Acquired hypothalamic obesity: A clinical overview and update.

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.

Weight management in youth with rapid-onset obesity with hypothalamic dysregulation, hypoventilation, autonomic dysregulation, and neural crest tumor (ROHHAD-NET): literature search and case report.

OBJECTIVES: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural endocrine tumor (ROHHAD-NET) syndrome is a youth-onset constellation of symptoms including rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation. Despite growing understanding of the clinical classification of this syndrome there is limited investigation into treatment of the rapid-onset obesity which can be progressive and life-limiting. The purpose of this case report is to describe the clinical timeline and treatment of severe obesity in a patient with of ROHHAD-NET and propose recommendations for the treatment of associated obesity. CASE PRESENTATION: We present the case of a 10-year-old female with a clinical presentation consistent with ROHHAD-NET who achieved clinically meaningful weight loss with a combination of lifestyle modification and anti-obesity pharmacotherapies. We report on the use of three separate pharmacological agents and ultimately the referral for bariatric surgery. CONCLUSIONS: Given that early-onset obesity and hypoventilation are life-limiting components of this condition, early recognition and treatment are essential to improve health outcomes.

Hypothalamic Hamartomas: Evolving Understanding and Management.

Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in GLI3 and other patterning genes are involved in HH pathogenesis. About 50%-80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.

Adult growth hormone deficiency guidelines: more difficult than it seems to incorporate into clinical practice universally.

Adult growth hormone deficiency (GHD) is a syndrome characterized by adverse phenotypic, metabolic, and quality-of-life features. Over the past 2 decades, there is accumulating evidence demonstrating improvement of most of these parameters when GH is optimally replaced. Appropriate selection of patients at risk of GHD is crucial when considering and performing testing to establish the diagnosis. While generally safe, GH replacement requires careful dose initiation and monitoring to assure effectiveness and tolerance in treated patients. Several consensus clinical practice guidelines recommend evaluation of adults presenting with hypothalamic-pituitary disorders for GHD. However, the clinical practice of managing such patients varies among countries largely due to lack of recognition of the condition, lack of GH availability, and lack of reimbursement of the drug, as demonstrated from a large online survey prepared by the European Society of Endocrinology involving 2148 patients from Europe and Australia. These data reinforce the notion of the large variability of disease recognition, clinical practice and education of adult GHD amongst healthcare professionals, and the lack of availability and reimbursement of the drug contributing to the under-utilization of GH replacement therapy in several countries. This commentary article highlights the fact that despite the publication of several guideline recommendations and positive long-term safety and efficacy data of GH replacement, there is still a need for increased education to enhance the awareness in the general population and improve the knowledge of healthcare professionals and administrators of adult GHD as a disease state to allow for early identification and treatment optimization.

The Role of Hypothalamic Inflammation in Diet-Induced Obesity and Its Association with Cognitive and Mood Disorders.

Obesity is often associated with cognitive and mood disorders. Recent evidence suggests that obesity may cause hypothalamic inflammation. Our aim was to investigate the hypothesis that there is a causal link between obesity-induced hypothalamic inflammation and cognitive and mood disorders. Inflammation may influence hypothalamic inter-connections with regions important for cognition and mood, while it may cause dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis and influence monoaminergic systems. Exercise, healthy diet, and glucagon-like peptide receptor agonists, which can reduce hypothalamic inflammation in obese models, could improve the deleterious effects on cognition and mood.

Management of Hypothalamic Obesity.

Energy homeostasis, appetite, and satiety are modulated by a complex neuroendocrine system regulated by the hypothalamus. Dysregulation of this system resulting in hypothalamic obesity (HO) is caused by brain tumors, neurosurgery, and/or cranial irradiation. Craniopharyngioma (CP) is a paradigmatic disease with regard to the development of HO. Initial hypothalamic involvement of CP and/or treatment-related damage to hypothalamic-pituitary axes result in HO. Attempts to control HO with lifestyle interventions have not been satisfactory. No generally accepted pharmacologic or bariatric therapy for HO in CP has been effective in randomized controlled trials. Accordingly, prevention of HO is recommended.

Hypothalamic Hamartomas: A comprehensive review of literature - Part 2: Medical and surgical management update.

Hypothalamic hamartomas (HH) are rare, non-neoplastic heterotopic tissues which contains normal neurons and glia including oligodendrocytes and fibrillary astrocytes but in an abnormal distribution. They arise from the floor of the third ventricle, tuber cinereum, or mammillary bodies. Estimated incidence ranges from 1 in 50,000 to 1 in 1,000,000. Hypothalamic hamartomas are associated with different clinical presentations including various types of seizures, most characteristically; the gelastic seizures, precocious puberty, cognitive impairment and behavioral changes. In this review, the authors discuss the recent advancements in the medical and surgical management of hypothalamic hamartoma that have been achieved over the past few decades. This review also discusses the advantages and disadvantages of each surgical line of management and factors determining the best individualized approach.

Late Effects of Parasellar Lesion Treatment: Hypogonadism and Infertility.

Central hypogonadism, also defined as hypogonadotropic hypogonadism, is a recognized complication of hypothalamic-pituitary-gonadal axis damage following treatment of sellar and parasellar masses. In addition to radiotherapy and surgery, CTLA4-blocking antibodies and alkylating agents such as temozolomide can also lead to hypogonadism, through different mechanisms. Central hypogonadism in boys and girls may lead to pubertal delay or arrest, impairing full development of the genitalia and secondary sexual characteristics. Alternatively, cranial irradiation or ectopic hormone production may instead cause early puberty, affecting hypothalamic control of the gonadostat. Given the reproductive risks, discussion of fertility preservation options and referral to reproductive specialists before treatment is essential. Steroid hormone replacement can interfere with other replacement therapies and may require specific dose adjustments. Adequate gonadotropin stimulation therapy may enable patients to restore gametogenesis and conceive spontaneously. When assisted reproductive technology is needed, protocols must be tailored to account for possible long-term gonadotropin insufficiency prior to stimulation. The aim of this review was to provide an overview of the risk factors for hypogonadism and infertility in patients treated for parasellar lesions and to give a summary of the current recommendations for management and follow-up of these dysfunctions in such patients. We have also briefly summarized evidence on the physiological role of pituitary hormones during pregnancy, focusing on the management of pituitary deficiencies.

Long-term neuroendocrine consequences of traumatic brain injury and strategies for management.

Introduction: Traumatic brain injuries (TBI) are reported to cause neuroendocrine impairment with a prevalence of 15% with confirmatory testing. Pituitary dysfunction (PD) may have detrimental effects on vital parameters as well as on body composition, cardiovascular functions, cognition, and quality of life. Therefore, much effort has been made to identify predictive factors for post-TBI PD and various screening strategies have been offered.Areas covered: We searched PubMed and reviewed the recent data on clinical perspectives and long-term outcomes as well as predictive factors and screening modalities of post-TBI PD. Inconsistencies in the literature are overviewed and new areas of research are discussed.Expert opinion: Studies investigating biomarkers that will accurately predict TBI patients with a high risk of PD are generally pilot studies with a small number of participants. Anti-pituitary and anti-hypothalamic antibodies, neural proteins, micro-RNAs are promising in this field. As severity of TBI has been the most commonly associated risk factor for post-TBI PD, we suggest prospective screening based on severity of head trauma until new evidence emerges. There is also a need for more studies investigating the clinical effects of hormone replacement in TBI patients with PD.

Hypothalamic hamartomas in adulthood: Clinical spectrum and treatment outcome-A unicenter experience.

INTRODUCTION: Clinical manifestations of the hypothalamic hamartoma-epilepsy syndrome (HH-ES) in adulthood are variable. Efficacy of therapeutic options and outcome are diverse. METHODS: Retrospective study of adult patients diagnosed with a HH in magnetic resonance imaging and epilepsy who attended our tertiary Epilepsy Unit between 2003 and 2018. We report the clinical and electroencephalographic features of a series of adult patients with HH and related epilepsy seen in our center together with the treatments and seizure outcome. RESULTS: We describe a series of eight patients. Five males (62.5%), median age at evaluation was 28.5 years (IQR: 15.5). Clinical manifestations included focal with preserved and impaired awareness emotional seizures (gelastic seizures [GS]) in six patients (75%), focal tonic, atonic with impaired awareness and focal to bilateral tonic-clonic seizures. Mild GS were the only symptom in one patient. Three patients (37.5%) had endocrinological disturbances such as obesity and hypothyroidism. Fifty percent of the patients showed psychiatric comorbidity such as anxiety disorder and aggressiveness, and two patients had psychomotor delay. Seven patients (87.7%) had drug-resistant seizures and three of them were treated with radiosurgery. Out of the treated group, only one (33.3%) became seizure-free 2 years after surgery but developed psychiatric problems. The other two patients had an Engel IV outcome and received a vagal nerve stimulation (VNS) implant. VNS did not lead to changes either in intensity nor in seizure frequency. CONCLUSIONS: Hypothalamic hamartoma-epilepsy syndrome clinical manifestations in adult patients are as variable as at pediatric age. Outcome of therapeutic options such as radiosurgery or VNS may be poorer at this stage.

Advances in the management of craniopharyngioma in children and adults.

Background Childhood 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. Conclusions Craniopharyngioma 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.

Hypothalamic sydrome as an initial presentation of Wernicke encephalopathy: A case report.

RATIONALE: Wernicke encephalopathy (WE) is a syndrome characterized by an acute or subacute onset of ataxia, ophthalmoplegia, and mental status changes. To our knowledge, hypothalamic syndrome is rare in WE. PATIENT CONCERNS: A 73-year-old female patient with acute cerebral infarct, who showed initial symptoms of vomiting, nausea, ataxia, and subsequent anorexia, was treated with parenteral nutritional supplement for 20 days. Nevertheless, the patient still developed refractory hyponatremia despite the appropriate sodium supplement given for a week following parenteral nutritional supplement. In fact, after 14 days of parenteral nutritional supplement, the patient gradually showed hypotension and apathy. Hyponatremia, hypotension, anorexia and apathy were signs of hypothalamic syndrome. DIAGNOSES: Finally, the patient was diagnosed as WE by head magnetic resonance imaging, which showed symmetrical lesions in T2-weighted imaging images and FLAIR high signal intensity in the periaqueduct, hypothalamus, thalamus, mammiliary bodies, medulla oblongata, and vermis cerebelli. INTERVENTIONS: The patient was given thiamine supplementation. OUTCOMES: The patient regained consciousness within 3 days. The sings of hyponatremia, hypotension, and apathy were relieved subsequently. LESSONS: When patients develop unexplained hypothalamic syndrome, we should think of the possibility of WE. The concomitant presence of hyponatremia, hypotension, anorexia, and apathy in WE is rare. Therefore, this case is reported here for discussion.

Anti-Hypothalamus and Anti-Pituitary Auto-antibodies in ROHHAD Syndrome: Additional Evidence Supporting an Autoimmune Etiopathogenesis.

BACKGROUND: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a very rare and complex pediatric syndrome characterized by altered hypothalamic thermal regulation, pain threshold, and respiratory control, hyperphagia with rapid weight gain and, often, hypothalamic-pituitary dysfunction. Its etiopathogenesis remains undetermined. We investigated the presence of alterations to target genes and hypothalamic-pituitary autoimmunity in a patient with -ROHHAD syndrome. METHODS: A 3-year-old girl presenting with obesity after rapid weight gain was diagnosed with ROHHAD syndrome based on clinical features and abnormal biochemical and functional testing results. Because of worsening of rapid symptoms and demonstration of oligoclonal bands on cerebrospinal fluid (CSF) analysis, she was treated with plasmapheresis, methylprednisolone, anti-CD20 monoclonal antibodies, and azathioprine. Despite initial partial clinical improvement, the patient soon died of cardiorespiratory arrest. Post-mortem, whole exome sequencing, high-resolution comparative genomic hybridization array, and optimized indirect immunofluorescence (IIF) analysis were performed on blood and CSF. RESULTS: No putative causative genomic variants compatible with dominant or recessive inheritance nor clinically significant structural rearrangement were detected. IIF on serum and CSF demonstrated the presence of anti-pituitary and anti-hypothalamus autoantibodies. CONCLUSIONS: These findings support the involvement of autoimmunity in ROHHAD syndrome. However, response to immunosuppressive treatment was only transient and the patient died. Further cases are required to define the complex disease pathogenesis.

Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline.

Objective: To formulate clinical practice guidelines for the endocrine treatment of hypothalamic-pituitary and growth disorders in survivors of childhood cancer. Participants: An Endocrine Society-appointed guideline writing committee of six medical experts and a methodologist. Conclusions: Due to remarkable improvements in childhood cancer treatment and supportive care during the past several decades, 5-year survival rates for childhood cancer currently are >80%. However, by virtue of their disease and its treatments, childhood cancer survivors are at increased risk for a wide range of serious health conditions, including disorders of the endocrine system. Recent data indicate that 40% to 50% of survivors will develop an endocrine disorder during their lifetime. Risk factors for endocrine complications include both host (e.g., age, sex) and treatment factors (e.g., radiation). Radiation exposure to key endocrine organs (e.g., hypothalamus, pituitary, thyroid, and gonads) places cancer survivors at the highest risk of developing an endocrine abnormality over time; these endocrinopathies can develop decades following cancer treatment, underscoring the importance of lifelong surveillance. The following guideline addresses the diagnosis and treatment of hypothalamic-pituitary and growth disorders commonly encountered in childhood cancer survivors.

Management of Hypothalamic Obesity during Transition from Childhood to Adulthood.

Hypothalamic obesity (HO) is a rare and serious disease of various origins: tumor, traumatism, radiotherapy, vascular, genetic, or even psychotropic drug use. HO usually begins in childhood with eating disorders and progresses with an aggregate of severe comorbidities. Transition from pediatric to adult health care is a critical period to assure weight stability and a good management of comorbidities. In case of loss to follow-up, there is an increased risk of major weight gain and long-term complications with severe obesity. To minimize this risk, pediatric and adult specialists must work together to prepare, supervise, and monitor transition. Transition ideally involves the patient, parents, and care providers with a good communication between pediatric and adult teams from expert centers. Maintaining a diet and physical activity management plan, acquisition of autonomy for hormone replacement therapy and management of psychosocial consequences of obesity are fundamental issues in patients with HO. Patient associations and specialized diet center weight loss programs can help as well as group approaches.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Optic nerve hypoplasia and septo-optic dysplasia]. / Optikushypoplasie und septooptische Dysplasie.

Optic nerve hypoplasia (ONH) is one of the most common causes of congenital visual impairment. It was first described in 1915 and represents a developmental disorder of the central nervous system. It is often associated with intracranial midline defects and is then referred to as septo-optic dysplasia (SOD). The symptoms of ONH range from minimal visual dysfunction to significant visual impairment with sensory defect nystagmus and even blindness. The ONH is often associated with further systemic, endocrinological and neurological abnormalities requiring a close interdisciplinary treatment of the patients.

Hypothalamic hamartoma with epilepsy: Review of endocrine comorbidity.

The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor α[TGFα) and (2) γ-aminobutyric acid (GABA)-mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention.