Novel clinical algorithm for hypothalamic obesity in youth with brain tumours and factors associated with excess weight gain.

BACKGROUND: A standardized approach for identifying and treating hypothalamic obesity (HO) in children with hypothalamic tumours is lacking. OBJECTIVES: To describe children with hypothalamic tumours at risk for obesity, assess outcomes of a novel HO clinical algorithm, and identify factors associated with weight gain. METHODS: Retrospective analysis of youth with hypothalamic and suprasellar tumours, seen at a paediatric tertiary care centre from 2010 to 2020. RESULTS: The study cohort (n = 130, 50% female, median age at diagnosis 5 [range 0-17]y) had a median duration of follow up of 5 (0.03-17)y. At last recorded body mass index (BMI) measurement, 34% had obesity, including 17% with severe obesity. Median onset of overweight and obesity after diagnosis was 6.2 (0.3-134) and 8.9 (0.7-65) months, respectively. After algorithm implementation (n = 13), the proportion that had an early dietitian visit (within 6 months) increased from 36% to 54%, (p = 0.498) and weight management referrals increased from 51% to 83% (p = 0.286). Higher BMI z-score at diagnosis was associated with overweight and obesity development (p < 0.001). CONCLUSION: Patients with hypothalamic tumours commonly develop obesity. Use of a clinical algorithm may expedite recognition of HO. Further research is needed to identify predictors of weight gain and to develop effective treatment.

Our experience in prolactinomas larger than 60mm / Nuestra experiencia en prolactinomas mayores de 60mm

INTRODUCTION: Giant prolactinomas (tumor size larger than 40mm) are a rare entity of benign nature. Prolactinomas larger than 60mm are usually underrepresented in published studies and their clinical presentation, outcomes and management might be different from smaller giant prolactinomas. PATIENTS AND METHODS: We retrospective collected data from patients with prolactinomas larger than 60mm in maximum diameter and prolactin (PRL) serum levels higher than 21,200μIU/mL in our series of prolactinomas (283). Data were collected from January 2012 to December 2017. We included three patients with prolactinomas larger than 60mm. RESULTS: At diagnosis, two patients presented neurological symptoms and one nasal protrusion. All patients received medical treatment with dopamine agonists. No surgical procedure was performed. Median prolactin levels at diagnosis was 108,180 [52,594-514,984]μIU/mL. Medical treatment achieved a marked reduction (>99%) in prolactin levels in all cases. Tumor size reduction (higher than 33%) was observed in all cases. In one patient cerebrospinal fluid (CSF) leak was observed after tumor shrinkage. CONCLUSIONS: Dopamine agonists appear to be an effective and safe first-line treatment in prolactinomas larger than 60mm even in life-threatening situations. More studies with a higher number of patients are necessary to obtain enough data to make major recommendations

INTRODUCCIÓN: Los prolactinomas gigantes (de tamaño superior a 40mm) son una entidad rara de naturaleza benigna. Los prolactinomas mayores de 60mm suelen estar infrarrepresentados en los estudios publicados, y su presentación clínica, resultados y tratamiento podrían ser diferentes de los de prolactinomas gigantes más pequeños. PACIENTES Y MÉTODOS: Recogimos retrospectivamente datos de pacientes con prolactinomas de más de 60mm de diámetro máximo y con concentraciones séricas de prolactina (PRL) superiores a 21.200μIU/ml de nuestra serie de prolactinomas (283). Los datos se recogieron entre enero de 2012 y diciembre de 2017. Se incluyeron 3 pacientes con prolactinomas mayores de 60mm. RESULTADOS: En el momento del diagnóstico, 2 pacientes presentaban síntomas neurológicos, y uno protrusión nasal. Todos los pacientes recibieron tratamiento médico con agonistas dopaminérgicos. No se realizó ninguna intervención quirúrgica. La mediana de las concentraciones de PRL al diagnóstico fue de 108.180 (52.594-514.984)μIU/ml. El tratamiento médico logró una reducción notable (>99%) de los valores de prolactina en todos los casos. En todos los casos se observó una reducción del tamaño del tumor (superior al 33%). En un paciente se observó una fuga de líquido cefalorraquídeo (LCR) tras la reducción del tumor. CONCLUSIÓN: Los agonistas dopaminérgicos parecen ser un tratamiento de primera línea eficaz y seguro en los prolactinomas mayores de 60mm incluso en situaciones peligrosas para la vida. Se necesitan más estudios con un mayor número de pacientes para obtener datos suficientes para hacer recomendaciones importantes

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.

Occurrence and distribution of pilomyxoid astrocytoma.

PURPOSE: To know the occurrence and distribution of Pilomyxoid Astrocytomas amongst tumours previously diagnosed histologically as Pilocytic Astrocytoma and to assess the clinical impact of this new entity. METHODS: Retrospective Diagnostic review of all cases histologically diagnosed as WHO Grade I Astrocytoma at a single Neurosurgical unit between 1990 and 2003. RESULTS: Of a total of 91 cases identified, 9 were found to have Pilomyxoid histology. Of these, 8 were children (mean age 3.33 years) and 1 adult. 6 tumours were hypothalamochiasmatic in location. The clinical course of Pilomyxoid tumours was aggressive marked by maturation, multiple recurrences and disease control was rarely achieved with single treatment modality as opposed to typical pilocytics. The overall survival of the pilomyxoid group was not statistically different from the pilocytic tumours. CONCLUSIONS: Encompassing all age-groups and locations, Pilomyxoid Astrocytomas constitute about 10% of all tumours previously diagnosed as Pilocytic Astrocytoma. Nearly two-thirds are hypothalamo-chiasmatic in location. Knowledge of this entity is essential for appropriate aggressive treatment and follow-up.

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.

Incidence of vasculopathy in children with hypothalamic/chiasmatic gliomas treated with brachytherapy.

INTRODUCTION: External brain irradiation in children can cause cognitive decline, endocrine dysfunctions and second malignancies. A rare complication is cerebral vasculopathy, which occurs most often in patients with neurofibromatosis type 1. Interstitial radiotherapy using transient Iodine-125 implants is a radiotherapy option, called brachytherapy, offering excellent survival rates, but little is known on treatment-related morbidity, especially long time vascular changes. PATIENTS AND METHODS: Thirteen children with low-grade hypothalamic gliomas, four of them with neurofibromatosis type 1, were diagnosed and treated at the University Hospital Freiburg, Germany. They belong to a larger group of 44 children with suprasellar low-grade gliomas, treated with transient Iodine-125 seeds and include those who attended all routine follow-up examinations in Freiburg. After written informed consent from the parents or caregivers all patients underwent magnetic resonance imaging with angiographic techniques in 2001, 3 to 13 years after treatment. RESULTS AND DISCUSSION: Six out of 13 revealed cerebral vasculopathies, only one of them revealed symptoms of intermittent cerebral ischemia. Neurofibromatosis type 1 was present in one affected patient. The aetiology of the cerebral vascular changes is not fully understood so far. Tumour encasement, surgical damage and brachytherapy may contribute as a single risk factor or in combination. To get more information, we recommend MRA for artery vasculopathy at follow-up in all patients with suprasellar brain tumours irrespectively to their former treatment or presence of cerebrovascular symptoms.

Safety aspects of GH replacement.

In adults, GH replacement therapy will often be maintained for decades. Owing to the long duration of GH replacement in many adults, it is essential to establish the long-term safety aspects of the treatment. In this review, studies that have investigated the safety profile of long-term GH replacement will be reviewed with an emphasis on studies based on data from the Pfizer International Metabolic Database (KIMS). These studies show that long-term GH replacement in adults is safe and that long-term GH replacement may even improve cardiovascular mortality and morbidity in GH-deficient adults.

Hypothalamic hamartoma and infantile spasms.

PURPOSE: A small number of patients with hypothalamic hamartoma (HH) present with infantile spasms (IS) as an initial or early seizure type. We describe the clinical features of IS associated with HH. METHODS: Our series of patients with HH and epilepsy was reviewed to identify cases with a history of IS. The clinical features and neuroradiological findings in this study group were compared to a control group of patients with HH and refractory epilepsy, but without a history of IS. RESULTS: We identified six patients with HH and a history of IS in this series (n = 122, 4.9%). Five of the six are male. Four of the six patients (67%) developed IS as their first seizure type. The mean age for onset of IS was 6.2 months (range 4-9 months). Results of electroencephalographic (EEG) study at the time of IS diagnosis showed hypsarrhythmia in two (33%). Five patients were treated with adrenocorticotropic hormone (ACTH), and four of the five (80%) responded with control of IS. However, these patients developed other seizure types, and were ultimately refractory to medical management. Aside from the IS, no significant differences in clinical and imaging features were determined between the study group and the control group. CONCLUSIONS: HH should be included in the differential diagnosis for infants presenting with IS. These patients may have hypsarrhythmia on initial EEG, and may respond to ACTH treatment with improvement of IS. However, all became refractory with other seizure types, more commonly seen in HH patients. Focal pathologies associated with IS may be subcortical, as well as cortical, in nature. We have not identified any predictive features for the occurrence of IS in the HH population.

Late-onset optic pathway tumors in children with neurofibromatosis 1.

Identification of new optic pathway tumors (OPTs) and progression of pre-existing OPTs in children with neurofibromatosis 1 (NF1) have been reported infrequently after age 6. The authors present eight children with NF1 (mean age 12.2 years) seen in three NF1 centers who had either late-onset (four of eight) or late-progressive (seven of eight) OPT. Continued monitoring of individuals with NF1 into adulthood for the development of OPTs and for progression of known OPTs is warranted.

Recognition of the various expressions of anxiety, psychosis, and aggression in epilepsy.

Anxiety, psychosis, and aggressive behavior are among the frequent comorbid psychiatric disorders identified in patients with epilepsy. Often the clinical manifestations of these disorders vary according to their temporal relation relative to seizure occurrence. Thus, postictal symptoms of anxiety or psychosis differ in severity, duration, and response to treatment with interictal symptomatology. Psychiatric symptomatology in epilepsy can appear concurrently with the seizure disorder and improve or remit on the abolition of epileptic activity. We refer to these as paraictal psychiatric phenomena. Such is the case of aggressive disturbances associated with gelastic seizures caused by hypothalamic hamartomas. In this article, three case studies are presented to illustrate the importance of distinguishing psychiatric symptoms of anxiety, psychosis, and aggression, with respect to their temporal relation with seizure occurrence.

An integrated approach to the treatment of chiasmatic-hypothalamic gliomas.

The treatment of visual pathway gliomas is controversial. The many retrospective studies reporting outcome data for patients with chiasmatic/hypothalamic gliomas are difficult to interpret for several reasons. First the natural history of these tumors is erratic with some reports suggesting that most visual pathway gliomas are hamartomas and follow an indolent course, and others reporting 10-year survival rates of close to 60%. Second, earlier studies did not clearly indicate which patients had neurofibromatosis type 1 (NF1) and recent evidence suggests that the natural history of optic gliomas is more favorable in patients with NF1. Third the methods and accuracy of diagnosis have changed dramatically and patients diagnosed before and after the advent of CT/MR imaging have often been included in the same series. While surgical resection is usually not a viable option for definitive treatment of these tumors, recent studies have shown favorable results after subtotal resection in selected patients. The efficacy of radiotherapy has not been unequivocally demonstrated and treatment-related morbidity has become a major concern, in particular, adverse effects on cognition and growth. Chemotherapy has been advanced as an viable alternative to avoid or delay the adverse affects of RT, but the long-term outcome benefits and adverse effects of treatment are just being defined. Despite the limitations of currently available information, sufficient data are now available to rational management quotelines for the majority of children with chiasmatic/hypothalamic gliomas.

Hamartomas of the tuber cinereum: CT, MR, and pathologic findings.

The neuroimaging studies, clinical evaluations, and surgical and pathologic findings in five children with biopsy-proved hamartomas of the tuber cinereum were reviewed. Surgical and/or MR findings showed that patients with precocious puberty had pedunculated lesions while those with seizures had tumors that were sessile with respect to the hypothalamus. The radiologic studies included six MR examinations in four patients and CT studies in all five patients. Three children presented with precocious puberty and two with seizures, one of which was a gelastic (spasmodic or hysteric laughter) type of epilepsy. MR studies were obtained both before and after surgery in two patients, only preoperatively in a third patient, and only postoperatively in the fourth child. MR was superior to CT in displaying the exact size and anatomic location of the hamartomas in all cases. The mass was isointense with gray matter on sagittal and coronal T1-weighted images, which best displayed the relationship of the hamartoma to the third ventricle, infundibulum, and mammillary bodies. Intermediate- or T2-weighted images showed signal characteristics of the hamartoma to be isointense (one case) or hyperintense (two cases) relative to gray matter. The difference in T2 signal intensity did not correlate with any obvious differences in histopathology. CT showed attenuation isodense with gray matter, and no calcium. There was no enhancement on CT. There was no enhancement on MR in the one case in which contrast medium was administered. Preservation of the posterior pituitary bright spot was noted on all pre- and postoperative T1-weighted MR scans.(ABSTRACT TRUNCATED AT 250 WORDS)

A cluster of Pallister-Hall syndrome cases, (congenital hypothalamic hamartoblastoma syndrome).

We report on three infants with hand anomalies and congenital hypopituitarism. In two of the cases, a hypothalamic tumor was found; the third infant died without postmortem brain studies. Family history in the first case suggested possible familial recurrence; the mother's sister had died at 17 hr of age with polydactyly, microglossia, and flat nasal bridge (no autopsy done). Our second case was born by cesarean section after a pregnancy complicated by extremely low maternal estriols. At birth, hypopituitarism was diagnosed, a cranial CT scan was read as normal, and hormonal replacement was begun with thyroxine, hydrocortisone, and growth hormone. At 11.5 mo of age she developed seizures; and a repeat CT scan showed a mass extending beneath the hypothalamus. This tumor was removed surgically at 12 mo, the first successful treatment of this disorder. Our third possible case had a bifid epiglottis, hypopituitarism, and hand anomalies. A CT scan at birth failed to reveal a mass in the hypothalamus. This child died from complications of untreated hypopituitarism, and no neuropathology studies were done. These three cases were conceived between March 10th and April 17th in three different years in three geographically contiguous counties of Vermont. Clustering in time and space and possible familial recurrence, in one of these cases, suggest a possible gene/environment interaction.