Symposium for Patients & Caregivers

Hypothalamic Obesity Constantine Stephen Djedjos MD Pediatric Endocrinologist Phoenix Children’s Hospital

Hypothalamic Obesity Significant advances in basic science have greatly improved our understanding of the mechanisms of hypothalamic obesity Unfortunately, these advances have not yet translated into therapeutic advances for patients, many of whom are struggling with the nightmare of disordered eating and obesity

Hypothalamic Obesity Weight gain and obesity are common long term problems in patients with structural hypothalamic damage Exact incidence is unknown. Each individual cause is rare and taken in aggregate HyOb is still relatively uncommon Can be due to structural or genetic abnormalities Significant percentage of patients gain weight after hypothalamic surgery

Hypothalamic Obesity First case reports of hypothalamic tumors resulting in obesity published around the turn of the 20 th century Initially identified the ventromedial hypothalamus (VMH) associated with polyphagia Later demonstrated polyphagia is sufficient but not required Later identification of peripheral and central neurochemicals and cytokines

Hypothalamus Stanford CNS Visual Perspectives

Anatomy Only 4ml in volume Organized into discrete nuclei or collections of similar neurons ‘Dual-Center’ hypothesis – experimental lesions in the medial (midline) hypothalamus result in weight gain while lesions in the lateral areas result in wasting

Hypothalamic Nuclei Michigan State University Brain Bank and NSF

Mechanism The hypothalamus controls energy balance by integrating the neuroendocrine signals from other brain areas and the periphery Controls energy intake by regulating appetite Controls energy expenditure by regulating metabolism via sympathetic and parasympathetic nervous system

Appetite Hypothalamus receives signals from periphery Hypothalamus controls appetite by balancing orexigenic and anorexegenic signals Appetite regulated by the arcuate nucleus (ARC) by 2 types of neurons AGRP/NPYY neurons stimulate appetite (orexigenic) POMC/CART neurons signal satiety (anorexegenic) via MC4R receptor

Appetite Nutr J Apr 10;11:22. Gut-central nervous system axis is a target for nutritional therapies. Pimentel GD, Micheletti TO, Pace F, Rosa JC, Santos RV, Lira FS.

Metabolism Hypothalamus controls metabolism by balancing sympathetic and parasympathetic signals Hypothalamus via the locus ceruleus stimulates sympathetic nervous system (Fight or Flight) which increases metabolism Stimulates via the vagus nerve the parasympathetic nervous system which lowers metabolism

Metabolism VMH receives peripheral signals VMH increases sympathetic tone or parasympathetic tone Higher parasympathetic tone results in higher insulin

Peripheral Signals Leptin produced by fat cells signals fat storage Adiponectin is decreased in obesity Ghrelin stimulates appetite and food intake and secreted from stomach Many others

Mechanism In HyOb damage to the hypothalamus results in altered appetite and metabolism Increased appetite due to damage to POMC neurons and resulting in decreased MC4R signaling Decreased metabolism from increased parasympathetic tone and decreased sympathetic tone resulting in decreased resting energy expenditure, elevated insulin Leptin resistance and Ghrelin have a role as well

Treatment For mild-moderately overweight patient without overt food seeking or hyperphagic behaviors, we should focus on diet and lifestyle modification Requires full participation from the family and the school in order to make the home and school environments more conducive to weight loss

Treatment More severe HyOb is often refractory to diet and lifestyle Behavior therapy Pharmacologic therapy Surgical therapy

Pharmacologic Therapy No standard intervention and no medication has been proven successful in randomized clinical trials Due in part to small numbers of patients and also ineffectiveness of therapy Because of decreased sympathetic activity and decreased POMC/CART signaling, treatment with amphetamine derivatives has been considered

Pharmacologic Therapy Dextroamphetamine started 10months post surgery and lasting 24 months in CP patients showed less weight gain and stabilization of BMI Treatment with ephedrine/caffeine has also showed some promise Also had increased activity and wakefulness No large trials Polyphagia not significantly reduced likely because of damage to responsive neurons

Pharmacologic Therapy Leptin ‘resistance’ is possible cause of obesity Leptin therapy has been ineffective for weight loss Once forced weight loss is achieved, leptin supplementation has resulted in better success in weight maintenance

Pharmacologic Therapy Increased parasympathetic activity via vagus nerve activity results in insulin secretion Insulin is anabolic and contributes to appetite and weight gain Treatments aimed at lowering vagus nerve activity and insulin secretion have been considered Treatment with metformin which lowers insulin levels has been ineffective in HyOb

Pharmacologic Therapy Sandostatin is a medication that lowers insulin secretion Initial trial with small number of patients was successful Larger trial demonstrated no benefit Much controversy about the discordant results Vagus nerve blockade is being considered and is in early trials

Pharmacologic Therapy Increased parasympathetic activity results in lower thyroid hormone levels and very small trials have demonstrated some benefit with treatment Increased 11-beta hydroxysteroid dehydrogenase activity is also seen in HyOb patients but no selective inhibitor is yet available Concomitant growth hormone deficiency is often seen, despite normal growth, and treatment with GH has been tried

Pharmacologic Therapy Unlike patients with GH from other causes, treatment of HyOb patients with GH did NOT result in weight loss or changes in body fat distribution Surgical therapy has had mixed results

Surgical Therapy Criteria are unclear Some have suggested BMI >40 (above 99.5%) Failed 6-12 month organized weight loss attempt Skeletal and anatomic maturity Able to commit to rigorous psychologic and medical evaluation pre and post op Willing to participate in a multidisciplinary program

Surgical Therapy Restrictive procedures Gastric banding Adjustable band placed around the stomach Poor weight loss and frequent complications Sleeve Gastrectomy Removal of part of the stomach Not enough evidence yet with HyOb but appears promising

Surgical Therapy Malabsorption procedures Gastric bypass Stomach is bypassed surgically Restrictive and malabsorptive component Excellent weight loss but higher complications No significant experience with HyOb Duodenal switch Severe malabsorption and not routinely performed

Bariatric Surgery Complications Operative mortality varies Leaks, strictures, infection, blood clots, hernia, obstruction, nausea, vomiting have all been reported Nutritional deficiencies from malabsorption are not uncommon especially iron, b12, fat soluable vitamins (ADEK), trace minerals Dumping syndrome

Conclusions HyOb is a common, frustrating complication of hypothalamic disease and treatments Polyphagia and decreased metabolism play a role Advances in the last 10 years in basic science have helped unravel many of the mechanisms Treatment has lagged behind but still some promising therapies are being considered Behavior therapy and exercise are the cornerstones for current treatment

References A. Bereket et al Hypothalamic obesity in children Obesity reviews , J. Pinkney et al Hypothalamic obesity in humans: what do we know and what can be done? Obesity reviews , R. Lustig Hypothalamic obesity after craniopharyngioma: mechanisms, diagnosis, and treatment Babinski, J Tumeur du corps pituitaire sans acromegalie et avec arret developpment des organes de genitaux Rev Neurol 1900; 8, Zhang Y et al Positional cloning of the mouse obese gene and its human homologue Nature 1994; 372, Kreir et al Selective parasympathetic innervation of subcutaneous and intra-abdominal fat – functional implications J. Clin Invest 2002;110, Lustig RH et al Hypothalamic obesity in children caused by cranial insult: altered glucose and insulin dynamics, and reversal by a somatostatin agonist. J Pediatr 1999;135: 162–168. Lustig RH, Hinds PS, Ringwald-Smith K et al. Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metabol 2003; 88: 2586–2592. Mason PW, Krawiecki N, Meacham LR. The use of dextroamphetamine to treat obesity and hyperphagia in children treated for craniopharyngioma. Arch Pediatr Adolesc Med 2002; 156:887–892. Ismail D, O’Connell MA, Zacharin MR. Dexamphetamine use for management of obesity and hypersomnolence following hypothalamic injury. J Pediatr Endocrinol Metab 2006; 19: 129–134. Greenway FL, Bray GA. Treatment of hypothalamic obesity with caffeine and ephedrine. Endocr Pract 2008; 14: 697–703. Danielsson P, Janson A, Norgren S, Marcus C. Impact of sibutramine therapy in children with hypothalamic obesity or obesity with aggravating syndromes. J Clin Endocrinol Metab 2007; 92: 4101–4106. Weiss R. [WWW document]. URL ct2/show/NCT (accessed January 2012)./

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A Special Thanks to our Sponsors Aesculap Barrow Neurological St. Joseph’s Hospital Barrow Neurological Phoenix Children’s Hospital Great Council for the Improved Hope for Hypothalamic Hamartoma Foundation KARL STORZ Endoskope