International Journal of Obesity (2014) 38, 1573–1577 © 2014 Macmillan Publishers Limited All rights reserved 0307-0565/14 www.nature.com/ijo SHORT COMMUNICATION Loss of pons-to-hypothalamic white matter tracks in brainstem obesity JQ Purnell1, DL Lahna2, MH Samuels1, WD Rooney3,4 and WF Hoffman2,4,5 Hyperphagia and obesity have been reported following damage to the hypothalamus in humans. Other brain sites are also postulated to be involved in the control of food intake and body weight regulation, such as the amygdala and brainstem. The brainstem, however, is thought to primarily integrate short-term meal-related signals but not affect long-term alterations in body weight, which is controlled by higher centers. The objective of this study was to identify structural pathways damaged in a patient with a brainstem cavernoma who experienced sudden onset of hyperphagia and >50 kg weight gain in o1 year following surgical drainage via a midline suboccipital craniotomy. Diffusion tensor imaging revealed loss of nerve fiber connections between her brainstem, hypothalamus and higher brain centers with preservation of motor tracks. Imaging and endocrine testing confirmed normal hypothalamic structure and function. Gastric bypass surgery restored normal appetite and body weight to baseline. This is the first report of ‘brainstem obesity’ and adds to the brain regions that can determine the long-term body weight set point in humans. International Journal of Obesity (2014) 38, 1573–1577; doi:10.1038/ijo.2014.57 Keywords: brainstem; magnetic resonance imaging; diffusion tensor imaging; bariatric surgery INTRODUCTION presentation, she was at her lifetime maximal weight and had Unwanted weight gain and obesity result from dysregulation of been weight stable for several years with no complaint of systems that control food intake and energy expenditure.1 hyperphagia. She was a one-pack-per-day smoker beginning at Damage to the ventromedial hypothalamus, typically from tumor age 18 years. She denied excessive alcohol intake or illicit drug growth or surgical trauma in humans, leads to a well-described use. On exam, she was alert and oriented with mild dysarthria, a obesity syndrome characterized by sudden onset of hyperphagia right sixth cranial nerve deficit, reduced sensory perception of her and rapid weight gain.2 Experimental hyperphagia and obesity right face and mild dysmetria with left finger-to-nose testing. Her can also be induced in rodents and primates through lesions of muscle strength and reflexes were normal. Brain magnetic the amygdala.3 The brainstem is also involved in the regulation of resonance imaging (MRI) showed a 5 × 1.7 × 2.3-cm heteroge- food intake, in part through receiving vagal input from satiety neous lesion in the right posterior pons consistent with degrading factors and ghrelin, as well as direct binding of gut-derived blood (Figure 1). The remainder of her brain scan, including the hormones to their receptors in this area.4 Studies of decerebrate hypothalamus, was normal. A cerebral angiogram revealed a rodents have shown that the isolated brainstem is sufficient for brainstem cavernous malformation and hemorrhage. determination of meal size5 but have not clarified the brainstem’s Two-weeks after presentation, she underwent cavernoma role in long-term control of body weight. In the present report, we resection by a midline suboccipital craniotomy. Post surgery she describe a woman who experienced a brainstem lesion at the level was documented to have a new right-peripheral seventh cranial of the pons that resulted in unregulated hyperphagia and obesity, nerve palsy with new mild left-sided weakness and, beginning in which subsequently resolved with restoration of baseline body the hospital during recovery, she reported a marked increase in weight following gastric bypass. To our knowledge, this is the first hunger and failure to feel completely full when she ate a meal. reported case of ‘brainstem obesity’ in a human. Following discharge, incessant food craving resulted in near continuous eating and rapid weight gain (Supplementary Figure 1). After 5 months, her weight had increased by 30 kg and she began CASE HISTORY to experience fatigue, irregular menses, heat intolerance, snoring A 30-year-old woman presented with 1-week history of progres- and daytime somnolence and depression. Because of her rapid sive numbness of her right face, left body weakness, a right frontal weight gain, she was referred to an endocrinologist. She had no headache and double vision. Her past medical history was symptoms or biochemical evidence of hypothyroidism or hypo- unremarkable except for being obese (body mass index 32 cortisolism. Pulse and blood pressure were normal and pupils kg m−2) and she was taking no medications. At the time of her were equal, round and reactive to light and accommodation. 1Department of Medicine and Center for the Study of Weight Regulation, Oregon Health & Science University, Portland, OR, USA; 2Department of Neurology, Oregon Health & Science University, Portland, OR, USA; 3The Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, USA; 4Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA and 5Mental Health and Clinical Neurosciences Division, Veterans Affairs Medical Center, Oregon Health & Science University, Portland, OR, USA. Correspondence: Dr JQ Purnell, Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health & Science University, Mailstop L607, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. E-mail: [email protected] Received 5 August 2013; revised 11 March 2014; accepted 17 March 2014; accepted article preview online 14 April 2014; advance online publication, 6 May 2014 Brainstem obesity JQ Purnell et al 1574 Figure 1. Anatomical scans of patient in radiological convention. White arrows indicate the lesion. Upper T2-weighted scans (a–c) (axial, sagittal and coronal, respectively) taken before cavernoma resection show a 1.5 × 1.7 × 2.3-cm heterogeneous lesion in the right posterior pons that is hypointense centrally and hyperintense peripherally consistent with blood products in various stages of degradation. There is a small amount of associated edema in the adjacent structures and mass effect on the adjacent fourth ventricle. Hypothalamus and pituitary anatomy appear normal. Lower T1-weighted scans (d–f) (axial, sagittal and coronal, respectively) taken 6 months after cavernoma resection show hypointensity in the right posterior pons at site of previous cavernoma resection. Hypothalamus and pituitary anatomy appear normal. A sleep study was negative for sleep apnea. Repeat brain MRI Diffusion tensor imaging (DTI) and tractography showed a posterior defect at the site of the hematoma drainage, Imaging data were acquired on a 3T Siemens TIM Trio MRI instrument ipsilateral hypertrophic olivary degeneration and normal hypotha- (Erlangen, Germany). A localizer scan was used to guide slice align- lamus, and pituitary anatomy. ment for subsequent scans. A high-resolution T1-weighted anatomical She was subsequently given trials of phentermine and magnetization-prepared rapid gradient echo (144 slices 1-mm thick, sibutramine without successful control of her appetite or weight repetition time/echo time/TI/α = 2300 ms/4.38 ms/1200 ms/12°, field of gain (Supplementary Figure 1). Within 1 year of her initial injury, view = 208 × 256 mm) was acquired for anatomic co-registration. A single she had gained over 40 kg and by 21 months after surgery she DTI scan was acquired that consisted of 6 non-diffusion weighted (B0) images followed by 30 non-collinear directions of diffusion weighted had gained 53.2 kg, reaching a maximal body mass index of α −2 images (72 axial slices, 2-mm thick, repetition time/echo time/ = 9300 ms/ 53.7 kg m . Owing to no response to medical therapy, unabated 90 ms/90°, field of view = 256 × 256 mm). appetite and weight gain, she was referred for bariatric surgery Diffusion weighted data were corrected for head movement and eddy and underwent Roux-n-Y gastric bypass 2 years after her initial currents using the Oxford Centre for FMRI of the Brain (FMRIB) Software presentation. Immediately following this surgery, she noted a Library (FSL)’s ‘eddy correct’ tool.6 Non-brain voxels were excluded using marked decline in her hunger and restoration of meal-related the ‘Brain Extraction Tool’ (FSL).6 Fractional anisotropy was calculated using satiety. Within 12 months, she had returned to her baseline weight the FSL tool ‘dtifit’ (part of the FMRIB Diffusion toolbox (FDT) v2.0). The magnetization-prepared rapid gradient echo was coregistered to the (Supplementary Figure 1). Six years after her initial presentation fi she felt well, remained weight stable at her usual weight, had average B0 image using a 12-parameter af ne registration algorithm from FSL’s ‘Linear Image Registration Tool’ (FLIRT). The hypothalamus and the stopped all prescription medications and agreed to return to amygdala were manually drawn as regions of interest (ROI) for each Oregon Health & Science University for retesting. All study subject by an experienced research assistant using the magnetization- procedures were approved by the institutional review boards at prepared rapid gradient echo as an anatomical guide. These ROIs were PVAMC and Oregon Health & Science University, and informed then imported into MedINRIA for deterministic tractography to allow for consent was completed before undergoing study procedures. inspection