Hypothalamic Damage Research Articles

PRESERVED NUMBER OF OREXIN NEURONS IN POSTMORTEM HYPOTHALAMIC TISSUE OF CHRONIC ALCOHOLICS

The hypothalamic orexin system is critically involved in addiction, including chronic alcohol abuse. Microinjection of orexin into the lateral hypothalamus increases alcohol intake in rats, while reduced immunoreactivity of orexin neurons is associated with decreased alcohol drinking. Recently, the numbers of orexin neurons were found to be increased in opiate addiction in humans [4] and cocaine addiction in rats [2], but the integrity of orexin neurons has not yet been studied in human alcoholics. We examined the hypothalamus of 9 patients of chronic alcoholism and 10 subjects without a history of alcoholism or any other neurological or psychiatric disorder. We performed immunohistochemistry for orexin A, followed by stereological quantification. The hypothalamic tissue of chronic alcoholics exhibited a slightly increased number (9%) of orexin-containing neurons compared to the control group (123’087 ± 18’536 and 110’431 ± 14’439, p = 0.11). Mean Gundersen’s coefficient of error was 0.06 ± 0.01. The number of orexin neurons was similar in chronic alcoholics and control subjects without a history of alcoholism. Further examination of alcohol-induced hypothalamic damage is needed to understand, whether a neuroplastic increase in orexin neurons counterbalances a concurrent alcohol-toxic damage to these neurons.

Swimming reduces fatty acids-associated hypothalamic damage in mice

The arcuate and the paraventricular and lateral hypothalamic nuclei, related to hunger and satiety control, are generally compromised by excess fatty acids. In this situation, fatty acids cause inflammation via TLR4 (toll like receptor 4) and the nuclei become less responsive to the hormones leptin and insulin, contributing to the development of obesity. In this work, these nuclei were analyzed in animals fed with high-fat diet and submitted to swimming without and with load for two months. For this, frontal sections of the hypothalamus were immunolabelled with GFAP (glial fibrillary acidic protein), synaptophysin, IL-6 (interleukin 6) and TLR4. Also, proteins extracted from the hypothalamus were analyzed using Western blotting (GFAP and synaptophysin), fluorometric analysis for caspases 3 and 7, and CBA (cytometric bead array) for Th1, Th2, and Th17 profiles. The high-fat diet significantly caused overweight and, in the hypothalamus, decreased synapses and increased astrocytic reactivity. The swimming with load, especially 80 % of the maximum load, reduced those consequences. The high-fat diet increased TLR4 in the arcuate nucleus and the swimming exercise with 80 % of the maximum load showed a tendency of reducing this expression. Swimming did not significantly influence the inflammatory or anti-inflammatory cytokines in the hypothalamus or in plasma. The high-fat diet in sedentary animals increased the expression of caspases 3 and 7 and swimming practice reduced this increment to levels compatible with animals fed on a normal diet. The set of results conclude that the impact of swimming on the damage caused in the hypothalamus by a high-fat diet is positive. The different aspects analyzed in here point to better cellular viability and conservation of the synapses in the hypothalamic nuclei of overweight animals that practiced swimming with a load.

Advances in the management of craniopharyngioma in children and adults.

BackgroundChildhood and adult-onset craniopharyngioma is a rare embryogenic tumor of the sellar, suprasellar, and parasellar region. Survival rates are high; however, tumor location and treatment sequalae including endocrine deficits, visual impairment, metabolic complications, cognitive and psychosocial deficits can significantly impair patient’s quality of life. There is considerable controversy regarding the optimal management of craniopharyngiomas. Subtotal resection of the tumor followed by targeted irradiation to avoid further hypothalamic damage is currently indicated. Novel insights in the tumor’s molecular pathology present the possibility for targeted therapy possibly decreasing the rate and severity of treatment-associated morbidity.ConclusionsCraniopharyngioma should be seen as a chronic disease. To achieve optimal outcomes a multidisciplinary team of specialized neurosurgeons, neuro-radiologists, neuro-oncologists, pathologists and endocrinologists should be involved in the diagnosis, planning of the surgery, irradiation and long-term follow-up.

Controversies in exertional heat stroke diagnosis, prevention, and treatment.

During the past several decades, the incidence of exertional heat stroke (EHS) has increased dramatically. Despite an improved understanding of this syndrome, numerous controversies still exist within the scientific and health professions regarding diagnosis, pathophysiology, risk factors, treatment, and return to physical activity. This review examines the following eight controversies: 1) reliance on core temperature for diagnosing and assessing severity of EHS; 2) hypothalamic damage induces heat stroke and this mediates "thermoregulatory failure" during the immediate recovery period; 3) EHS is a predictable condition primarily resulting from overwhelming heat stress; 4) heat-induced endotoxemia mediates systemic inflammatory response syndrome in all EHS cases; 5) nonsteroidal anti-inflammatory drugs for EHS prevention; 6) EHS shares similar mechanisms with malignant hyperthermia; 7) cooling to a specific body core temperature during treatment for EHS; and 8) return to physical activity based on physiological responses to a single-exercise heat tolerance test. In this review, we present and discuss the origins and the evidence for each controversy and propose next steps to resolve the misconception.

Kaolin-induced hydrocephalus causes acetylcholinesterase activity dysfunction following hypothalamic damage in infant rats

In hydrocephalus, the progressive accumulation of cerebrospinal fluid (CSF) causes dilatation of the lateral ventricles affecting the third ventricle and diencephalic structures such as the hypothalamus. These structures play a key role in the regulation of several neurovegetative functions by the production of the hormones. Since endocrine disturbances are commonly observed in hydrocephalic children, we investigated the impact of progressive ventricular dilation on the hypothalamus of infant rats submitted to kaolin-induced hydrocephalus. Seven-day-old infant rats were submitted to hydrocephalus induction by kaolin 20% injection method. After 14 days, the animals were decapitated and brain was collected to analyze mitochondrial function, neuronal activity by acetylcholinesterase (AChE) enzyme, oxidative damage, glial activation, and, neurotransmission-related proteins and anti-apoptotic processes in the hypothalamus. The hydrocephalic animals showed reduction in respiratory rates in the States of phosphorylation (P < 0.01) and non-phosphorylation (P < 0.05); increase in AChE activity in both the cytosol (P < 0.05) and the membrane (P < 0.01); decrease in synaptophysin (P < 0.05) and Bcl-2 (P < 0.05) contents and; increase in protein carbonyl (P < 0.01), GFAP (P < 0.01) and Iba-1 (P < 0.05) levels. The results demonstrate that ventricular dilation causes hypothalamic damage characterized by cholinergic dysfunction and suggests further investigation of the synthesis and secretion of hormones to generate new approaches and to assist in the treatment of hydrocephalic patients with hormonal alterations.

Preservation of Hypothalamic Function with Endoscopic Endonasal Resection of Hypothalamus-Invaded Craniopharyngiomas

To analyze the preservation of hypothalamic function using the endoscopic endonasal approach (EEA) in a single-center clinical series of patients with hypothalamus-invaded craniopharyngioma (CP) and compare this series with reported cases by the open transcranial approach (TCA). A retrospective review of hypothalamus-invaded CP surgical cases treated with EEA was performed. Hypothalamic damage was evaluated in terms of the body mass index (BMI), endocrine status, and quality of life before and after surgery. A review of the available literature reporting the use of EEA and TCA over the last decade was performed for comparison. In total, 63 cases amenable to EEA were investigated. The elevation in BMI was substantial and an increase in BMI greater than 9% was observed in 22 patients (34.92%). Most patients exhibited a BMI gain >9%within 3 months postoperatively. A total of 16 of the 19 patients who had normal anterior pituitary function preoperatively worsened after surgery. Of the 27 cases reporting preoperative partial hypopituitarism, 16 cases worsened postoperatively and 11 cases remained unchanged. All 9 cases with preoperative panhypopituitarism remained unchanged postoperatively. A total of 40 new cases developed diabetes insipidus, and 3 of the 10 patients with preoperative diabetes insipidus exhibited resolved at the latest follow-up. The quality of life showed no significant difference. EEA can achieve greater gross total resection than TCA when performed by an experienced surgeon. Combined with the reduced postoperative hypothalamic damage in our patients with only hypothalamus-invaded CP, especially the shortened time horizons of hypothalamic obesity development and reduced percentage of patients with obesity, the EEA technique should be a preferred alternative over TCA.

Hypothalamic impairment underlying heat intolerance in pregnant mice

Pregnant women are vulnerable to heat stroke reactions caused by high environmental temperatures. Heat intolerance is associated with hypothalamic impairment. Here, we aim to ascertain whether pregnancy causes heat intolerance by inducing hypothalamic impairment in mice. In the heated groups, mice were exposed to whole body heating (WBH; 41.2 °C for 1 h) in an environment-controlled chamber. Then, they were returned to normal room temperature (26 °C) immediately after WBH. In the hyperbaric oxygen therapy (HBO2T) groups, mice were exposed to 100% O2 at 2.0 atm absolute (ATA) for 4 h immediately post-WBH. Mice that survived after 4 h of WBH were considered survivors. Here, we show that when pregnant mice underwent non-HBO2T (21% O2 at 1.0 ATA for 4 h) after WBH, the survival rate was 4/20, and the core temperature at 4 h post-WBH was 31.2 ± 0.2 °C. Both the survival rate and core temperature of HBO2T pregnant mice (10/10 and 35.2 ± 0.3 °C, respectively) were significantly greater than those in non-HBO2T pregnant mice. Compared to non-HBO2T heated mice, the HBO2T heated mice exhibited lower neurological severity scores, reduced hypothalamic neuronal damage, fewer apoptotic cells, reduced multiorgan damage scores, and lower hypothalamic levels of proinflammatory cytokines and nitrogen and oxygen radical species. Compared to non-HBO2T heated mice, the HBO2T-treated heated mice had significantly higher hypothalamic-pituitary-adrenal axis activity (evidenced by higher serum levels of both adrenocorticotrophic hormone and corticosterone). In conclusion, pregnancy induces heat intolerance by inducing hypothalamic impairment in mice. Additionally, HBO2T protects against heat intolerance in pregnant mice by preserving hypothalamic integrity.

SAT-254 Combination of Octreotide and Dexamphetamine to Control Weight Gain in Pediatric Patients with Hypothalamic Obesity

Hypothalamic obesity (HO) is a devastating complication, that occurs in patients with hypothalamic damage. It is characterized by polyphagia, and adynamia leading to a severe form of obesity, which is intractable to caloric restriction or lifestyle modification. HO is suggested to be a result of hypothalamic damage, leading to declined efferent sympathetic activity and reduced energy expenditure as well as raised vagal activity resulting in increased insulin secretion and adipogenesis. Trials of both single octreotide (OCT) and single dexamphetamin (DEX) were conducted and showed some effect to weight control. However no trial of combined OCT and DEX (OCT/DEX) was reported until now. A monocentric retrospective cohort study was conducted. All patients, who were diagnosed to suffer from HO in between January 1st, 2010 and September 30st, 2018, were included (n =11; mean age: 14.7 years; mean weight 104.6 +/- 11.6 kg; body mass index (BMI), 36.4 +/- 1.3 kg/m2). All subjects were suffering from a brain tumor (craniopharyngioma: 6/11; germinoma 3/11; astrocytoma 1/11) followed by neurosurgery and/or irradiation. Panhypopituitarism and type 2 diabetes, which was verified in all subjects, was replaced in usual hormone dosages and metformin, respectively. A specialized diet and raised physical activity was recommended. Six subjects received a combination of OCT (15-20 µg/kg/d) and DEX (5-15 mg/d) for at least 36 months, when the observation was stopped. Seven patients were not treated with this combination. In the first 12 months patients with OCT/DEX the Δweight (mean ± sem) was -0.7 ± 0.5 kg vs. 9.4 ± 1.6 kg for untreated patients. After 36 months with OCT/DEX the Δweight was +8.2 ± 0.6 kg vs. 27.1 ± 4.7 kg for the untreated group, and ΔBMI was +0.5 ± 0.4 vs. +6.8 ± 3.4 kg/m2, respectively. With oGTT we observed Δinsulin response (peak−basal) of -397± 244 pmol/L and +188±201 pmol/L in the treated and untreated patient groups, respectively. Parents reported marked improvement in physical activity of patients on OCT/DEX, but not in the untreated group. Complications and adverse events were mostly mild and self-limited. One patient with OCT/DEX developed gallstones 32 months after start, when OCT was stopped. Three patients without OCT/DEX leg died probably due to sleep apnea by known obesity-hypoventilation syndrome. Regarding the hypothalamus being extremely sensitive to irradiation and neurosurgical intervention, we consider a brain-saving surgery remains the best treatment. We combined both OCT and DEX in attempt to reduce hyperinsulinemia and increase patients` activity level. We report about a significant lower weight gain in patients treated with OCT/DEX than in the comparative cohort and therefore suggest OCT/DEX as an effective combination to control weight in patients with HO due to hypothalamic damage. Further prospective controlled studies are required to confirm this observation.

MON-456 Determinants of Hypothalamic Obesity Following Surgical Treatment for Craniopharyngioma in Adults

Background: Craniopharyngiomas (CPs) are associated with hypothalamic damage that causes hypothalamic obesity in 30-70% of cases. However, there is an issue of debate for the mechanisms by which CPs cause body weight gain after surgery. In this study, we aimed to reveal the determinants of postoperative weight gain in CP patients compared with non-functioning pituitary adenoma (NFPA) patients. Materials and Methods: We included 48 CP patients aged ≥18 years, who underwent transsphenoidal surgery and measured pre- and postoperative body weight (<120 days after surgery) between 2010 and 2018 in a single tertiary center. One hundred forty-four age- and body mass index (BMI)-matched NFPA patients were recruited. Results: Mean age of diagnosis was 51.3 years and preoperative BMI was 25.0 kg/m2 in overall patients (mean duration of follow-up: 91.2 days). Tumor volume was larger in NFPA patients than in CP patients (119856±18546 mm3 vs. 6285±7795 mm3, P=0.042). CP patients experienced greater postoperative weight gains than NFPA patients (3.0±5.1 kg vs 0.1±3.6 kg, P<0.001). The prevalence of postoperative steroid users was significantly higher in CP patients than in NFPA patients (89.6% vs. 34.0%, P<0.001). The presence of postoperative hormone deficiency did not differ between the two groups (P=0.187). In subgroup analysis with postoperative steroid users, weight gain was significantly greater in CP patients (n=43, 0.96±0.25 kg/month) than in NFPA patients (n=49, 0.26±0.23 kg/month) even after adjusting for steroid replacement dose (P=0.048). Conclusion: CP patients experience greater weight gain than those with NFPA after surgical treatment. Our findings suggest that hypothalamic damage itself as well as steroid replacement therapy may contribute to the postoperative weight gain in CP patients.

SUN-422 Panhypopituitarism Secondary to Pituitary Macroadenoma with Optic Chiasm Compression and Possible Apoplexy

Learning Objective: To recognize profound hyponatremia as a presenting feature of pituitary adenoma. Ten percent of the population have undiagnosed pituitary adenomas; rarely leading to hypopituitarism and apoplexy. A 75 year old man presented to the hospital with severe headache, vomiting and double- vision. He reported decreased libido, axillary and pubic hair for the past year. Vital signs were stable and physical exam revealed diplopia but no bitemporal hemianopsia or other visual defects. Initial lab work showed a sodium level of 116. Testosterone was <7.0, LH 0.54 and FSH of 4.3, ACTH <5.0, TSH 0.772, free Thyroxine of 0.44 which raised concern for hypopituitarism. Brain MRI was contraindicated due to a pacemaker. CT head with contrast confirmed a pituitary macroadenoma measuring 2.6 cm by 2.0 cm by 1.2 cm with compression of the optic chiasm. There was increased attenuation diffusely in the pituitary and pituitary apoplexy could not be ruled out. Prompt therapy was initiated with dexamethasone, levothyroxine, and intravenous fluids. He underwent a successful transsphenoidal resection with development of diabetes insipidus post-operatively. Discharge medications included desmopressin, hydrocortisone and levothyroxine. Hypopituitarism can occur from direct pituitary dysfunction or hypothalamic damage and can be congenital or acquired. Most causes are acquired such as pituitary macroadenoma, transcranial surgery or apoplexy. The anterior pituitary gland is extremely well-vascularized and depends on this for release of hypothalamic factors to the pituitary cells and release of hormones into blood. Blood-supply lesions are caused by compression of the long portal blood vessels or apoplexy from a tumor or local hemorrhage. Apoplexy occurs only in 2-12% of adenomas, most commonly in nonfunctioning tumors. Recognition is crucial as it is life-threatening due to the corticotropic deficiency. Recent evidence suggests that pituitary tumors are at an increased risk of spontaneous infarct even without evident hemorrhage. This is due to the intrinsic features of the tumor, high demand for nutrients and limited blood supply. This makes the tumor vulnerable to infarction from surgery, hypotension, hypoglycemia from insulin or from given hypothalamic releasing factors which causes increased metabolic demand. We present a patient with panhypopituitarism from a pituitary adenoma and possible pituitary apoplexy. Hyponatremia is a unique presentation of an underlying pituitary adenoma and occurs due to cortisol deficiency. Recognition of such subtle clinical signs is key for the prompt treatment of an underlying pituitary dysfunction. Oldfield, EH & Merrill, MJ. (2015) Apoplexy of pituitary adenomas: the perfect storm. Journal of Neurosurgery. 122:1444-1449 Stieg, MR, Renner, U, Stalla, GR, Kopczak, A. (2017) Advances in understanding hypopituitarism. F1000Research. 6;178

MON-096 Body Composition in Patients with Craniopharyngioma: Is DXA-Scanning Necessary for Evaluating the Metabolic Syndrome?

In craniopharyngioma patients, an important clinical feature is an adverse metabolic profile due to hypothalamic damage and pituitary deficiencies. In our Dutch/Swedish craniopharyngioma cohort, the occurrence of the metabolic syndrome (MetS) was higher than in the general population (46% vs.15% in the Swedish and 26% in Dutch population) (Wijnen 2017). However, in previous analysis we have used increased body mass index (BMI) to define adiposity. BMI misclassifies more than 50% of childhood cancer survivors as normal, while DXA measures increased body fat percentage (BF%) as BMI does not take an altered body composition into account (Blijdorp 2012). Our hypothesis was that MetS (defined according to the adjusted Joint Interim Statement) (Alberti 2009) and adiposity are underestimated in our previous study (Wijnen 2017). In the current retrospective cross-sectional study, craniopharyngioma patients (aged ≥ 18 yrs) were included if they had had at least one DXA-scan in the past. BMI, BF% and fat mass index (FMI) at the moment of first and, if available, last DXA-scan were gathered. These measurements or calculated standardized deviation scores (SDS) were used to evaluate obesity. The different definitions of obesity were applied as component in the definition of MetS; the laboratory results evaluating other components of MetS were gathered within 3 years of DXA-scan. We included 95 patients, 51% females and 49% with childhood-onset disease. Between 34 and 53 patients with craniopharyngioma fulfilled the criteria for the MetS (45-51% depending on the different assessment of adiposity), which was higher than the general population independent of the definition (P<0.05). Occurrence of MetS was higher if obesity was defined by DXA-measured BF% (52% vs. 42%, P=0.031) or FMI (51% vs. 43%, P=0.063) compared to BMI at last DXA-scan. A misclassification appeared in 8-9% (BF% vs. BMI) and 5-7% (FMI vs. BMI) for MetS, and respectively 25-29% and 9-13% for obesity. For MetS, an almost perfect agreement was found if increased BMI was compared with either increased BF% (Cohen’s Kappa 0.82-0.90, P<0.001) or FMI (Cohen’s Kappa 0.85-0.88, P<0.001). For obesity, agreement was only fair (Kappa 0.37, P=0.002 at last DXA-scan) to moderate (Kappa 0.53, P<0.001 at first DXA-scan) if increased BMI is compared with increased BF%. An Altman-Bland plot of BMI SDS and BF% SDS shows an upward trend with values outside limits of agreement at low and high averages. In conclusion, craniopharyngioma patients are at high risk for the MetS and obesity. DXA-scan measured BF% contributes to a more precise evaluation of obesity identification. Using BMI to estimate obesity may even underestimate the true prevalence of MetS. However, as craniopharyngioma patients have an extreme metabolic phenotype, the contribution of a better defined obesity component for identification and confirmation of MetS might be limited.

Management of hypothalamic disease in patients with craniopharyngioma.

Patients with craniopharyngioma experience excess morbidity and mortality when compared with the background population and with other hypopituitary patients. Large, suprasellar tumours which form micropapillae into surrounding structures can cause hypothalamic damage before any therapeutic intervention; attempted gross total resection can lead to hypothalamic obesity, sleep disorders, thirst disorders and dysregulation of temperature as well as panhypopituitarism. The management of tumour bulk and the pathophysiology of hypothalamic complications have been reviewed extensively. We present a practical, clinical approach to management of hypothalamic disease in a patient with craniopharyngioma and highlight potential targets for future pharmacological or surgical intervention.

ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study

PurposeLow plasma ACTH in critically ill patients may be explained by shock/inflammation-induced hypothalamus-pituitary damage or by feedback inhibition exerted by elevated plasma free cortisol. One can expect augmented/prolonged ACTH-responses to CRH injection with hypothalamic damage, immediately suppressed responses with pituitary damage, and delayed decreased responses in prolonged critical illness with feedback inhibition.MethodsThis randomized, double-blind, placebo-controlled crossover cohort study, compared ACTH responses to 100 µg IV CRH and placebo in 3 cohorts of 40 matched patients in the acute (ICU-day 3–6), subacute (ICU-day 7–16) or prolonged phase (ICU-day 17–28) of critical illness, with 20 demographically matched healthy subjects. CRH or placebo was injected in random order on two consecutive days. Blood was sampled repeatedly over 135 min and AUC responses to placebo were subtracted from those to CRH.ResultsPatients had normal mean ± SEM plasma ACTH concentrations (25.5 ± 1.6 versus 24.8 ± 3.6 pg/ml in healthy subjects, P = 0.54) but elevated free cortisol concentrations (3.11 ± 0.27 versus 0.58 ± 0.05 µg/dl in healthy subjects, P < 0.0001). The order of the CRH/placebo injections did not affect the ACTH responses, hence results were pooled. Patients in the acute phase of illness had normal mean ± SEM ACTH responses (5149 ± 848 pg/mL min versus 4120 ± 688 pg/mL min in healthy subjects; P = 0.77), whereas those in the subacute (2333 ± 387 pg/mL min, P = 0.01) and prolonged phases (2441 ± 685 pg/mL min, P = 0.001) were low, irrespective of sepsis/septic shock or risk of death.ConclusionsSuppressed ACTH responses to CRH in the more prolonged phases, but not acute phase, of critical illness are compatible with feedback inhibition exerted by elevated free cortisol, rather than by cellular damage to hypothalamus and/or pituitary.

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

This study provides a systematic review and meta-analysis of psychiatric disorders caused by craniopharyngiomas and the hypothalamic alterations underlying these symptoms. 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. 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. Craniopharyngiomas primarily involving the hypothalamus represent a neurobiological model of psychiatric and behavioral disorders.

Detailed assessment of hypothalamic damage in craniopharyngioma patients with obesity.

Hypothalamic obesity (HO) occurs in 50% of patients with the pituitary tumor craniopharyngioma (CP). Attempts have been made to predict the risk of HO based on hypothalamic (HT) damage on magnetic resonance imaging (MRI), but none have included volumetry. We performed qualitative and quantitative volumetric analyses of HT damage. The results were explored in relation to feeding related peptides and body fat. A cross-sectional study of childhood onset CPs involving 3 Tesla MRI, was performed at median 22 years after first operation; 41 CPs, median age 35 (range: 17-56), of whom 23 had HT damage, were compared to 32 controls. After exclusions, 35 patients and 31 controls remained in the MRI study. Main outcome measures were the relation of metabolic parameters to HT volume and qualitative analyses of HT damage. Metabolic parameters scored persistently very high in vascular risk particularly among HT damaged patients. Patients had smaller HT volumes compared to controls 769 (35-1168) mm3 vs. 879 (775-1086) mm3; P < 0.001. HT volume correlated negatively with fat mass and leptin among CP patients (rs = -0.67; P < .001; rs = -0.53; P = 0.001), and explained 39% of the variation in fat mass. For every 100 mm3 increase in HT volume fat mass decreased by 2.7 kg (95% CI: 1.5-3.9; P < 0.001). Qualitative assessments revealed HT damage in three out of six patients with normal volumetry, but HT damage according to operation records. A decrease in HT volume was associated with an increase in fat mass and leptin. We present a method with a high inter-rater reliability (0.94) that can be applied by nonradiologists for the assessment of HT damage. The method may be valuable in the risk assessment of diseases involving the HT.

Interventions for the Treatment of Craniopharyngioma-Related Hypothalamic Obesity: A Systematic Review

Craniopharyngiomas (CPs) and their treatment are associated with hypothalamic damage that causes hypothalamic obesity (HO) in 30%-70% of cases. Thus, there is ongoing research regarding tangible solutions for HO, because these patients have unrelenting resistance to basic weight-loss interventions. This review aims to summarize the interventions that are used to treat CP-related HO (CP-HO), including pharmacotherapy and bariatric surgery. The Cochrane Library, EMBASE, and PubMed databases were searched up to June 2017 for relevant reports. Two reviewers conducted independent evaluations of the studies identified. Eighteen articles were included in the systematic review, with 3 reports describing pharmacotherapy in randomized controlled trials and 15 reports describing bariatric surgery. Although several studies described effective interventions for treating CP-HO, the evidence base was limited by its low quality and our inability to perform a meta-analysis, which was related to a lack of adequate or integrated data. Octreotide appears to be a preferred treatment for patients with CP-HO, based on limited data. Gastric bypass surgery may also be suitable for select patients with CP-HO, based on a review of various procedures in this setting. Microsurgical preservation of the hypothalamic structures is mandatory to decrease CP-HO-related morbidity and mortality. Further studies with adequate analytical power and sufficient follow-up are needed to identify effective strategies for CP-HO treatment.

Cranial Irradiation Induces Hypothalamic Injury and Late-Onset Metabolic Disturbances in Juvenile Female Rats

Cranial radiotherapy is one of the most effective tools for treating children with brain tumors. However, radiotherapy-induced late-onset side effects have a significant impact on patients’ quality of life. The purpose of this study was to investigate the effects of irradiation on metabolism and the possible molecular and cellular mechanisms behind such effects. Female Wistar rats were subjected to a single dose of 6-Gy whole-brain irradiation on postnatal day 11. The animals were sacrificed 6 h or 20 weeks after irradiation. Cell death and proliferation, microglial activation, and inflammation were analyzed and RNA sequencing was performed. We found that irradiation led to a significantly increased body weight from 15 weeks (p < 0.05) along with white adipose tissue accumulation and adipocyte hypertrophy at 20 weeks, and these changes were accompanied by glucose and lipid metabolic disturbances as indicated by reduced glucose tolerance, increased insulin resistance, increased serum triglycerides, and an increased leptin/adiponectin ratio. Furthermore, irradiation induced cell death, microglial activation, inflammation, and persistent astrocyte reactivity in the hypothalamus. Hypothalamic transcriptome analysis showed that 865 genes were downregulated and 290 genes were upregulated in the irradiated group 20 weeks after irradiation, and further pathway analysis showed that the insulin resistance-related PI3K-Akt signaling pathway and the energy expenditure-related adipocytokine signaling pathway were downregulated. Gene Ontology enrichment analysis showed that the expression of fatty acid metabolism-related proteins and effector proteins was significantly different in the irradiation group. This study demonstrates that ionizing radiation to the juvenile female brain induces hypothalamic damage that is likely to be associated with delayed metabolic abnormalities, and this critical vulnerability of the hypothalamus to irradiation should be taken into consideration in the development of future protective strategies for radiotherapy.

NFATc3 deficiency protects against high fat diet (HFD)-induced hypothalamus inflammation and apoptosis via p38 and JNK suppression

Hypothalamic inflammation and apoptosis cause neural injury, playing an important role in metabolic syndrome development. Nuclear Factors of Activated T cells (NFATc3) show many physiological and pathological effects. However, the function of NFATc3 in high fat diet (HFD)-induced hypothalamus injury remains unknown. The wild type (WT) and NFATc3-knockout (KO) mice were subjected to HFD feeding for 16 weeks to examine NFATc3 function in vivo. Astrocytes isolated from WT or KO mice were cultured and exposed to fructose (Fru) in vitro. The liver damage, hypothalamus injury, pro-inflammatory markers, NF-κB (p65), Caspase-3 and mitogen-activated protein kinases (MAPKs) pathways were evaluated. NFATc3 was significantly up-regulated in hypothalamus from mice challenged with HFD, and in astrocytes incubated with Fru. Both in vivo and in vitro studies indicated that NFATc3-deletion attenuated metabolism syndrome, reduced inflammatory regulators expression, inactivated NF-κB (p65), Caspase-3 and p38/JNK signaling pathway. Of note, we identified that promoting p38 or JNK activation could rescue inflammatory response and apoptosis in NFATc3-KO astrocytes stimulated by Fru. Together, these findings revealed an important role of NFATc3 NFATc3 for HFD-induced metabolic syndrome and particularly hypothalamus injury, and understanding of the regulatory molecular mechanism might provide new and effective therapeutic strategies for prevention and treatment of hypothalamic damage associated with dietary obesity-associated neuroinflammation and apoptosis.

Low concordance between surgical and radiological assessment of degree of resection and treatment-related hypothalamic damage: results of KRANIOPHARYNGEOM 2007.

Assessment of presurgical hypothalamic involvement (psHI) and treatment-related hypothalamic damage (trHD) is relevant for the decision on risk-adapted treatment and rehabilitation strategies in craniopharyngioma. 129 surgical reports of childhood-onset craniopharyngioma patients recruited 2007-2014 in KRANIOPHARYNGEOM 2007 were analyzed. Data on psHI were available based on surgeon's (63%), reference neuroradiologist's (95%), and local radiologist's (23%) assessment. The surgical degree of resection (DoR) was assessed by neurosurgeon (95%), reference neuroradiologist (73%), and local radiologist (61%). TrHD was assessed by neurosurgeon (33%), by reference neuroradiologist (95%), and by local radiologist (2%). Neurosurgical center size was categorized based on patient load. Surgical assessments on psHI (n = 78), DoR (n = 89) and trHD (n = 42) as documented in surgical reports could be compared with the assessment of respective parameters by reference neuroradiologist. Differences with regard to DoR (p = 0.0001) and trHD (p < 0.0001) were detectable between surgeon's and reference neuroradiologist's assessment, whereas psHI was assessed similarly. Concordance for DoR and trHD was observed in 48 and 62%, respectively. Surgeons estimated a higher rate of complete resections and a lower rate of trHD. Neuroradiological reference assessment of trHD had higher predictive value for hypothalamic sequelae then surgical assessment. Observed differences were not related to neurosurgical center size. Observed differences between surgical and neuroradiological estimation of risk factors in craniopharyngioma support the necessity of neuroradiological reference review to assure standards of quality. This could be established by central internet-based neuroradiological review in KRANIOPHARYNGEOM 2007. Standardization of surgical reports including specific assessment of tumor/damage location is recommended.

Hepatopulmonary syndrome caused by hypothalamic obesity and nonalcoholic fatty liver disease after surgery for craniopharyngioma: a case report

Hypothalamic obesity is often complicated in patients with craniopharyngioma due to hypothalamic damage by the tumor itself, treatment modalities, and associated multiple pituitary hormone deficiency. Hypothalamic obesity causes secondary diseases such as nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM). We report a 19-year-old female who was diagnosed with craniopharyngioma, developed hypothalamic obesity after tumor resection, and progressed to hepatopulmonary syndrome. She manifested NAFLD 1 year after tumor resection. Two years later, the craniopharyngioma recurred, and she underwent a second resection. Three years after her second operation, she was diagnosed with type 2 DM, after which she did not visit the outpatient clinic for 2 years and then suddenly reappeared with a weight loss of 25.8 kg that had occurred over 21 months. One month later, she presented to the Emergency Department with dyspnea. Laboratory findings revealed liver dysfunction and hypoxia with increased alveolar artery oxygen gradient. Liver biopsy showed portal hypertension and micronodular cirrhosis. Echocardiography and a lung perfusion scan demonstrated a right to left shunt. She was finally diagnosed with hepatopulmonary syndrome and is currently awaiting a donor for liver transplantation. Patients surviving craniopharyngioma need to be followed up carefully to detect signs of hypothalamic obesity and monitored for the development of other comorbidities such as DM, NAFLD, and hepatopulmonary syndrome.