hypothalamic astrocytoma: hyperphagia syndrome & accompanying issues

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  • 8/2/2019 Hypothalamic Astrocytoma: Hyperphagia Syndrome & Accompanying Issues

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    Hypothalamic AstrocytomaSyndrome of Hyperphagia, Obesity, and Disturbances of Behaviorand Endocrine and Autonomic Function

    Robert M. Haugh, MD, William R. Markesbery, MD

    \s=b\A 26-year-old woman had hyperpha-gia, obesity, aggressive behavior, visualhallucinations, reversal of wake-sleeppatterns, hypothermia, hypothyroidism,and amenorrhea. She died of pancreatitis,probably secondary to hypothermia.Autopsy revealed a low-grade astrocyto-ma in the third ventricle and medial ante-rior and mid hypothalamus, primarily onthe right. Although she exhibited thyroidand ovarian hypofunction, the patient hadintact median eminence and pituitaryfunction, suggesting end-organ failure,possibly of an autoimmune nature.

    (Arch Neurol 1983;40:560-563)

    "Uypothalamic tumors are of specialinterest since they offer confir

    mation in humans of the various

    hypothalamic functions described experimentally in others species. Only afew reports of the clinical correlatesof discrete hypothalamic lesions inhumans have been published (review15). It is well known that a variety

    of clinical syndromes can occur withlesions of the hypothalamus, such asdiabetes insipidus; alterations of temperature regulation, food intake,sleep, and behavior; disturbances ofautonomie nervous system function;

    and others.4-5 It is also believed thattumors and other lesions of the hypothalamus can cause changes in themedian eminence and/or tuber cinere-

    um, which are thought to lead todiminution of releasing factors,resulting in decreased pituitary andendocrine function.

    Our purpose is to describe a patientwith a hypothalamic neoplasm thatresulted in behavioral changes, reversal of

    day-night rhythms, hyperpha-gia, obesity, hypogonadism, and hypo-thyroidism. However, this patientalso had documented maintenance ofadequate median eminence-pituitaryaxis function.

    REPORT OF A CASE

    A 26-year-old woman was admitted tothe University of Kentucky Medical Center, Lexington, because of increasing somnolence and lethargy. She had been inexcellent health until two years prior toadmission, when she had been admitted toanother hospital because of an intracerebral hemorrhage. A computed tomograph

    ic (CT) scan of the head was reported toshow blood in the thalamic area and thirdventricle. Four-vessel cerebral angiography demonstrated no aneurysm or tumor.After she recovered from the hemorrhage,the patient had episodes of combative,aggressive behavior and visual hallucinations. She had reversal of her day-nightrhythms, sleeping during the day and staying awake through the night. With thearrival of spring, her behavior and disturbed sleep cycle improved and remainedstable until winter weather returned, atwhich time the hallucinations, combativebehavior, and reversal of day-nightrhythms returned. During this two-year

    period amenorrhea developed, and herweight increased from 68 to 135 kg. Threeweeks prior to admission progressive lethargy and weakness and decline in mentalfunction occurred. The patient had no history of occupational or environmentalexposure to toxins, and she did not usedrugs or alcohol.

    Physical examination showed a somnolent woman weighing 135 kg, with a rectaltemperature of 34.4 C, pulse of 40 beatsper minute, BP of 110/60 mm Hg, andCheyne-Stokes respiration. Remarkable

    findings on physical examination includedmarked obesity, pendulous breasts withoutgalactorrhea, diffuse abdominal tenderness, and decreased bowel sounds. Neurologic examination revealed the patient tobe difficult to arouse. Funduscopic examination showed bilateral optic atrophy. Noother cranial nerve abnormalities werefound. Sensory, motor, and cerebellar functions and muscle stretch reflex were normal. The patient could not cooperate formental status or visual field testing.

    Laboratory Data

    Laboratory findings were as follows: leukocyte count, normal; hematocrit reading,

    33%; platelet count, 78,000/cu mm; bloodchemistry study using an automated multiple analysis system, normal; calcium level, 2.8 mEq/L; amylase level, 328 IU/L; andlipase level, 2.2 Sigma-Tietz units/mL. Liver and renal function test results wereunremarkable. Tests of arterial blood gases showed a pH of 7.40; Pco2, 26 mm Hg;Po2, 79 mm Hg; and 02 saturation, 96%.Thyroxine level was 3.6 Mg/dL (normal, 5 to12 Mg/dL). Triiodothyronine resin uptakewas 24% (normal, 24% to 34%). Thyroid-stimulating hormone (TSH) level onadmission was 43.4 /mL (normal, 2 to 8 /mL). Thyroid antibodies were positiveat a titer of 1:1,600. A protirelin (thyrotro-

    Accepted for publication Dec 16, 1982.From the Departments of Pathology (Drs

    Haugh and Markesbery) and Neurology (DrMarkesbery) and the Sanders-Brown ResearchCenter on Aging (Dr Markesbery), University ofKentucky Medical Center, Lexington.

    Reprint requests to Department of Pathology,University of Kentucky Medical Center, Lexing-ton, KY 40536-0230.

    at Washington State University, on November 14, 2011www.archneurol.comDownloaded from

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  • 8/2/2019 Hypothalamic Astrocytoma: Hyperphagia Syndrome & Accompanying Issues

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    Fig 1.Coronal section of brain showing tumor (arrows) in thirdventricle ust above optic chiasm, with thinning of anterior commissure.

    Fig 2.

    Moderately cellular astrocytoma composed of cells with roundto oval nuclei and abundant fibrillary processes (hematoxylin-eosin,original magnification X395).

    pin-releasing hormone) stimulation testrevealed the following:

    TSH, Prolactin, /mL ng/mL

    Baseline 53 4530 min 85 8660 min 105 8490 min 68 77

    Luteinizing hormone (LH) level was 120ImU/mL, and follicle-stimuating hormone(FSH) level was 9 ImU/mL. Serum cortisollevel was 14.3 Mg/dL. A cortrysyn stimulation test showed normal results. The CSFcontained no cells, a protein level of 159mg/dL, and a glucose level of 93 mg/dL. AnECG revealed nonspecific T-wave changesand

    prolonged Q-Tc, suggestive of hypothy-roidism. A CT scan and ultrasonogram ofthe abdomen were consistent with acutepancreatitis.

    Hospital Course

    The patient's temperature remained inthe range of 33.9 C to 34.4 C during thefirst three days of hospitalization but onthe fourth day rose to 38.3 C. Serumamylase level continued to rise, calciumlevel declined, and abdominal tendernessworsened. Treatment for pancreatitis wasstarted, and antibiotics were given forpresumed sepsis. The results of the TSHand prolactin response were thought to beconsistent with a hypothalamic diseaseprocess. Intravenous (IV) thyroxine wasadministered, and serum TSH level eventually returned to normal. The initial bradycardia resolved after institution of dopamine hydrochloride and aminophyllinetherapy; however, the patient remainedhypotensive. Flank hematomas developed,and hypocalcemia persisted in spite ofhigh-dose IV calcium gluconate replacement. Despite vigorous supportive efforts,the patient died on the 15th hospital day.

    Autopsy Findings

    The autopsy showed an edematous pancreas discolored by hemorrhage, with fat

    necrosis and saponification of the sur

    rounding retroperitoneal fat. A fibrinopu-rulent exdate covered most intraperitone-al surfaces. The ovaries were markedlyatrophie, and each weighed 3.5 g (normalpremenopausal weight, 8 to 12 g). Microscopic examination revealed rare ovarianfollicles, a few corpora albicantia, and noevidence of corpus luteum formation.Parenchymal fibrosis was present. Therewere no inflammatory infiltrates in theovaries. These histologie findings are consistent with features of an autoimmuneovarian failure. The thyroid was grosslynormal (weight, 17.5 g), but microscopically, lymphocytic and plasma cell infiltrationwas seen in the gland, consistent with

    chronic thyroiditis. Therewere no

    inflammatory infiltrates in other endocrineorgans.

    The brain weighed 1,340 g. There was noevidence of herniation or abnormalities ofthe cortical surfaces. No gross abnormalities of the tuber cinereum, infundibulum,or pituitary were noted. Coronal sectionsrevealed a soft, gray-brown, well-circumscribed tumor arising in the right anteriorhypothalamus (Fig 1). The neoplasm filledmuch of the anterior and mid third ventricle. The lateral ventricles were notenlarged. No other gross lesions werefound in the cerebral hemispheres, brainstem, or cerebellum.

    Histologie examination demonstrated amoderately cellular neoplasm with cellscontaining slightly pleomorphic oval- tospindle-shaped nuclei (Fig 2). Eosinophiliccellular processes gave rise to a fibrillarybackground, and Rosenthal fibers wereabundant. Vascular channels were prominent in the tumor; however, endothelialproliferation was not present. No tumornecrosis was seen. Hemosiderin pigmentwas prominent in many macrophages andlying free within the medial and inferiormargin of the tumor. There was a rim ofreactive gliosis lateral to the tumor. On theright, the astrocytoma and its gliotic rimreplaced the suprachiasmatic, paraventric-

    ular, and anterior hypothalamic nuclei, aswell as a great portion of the medial hypothalamic nucleus (Figs 3 and 4). The tumorbreached the lamina terminalis, and itsmost superior extension bisected the anterior commissure. In its anterior and middle portions the tumor exerted a compressive effect on the optic chiasm (Fig 4). Itessentially replaced the entire right ventromedial and dorsomedial nuclei. Therewas minimal involvement of the right posterior hypothalamic nucleus. The right for-nix was interrupted. It had extended intothe left anterior hypothalamus, with obliteration of the preoptic and suprachiasmat-ic nuclei, a small portion of the anteriorhypothalamic nucleus, and the inferior

    portion of the paraventricular nucleus(Figs 3 and 4). Tumor and gliosis involvedonly a small part of the inferior left ventromedial nucleus. Other hypothalamicnuclei were not involved on the left. Thetumor did not involve the tuber cinereum,pituitary gland, or mammillary bodies.The median eminence was slightlyinvolved by the gliosis delimiting the edgeof the tumor. In the anterior pituitary,acidophils were prominent and had a normal pattern of granulation. Some baso-phils showed mild degranulation. Therewas no evidence of compression or ischemia in the anterior pituitary. The posteriorpituitary was unremarkable.

    COMMENT

    This patient had a low-grade astrocytoma involving the right anteriorand mid hypothalamus and a smallportion of the left anterior hypothalamus. The presence of many hemosid-erin-laden macrophages in the tumorand on its surface indicated that thepatient's initial symptoms werecaused by hemorrhage into the tumor.She subsequently had hyperphagia,obesity, periods of unprovoked aggressive behavior, visual hallucinations,

    at Washington State University, on November 14, 2011www.archneurol.comDownloaded from

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  • 8/2/2019 Hypothalamic Astrocytoma: Hyperphagia Syndrome & Accompanying Issues

    3/4

    Massa Intermedia

    Fig 3.Sagittal diagrams showing location of tumor (pitted area) in hypothalamus. SCNindicates suprachiasmatic nucleus; PO, preoptic area; PV, paraventricular nucleus; DM,dorsomedial nucleus; VM, ventromedial nucleus; and P, posterior hypothalamic nucleus.

    Left Fornix Right LeftFornix Right

    Optic TractOptic Tract

    Optic Chiasm

    Fig 4.Transverse diagrams showing tumor location in hypothalamus and third ventricle at levelof optic chiasm (left) and mid hypothalamus (right). SO indicates supraoptic nucleus; A, anteriorhypothalamic nucleus; L, lateral hypothalamic nucleus; M, medial hypothalamic area; PV,paraventricular nucleus; DM, dorsomedial nucleus; VM, ventromedial nucleus; and 3V, thirdventricle.

    reversal of wake-sleep pattern,marked hypothermia, hypothyroid-ism, and amenorrhea.

    It has been shown that bilaterallesions in the ventromedial hypothalamic nuclei result in hyperphagia,

    obesity, and rage attacks in humanbeings. A wealth of data from experimentally induced ventromedial hypothalamic lesions in animals showedsimilar clinical findings,6 although ithas been shown that ventromedial

    nucleus lesions alone do not produceobesity.7 Although the neoplasm inour patient primarily involved theright ventromedial nucleus with minimal involvement of the left ventromedial nucleus, it is likely that compres-

    at Washington State University, on November 14, 2011www.archneurol.comDownloaded from

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  • 8/2/2019 Hypothalamic Astrocytoma: Hyperphagia Syndrome & Accompanying Issues

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    sion of the latter caused functionalimpairment that led to hyperphagia,obesity, and episodes of unprovokedaggression.

    In our patient the only other bilateral hypothalamic involvement included the suprachiasmatic andpreoptic nuclei and a portion of theparaventricular nuclei. Bilateral lesions of the preoptic nuclei are associated with faulty temperature control.8Our patient's marked hypothermiapossibly resulted from bilateral tumorinvolvement of the preoptic nuclei,hypothyroidism, or a combination ofthese two. Hypothermia probablycaused her severe, acute pancreatitis,with the sequelae of hypocalcemia andsecondary bacterial sepsis that led toher death. Massive pancreatitis is amajor cause of death among survivorsof accidental hypothermia.911

    The development of hypothyroidismand hypogonadism in our patient is ofconsiderable interest. The mechanism

    documented in reports of experimental hypothalamic lesions in animalsand in some humans is that ablationof the median eminence or tuber cine-reum causes cessation of productionof releasing factors.2 In turn, therewould be decreased levels of one ormore of TSH, FSH, LH, growth hormone, and adrenocorticotropic hormone, and an increase in prolactinlevel, resulting in hypofunction of theendocrine end organs. The medianeminence and tuber cinereum werespared in our patient, and TSH, FSH,and LH levels were

    elevated,indicat-

    ing endocrine end-organ hypofunc-tion. More specifically, the patientwas found to have hypofunction of thethyroid and ovary, possibly secondaryto autoimmune disease, and wouldtherefore have autoimmune polyglan-dular organ-failure syndrome. Therewas serologie confirmation of thyroidautoantibodies, and histopathologicfindings were compatible with a diagnosis of autoimmune thyroiditis. Theovaries were atrophie and fibrotic,with only rare primordial follicles andno corpus luteum formation despiteelevated gonadotropin levels. Although serologie evidence of ovarianantibodies was not available, our findings are certainly consistent with anautoimmune ovarian failure.12

    It is possible that this patient hadtwo rare, unrelated disease processesor diverse clinical findings all relatedto the hypothalamic tumor. Whatmakes the autoimmune endocrine

    organ hypofunction interesting is

    emerging evidence of the hypothalamus' role in modulating the immuneresponse.1314 Experimental data forthe role of the hypothalamus, limbicsystem, and pituitary in suppressionand enhancement of the immune

    response in the rat are accumulat

    ing.1416 However, there is no evidenceto date suggesting that alterations inthe hypothalamus can trigger anautoimmune reaction.

    The reversal of day-night rhythmsin our patient is also of interest. Ablation of the suprachiasmatic nucleus inthe rat leads to loss of normal circadi-

    an rhythms, including sleep-wakecycle, drinking, activity, temperature,ovulation, and adrenocorticosteroneproduction, which has been referredto as the suprachiasmatic syndrome.17Convincing evidence has accumulatedfor the suprachiasmatic nucleus as animportant link between the eye andthe body that controls circadianrhythms and functions as a primarycircadian oscillator, at least in therat.18 Our patient had bilateral ablation of the suprachiasmatic nucleusand changes in day-night rhythm,indicating loss of normal circadianrhythms. The normal four-day ovula-tory cycle of the rat depends on itscircadian rhythm. Ablation of thesuprachiasmatic nucleus will abolishthe LH surge and, therefore, ovulation.19 Thus, an alternative explanation to an autoimmune disorder forour patient's amenorrhea would bethat the bilateral lesions of the suprachiasmatic nucleus resulted in loss of

    menstrual rhythm. Perhaps ourpatient's findings represent a partialexpression of the suprachiasmaticsyndrome.

    The patient's clinical manifestations reaffirm the hypothalamus'complex functions. We documentednumerous abnormalities in thispatient, some of which may have theirbasis in the destruction of nuclei andtheir connections in a relatively smallarea of the anterior and mid hypothalamus.

    References

    1. Bauer HG: Endocrine and other clinicalmanifestations of hypothalamic disease. J ClinEndocrinol Metabol 1954;14:13-31.

    2. Reeves AG, Plum F: Hyperphagia, rage, anddementia accompanying a ventromedial hypo-thalamic neoplasm. Arch Neurol 1969;20:616\x=req-\624.

    3. Bray GA, Gallagher TF: Manifestations ofhypothalamic obesity in man: A comprehensiveinvestigation of eight patients and a review ofthe literature. Medicine 1975;54:301-330.

    4. Boshes B: Syndromes of the diencephalon,in Vinken PJ, Bruyn GW (eds): Handbook ofClinical Neurology. Amsterdam, North HollandPublishing Co, 1969, vol 2, pp 432-468.

    5. Martin JB, Reichlin S, Brown GM: ClinicalNeuroendocrinology. Philadelphia, FA Davis Co,1977, pp 247-273.

    6. Powley TL, Opsahl CA, Cox JE, et al: Therole of the hypothalamus in energy homeostasis,in Morgane PJ, Panksepp J (eds): Handbook ofthe Hypothalamus. New York, Marcel DekkerInc, 1981, vol 3, pp 211-298.

    7. Gold RM: Hypothalamic obesity: The mythof the ventromedial nucleus. Science1973;182:488-490.

    8. Dinarello CA, Wolff SM: Pathogenesis offever in man. N Engl J Med 1978;298;607-612.

    9. Duguid H, Simpson RG, Stowers JM: Acci-dental hypothermia. Lancet 1961;2:1213-1219.

    10. Read AE, Emslie-Smith D, Gough KR, etal: Pancreatitis and accidental hypothermia.Lancet 1961;2:1219-1221.

    11. Revlev JB: Hypothermia: Pathophysiology,clinical settings, and management. Ann InternMed 1978;89:519-527.

    12. Fox H, Buckley HC: Pathologic factorsinvolved in infertility, in Blaustein A (ed):Pathology of the Female Genital Tract. NewYork, Springer-Verlag, 1982, pp 828-837.

    13. Besedovsky H, Sorkin E, Felix D, et al:Hypothalamic changes during the immuneresponse. Eur J Immunol 1977;7:323-325.

    14. Cross RJ, Markesbery WR, Brooks WH, etal: Hypothalamic-immune interactions: I. Theacute effect of anterior hypothalamic lesions on

    the immune response. Brain Res 1980;196;79-87.15. Brooks WH, Cross RJ, Roszman TL, et al:

    Neuroimmunomodulation: Neural anatomicalbasis for impairment and facilitation. Ann Neu-rol 1982;12:56-61.

    16. Cross RJ, Markesbery WR, Brooks WH, etal: Hypothalamic immune interaction: Effect ofhypophysectomy on neuromodulation. J NeurolSci 1982;53:557-566.

    17. Raisman B, Brown-Guent K: The supra-chiasmatic syndrome: Endocrine and behavioralabnormalities following lesions of the supra-chiasmatic nuclei in the female rat. Proc R SocLond Biol 1977;198:297-314.

    18. Moore RY: The suprachiasmatic nucleus,circadian rhythms and regulation of brain pep-tides, in Martin JB, Reichlin S, Bick KL (eds):Neurosecretions and Brain Peptides. New York,Raven Press, 1981, pp 449-458.

    19. Rusak B, Zucker I: Neural regulation ofcircadian rhythms. Physiol Rev 1979;59:449-526.

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