will be useful for research or registration purposes.
Abstract
Introduction: Treatment for childhood-onset craniopharyngioma (cCP) has shifted from complete to limited resection aiming to avoid additional hypothalamic morbidity. Up to 90% of cCP ...patients develop growth hormone deficiency (GHD). GH replacement therapy (GHRT) is of high importance for linear growth and metabolic state. Hardly any studies evaluated the optimal time to start GHRT in relation to tumor progression or recurrence. Our aim was to assess the effect of GHRT in cCP on tumor progression/recurrence.
Methods: Patients with cCP diagnosed between 2001 and 2022, with at least one year of follow-up were included. Tumor progression/recurrence was defined as tumor progression/recurrence requiring intervention. Kaplan Meier and multivariable cox regression analyses were estimated for tumor progression/recurrence. Comparison was made between cCP patients with GHRT and without GHRT. Of the cCP patients receiving GHRT, those given GHRT ≤ 1 year of cCP diagnosis were compared to those given GHRT >1 year after cCP diagnosis.
Results: Of 59 cCP patients, 52 were diagnosed with GHD and 51 (86.4%) received GHRT. Sixteen cCP patients (31.4%) developed tumor progression/recurrence during GHRT compared to four cCP patients (50.0%) without GHRT. Mean progression free survival (PFS) did not differ between cCP patients with or without GHRT (GHRT: 5.55 years 95% CI 3.74 - 7.36 vs. no GHRT: 3.69 years 95% CI 1.44 - 5.93). Of cCP patients who started GHRT ≤1 year after cCP diagnosis, 36.4% developed tumor progression/recurrence compared to 27.6% of cCP patients who received GHRT > 1 year after diagnosis (PFS: 8.45 years CI 95% 5.54 – 11.36 vs. 7.99 years CI 95% 6.03 – 9.94). Limited surgery was associated to tumor progression/recurrence (HR 6.99 CI 95% 2.10 – 23.25).
Conclusion: GHRT does not seem to influence tumor progression/recurrence in cCP. These results support early initiation of GHRT in cCP patients to optimize linear growth and metabolic outcome.
Abstract
Background
Childhood craniopharyngioma (cCP) has excellent survival, but quality of life may be severely hampered by hypothalamic dysfunction. We aimed to evaluate treatment and hypothalamic ...outcomes of a Dutch cCP cohort, and evaluate the effect of centralization of care.
Methods
A retrospective cohort study was performed, including cCP patients diagnosed between 2004 and 2021. Treatment characteristics and hypothalamic outcomes were evaluated and compared before and since centralization of care in May 2018.
Results
We included 87 cCP patients. Cyst drainage/fenestration was performed in 29.9%, limited resection in 27.6%, near-total resection in 16.1%, and gross total resection (GTR) in 25.4%. Radiotherapy was given in 46.0%. After a median follow-up of 6.5 years, hypothalamic obesity (HO) was present in 24.7% and panhypopituitarism with diabetes insipidus in 71.3%. Higher body mass index (BMI) SDS at diagnosis and Muller grade II at last magnetic resonance imaging of follow-up were associated with overweight/obesity. No association was found between extensiveness of resection and overweight/obesity at last follow-up. When comparing before and after centralization of care, rates of GTR remained similar, but BMI outcomes changed; mean ΔBMI SDS 1 year after diagnosis from 1.12 (SD 1.15) to 0.81 (SD 1.24), and HO after 1 year decreased from 33.3% to 12.0% (P = .067), and after 2 years from 28.6% to 6.7% (P = NS).
Conclusions
In our nationwide cohort, GTR was performed in a relatively low percentage of patients and extensiveness of resection was no longer associated with HO at follow-up. A trend toward improvement of BMI is observed since centralization of care, which needs further exploration.
Abstract
INTRODUCTION: Children with suprasellar brain damage are at risk for hypothalamic dysfunction (HD). HD may lead to decreased resting energy expenditure (REE) contributing to the development ...of hypothalamic obesity. Decreased REE, however, is not present in all children with hypothalamic damage. Our aim was to assess which children suspect for HD have low REE, and if REE outcome can be associated with clinical severity of HD or with radiological posterior hypothalamic damage. METHODS: A retrospective cohort study was performed evaluating all children diagnosed with brain injury at risk for HD in whom REE measurement was performed. Measured REE (mREE) was compared to predicted REE (pREE) using amongst others the Schofield equation. Low REE was defined as mREE<90% compared to pREE. Radiologic hypothalamic damage was scored using Muller grading score. The mREE/pREE quotient was associated to a clinical score for HD symptoms and to radiological hypothalamic damage. RESULTS: Sixty-seven children suspected for HD (94% brain tumor diagnosis) with a mean BMI SDS of +2.3 ± 1.0 were included. Of these, 45 (67.2%) had mREE <90% compared to the pREE. Children with severe HD symptoms had a significant lower mean mREE/pREE quotient compared to children with no, mild, or moderate HD symptoms. Mean mREE/pREE quotient of children with posterior hypothalamic damage was significantly lower compared to children with no damage or with anterior damage. Tumor progression or tumor recurrence, severe clinical HD, and panhypopituitarism with DI were significant risk factors for reduced REE. CONCLUSION: Not all children suspect for HD have a low REE. Low REE is associated with clinical and radiological scores for hypothalamic damage. REE measurements in childhood brain tumor survivors may be useful to distinguish between those who may benefit from obesity treatment that increases REE from those who would be better helped using other obesity interventions.
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