Hypothalamic Astrocytoma

Syndrome of Hyperphagia, Obesity, and Disturbances of Behavior

and Endocrine and Autonomic Function
Robert M.

Haugh, MD, William R. Markesbery, MD

and others.4-5 It is also believed that tumors and other lesions of the hypo thalamus can cause changes in the median eminence and/or tuber cinereum, which are thought to lead to diminution of releasing factors, resulting in decreased pituitary and endocrine function. Our purpose is to describe a patient with a hypothalamic neoplasm that resulted in behavioral changes, rever sal of day-night rhythms, hyperphagia, obesity, hypogonadism, and hypothyroidism. However, this patient also had documented maintenance of adequate median eminence-pituitary axis function.
REPORT OF A CASE

\s=b\ A 26-year-old woman had hyperphagia, obesity, aggressive behavior, visual hallucinations, reversal of wake-sleep patterns, hypothermia, hypothyroidism, and amenorrhea. She died of pancreatitis, probably secondary to hypothermia. Autopsy revealed a low-grade astrocyto-

period amenorrhea developed, and her weight increased from 68 to 135 kg. Three weeks prior to admission progressive leth
argy and weakness and decline in mental

ma in the third ventricle and medial anterior and mid hypothalamus, primarily on the right. Although she exhibited thyroid and ovarian hypofunction, the patient had intact median eminence and pituitary

function, suggesting end-organ failure, possibly of an autoimmune nature. (Arch Neurol 1983;40:560-563)

interest since they offer confir mation in humans of the various hypothalamic functions described ex perimentally in others species. Only a few reports of the clinical correlates of discrete hypothalamic lesions in humans have been published (re view15). It is well known that a variety of clinical syndromes can occur with lesions of the hypothalamus, such as diabetes insipidus; alterations of tem perature regulation, food intake, sleep, and behavior; disturbances of autonomie nervous system function;
Accepted for publication Dec 16, 1982. From the Departments of Pathology (Drs Haugh and Markesbery) and Neurology (Dr Markesbery) and the Sanders-Brown Research Center on Aging (Dr Markesbery), University of Kentucky Medical Center, Lexington. Reprint requests to Department of Pathology, University of Kentucky Medical Center, Lexington, KY 40536-0230.

"Uypothalamic tumors are of special

A 26-year-old woman was admitted to the University of Kentucky Medical Cen ter, Lexington, because of increasing som nolence and lethargy. She had been in excellent health until two years prior to admission, when she had been admitted to another hospital because of an intracere bral hemorrhage. A computed tomograph ic (CT) scan of the head was reported to show blood in the thalamic area and third ventricle. Four-vessel cerebral angiogra phy demonstrated no aneurysm or tumor. After she recovered from the hemorrhage, the patient had episodes of combative, aggressive behavior and visual hallucina tions. She had reversal of her day-night rhythms, sleeping during the day and stay ing awake through the night. With the arrival of spring, her behavior and dis turbed sleep cycle improved and remained stable until winter weather returned, at which time the hallucinations, combative behavior, and reversal of day-night rhythms returned. During this two-year

function occurred. The patient had no his tory of occupational or environmental exposure to toxins, and she did not use drugs or alcohol. Physical examination showed a somno lent woman weighing 135 kg, with a rectal temperature of 34.4 C, pulse of 40 beats per minute, BP of 110/60 mm Hg, and Cheyne-Stokes respiration. Remarkable findings on physical examination included marked obesity, pendulous breasts without galactorrhea, diffuse abdominal tender ness, and decreased bowel sounds. Neuro logic examination revealed the patient to be difficult to arouse. Funduscopic exami nation showed bilateral optic atrophy. No other cranial nerve abnormalities were found. Sensory, motor, and cerebellar func tions and muscle stretch reflex were nor mal. The patient could not cooperate for mental status or visual field testing.

Laboratory Data

Laboratory findings were as follows: leu kocyte count, normal; hematocrit reading, 33%; platelet count, 78,000/cu mm; blood chemistry study using an automated mul tiple analysis system, normal; calcium lev el, 2.8 mEq/L; amylase level, 328 IU/L; and lipase level, 2.2 Sigma-Tietz units/mL. Liv
and renal function test results were unremarkable. Tests of arterial blood gas es 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 to 12 Mg/dL). Triiodothyronine resin uptake
er

24% (normal, 24% to 34%). Thyroidstimulating hormone (TSH) level on admission was 43.4 /mL (normal, 2 to 8 /mL). Thyroid antibodies were positive at a titer of 1:1,600. A protirelin (thyrotrowas

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Fig 1.Coronal section of brain showing tumor (arrows) in third ventricle ust above optic chiasm, with thinning of anterior commis
sure.

Moderately cellular astrocytoma composed of cells with round fibrillary processes (hematoxylin-eosin, original magnification X395).
Fig 2.
to oval nuclei and abundant

pin-releasing hormone) stimulation revealed the following:

Baseline 30 min 60 min 90 min

test

TSH, /mL
53 85

Prolactin,

ng/mL
45 86 84 77

105 68 Luteinizing hormone (LH) level was 120 ImU/mL, and follicle-stimuating hormone (FSH) level was 9 ImU/mL. Serum cortisol level was 14.3 Mg/dL. A cortrysyn stimula tion test showed normal results. The CSF contained no cells, a protein level of 159 mg/dL, and a glucose level of 93 mg/dL. An ECG revealed nonspecific T-wave changes and prolonged Q-Tc, suggestive of hypothyroidism. A CT scan and ultrasonogram of the abdomen were consistent with acute

evidence of corpus luteum formation. Parenchymal fibrosis was present. There were no inflammatory infiltrates in the ovaries. These histologie findings are con sistent with features of an autoimmune ovarian failure. The thyroid was grossly normal (weight, 17.5 g), but microscopical ly, lymphocytic and plasma cell infiltration was seen in the gland, consistent with chronic thyroiditis. There were no inflam matory infiltrates in other endocrine The brain weighed 1,340 g. There was no evidence of herniation or abnormalities of the cortical surfaces. No gross abnormali ties of the tuber cinereum, infundibulum, or pituitary were noted. Coronal sections revealed a soft, gray-brown, well-circum scribed tumor arising in the right anterior hypothalamus (Fig 1). The neoplasm filled much of the anterior and mid third ventri cle. The lateral ventricles were not enlarged. No other gross lesions were found in the cerebral hemispheres, brain stem, or cerebellum. Histologie examination demonstrated a moderately cellular neoplasm with cells containing slightly pleomorphic oval- to spindle-shaped nuclei (Fig 2). Eosinophilic cellular processes gave rise to a fibrillary background, and Rosenthal fibers were abundant. Vascular channels were promi nent in the tumor; however, endothelial proliferation was not present. No tumor necrosis was seen. Hemosiderin pigment was prominent in many macrophages and lying free within the medial and inferior margin of the tumor. There was a rim of reactive gliosis lateral to the tumor. On the right, the astrocytoma and its gliotic rim replaced the suprachiasmatic, paraventricorgans.

saponification of the sur rounding retroperitoneal fat. A fibrinopurulent exdate covered most intraperitoneal surfaces. The ovaries were markedly atrophie, and each weighed 3.5 g (normal premenopausal weight, 8 to 12 g). Micro scopic examination revealed rare ovarian follicles, a few corpora albicantia, and no
necrosis and

pancreatitis.
Hospital Course
The patient's temperature remained in the range of 33.9 C to 34.4 C during the first three days of hospitalization but on the fourth day rose to 38.3 C. Serum amylase level continued to rise, calcium level declined, and abdominal tenderness worsened. Treatment for pancreatitis was started, and antibiotics were given for presumed sepsis. The results of the TSH and prolactin response were thought to be consistent with a hypothalamic disease process. Intravenous (IV) thyroxine was administered, and serum TSH level even tually returned to normal. The initial bra dycardia resolved after institution of dopa mine hydrochloride and aminophylline therapy; however, the patient remained hypotensive. Flank hematomas developed, and hypocalcemia persisted in spite of high-dose IV calcium gluconate replace
ment.

ular, and anterior hypothalamic nuclei, as well as a great portion of the medial hypo thalamic nucleus (Figs 3 and 4). The tumor breached the lamina terminalis, and its most superior extension bisected the ante rior commissure. In its anterior and mid dle portions the tumor exerted a compres sive effect on the optic chiasm (Fig 4). It essentially replaced the entire right ven tromedial and dorsomedial nuclei. There was minimal involvement of the right pos terior hypothalamic nucleus. The right fornix was interrupted. It had extended into the left anterior hypothalamus, with oblit eration of the preoptic and suprachiasmatic nuclei, a small portion of the anterior hypothalamic nucleus, and the inferior portion of the paraventricular nucleus (Figs 3 and 4). Tumor and gliosis involved only a small part of the inferior left ven tromedial nucleus. Other hypothalamic nuclei were not involved on the left. The tumor did not involve the tuber cinereum, pituitary gland, or mammillary bodies. The median eminence was slightly involved by the gliosis delimiting the edge of the tumor. In the anterior pituitary, acidophils were prominent and had a nor mal pattern of granulation. Some basophils showed mild degranulation. There was no evidence of compression or ische mia in the anterior pituitary. The posterior pituitary was unremarkable.
COMMENT

This

the

Despite vigorous supportive efforts, patient died on the 15th hospital day.
Autopsy Findings

The autopsy showed an edematous pan creas discolored by hemorrhage, with fat

and mid hypothalamus and a small portion of the left anterior hypothala mus. The presence of many hemosiderin-laden macrophages in the tumor and on its surface indicated that the patient's initial symptoms were caused by hemorrhage into the tumor. She subsequently had hyperphagia, obesity, periods of unprovoked aggres sive behavior, visual hallucinations,

cytoma involving the right anterior

patient had a low-grade astro

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Massa Intermedia

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

Left

Fornix

Right

Left

Fornix

Right

Optic

Tract

Optic

Tract

Optic

Chiasm

of

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

ventricle.

reversal of wake-sleep pattern, marked hypothermia, hypothyroidism, and amenorrhea. It has been shown that bilateral lesions in the ventromedial hypotha lamic nuclei result in hyperphagia,

obesity, and rage attacks in human beings. A wealth of data from experi mentally induced ventromedial hypo

thalamic lesions in animals showed similar clinical findings,6 although it has been shown that ventromedial

nucleus lesions alone do not produce obesity.7 Although the neoplasm in our patient primarily involved the right ventromedial nucleus with mini mal involvement of the left ventrome dial nucleus, it is likely that compres-

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sion of the latter caused functional impairment that led to hyperphagia, obesity, and episodes of unprovoked

aggression. In our patient the only other bilat eral hypothalamic involvement in cluded the suprachiasmatic and preoptic nuclei and a portion of the paraventricular nuclei. Bilateral le sions of the preoptic nuclei are associ ated with faulty temperature control.8 Our patient's marked hypothermia possibly resulted from bilateral tumor involvement of the preoptic nuclei, hypothyroidism, or a combination of these two. Hypothermia probably caused her severe, acute pancreatitis, with the sequelae of hypocalcemia and secondary bacterial sepsis that led to her death. Massive pancreatitis is a major cause of death among survivors of accidental hypothermia.911 The development of hypothyroidism and hypogonadism in our patient is of
considerable interest. The mechanism documented in reports of experimen tal hypothalamic lesions in animals and in some humans is that ablation of the median eminence or tuber cinereum causes cessation of production of releasing factors.2 In turn, there would be decreased levels of one or more of TSH, FSH, LH, growth hor mone, and adrenocorticotropic hor mone, and an increase in prolactin level, resulting in hypofunction of the endocrine end organs. The median eminence and tuber cinereum were spared in our patient, and TSH, FSH, and LH levels were elevated, indicat-

ing endocrine end-organ hypofunction. More specifically, the patient was found to have hypofunction of the thyroid and ovary, possibly secondary to autoimmune disease, and would therefore have autoimmune polyglandular organ-failure syndrome. There was serologie confirmation of thyroid autoantibodies, and histopathologic findings were compatible with a diag nosis of autoimmune thyroiditis. The ovaries were atrophie and fibrotic, with only rare primordial follicles and no corpus luteum formation despite elevated gonadotropin levels. Al though serologie evidence of ovarian antibodies was not available, our find ings are certainly consistent with an autoimmune ovarian failure.12 It is possible that this patient had two rare, unrelated disease processes or diverse clinical findings all related to the hypothalamic tumor. What makes the autoimmune endocrine organ hypofunction interesting is emerging evidence of the hypothala mus' role in modulating the immune response.1314 Experimental data for the role of the hypothalamus, limbic system, and pituitary in suppression and enhancement of the immune response in the rat are accumulat ing.1416 However, there is no evidence to date suggesting that alterations in the hypothalamus can trigger an autoimmune reaction. The reversal of day-night rhythms in our patient is also of interest. Abla tion of the suprachiasmatic nucleus in the rat leads to loss of normal circadiReferences

rhythms, including sleep-wake cycle, drinking, activity, temperature, ovulation, and adrenocorticosterone production, which has been referred to as the suprachiasmatic syndrome.17 Convincing evidence has accumulated for the suprachiasmatic nucleus as an important link between the eye and the body that controls circadian rhythms and functions as a primary circadian oscillator, at least in the rat.18 Our patient had bilateral abla tion of the suprachiasmatic nucleus and changes in day-night rhythm, indicating loss of normal circadian rhythms. The normal four-day ovulatory cycle of the rat depends on its circadian rhythm. Ablation of the suprachiasmatic nucleus will abolish the LH surge and, therefore, ovula tion.19 Thus, an alternative explana
an

tion to
our

an

autoimmune disorder for

that the bilateral lesions of the supra chiasmatic nucleus resulted in loss of menstrual rhythm. Perhaps our

patient's amenorrhea would be

patient's findings represent a partial expression of the suprachiasmatic syndrome. The patient's clinical manifesta tions reaffirm the hypothalamus' complex functions. We documented
numerous

abnormalities

in

this

patient, some of which may have their

basis in the destruction of nuclei and their connections in a relatively small area of the anterior and mid hypo thalamus.

1. Bauer HG: Endocrine and other clinical manifestations of hypothalamic disease. J Clin Endocrinol Metabol 1954;14:13-31. 2. Reeves AG, Plum F: Hyperphagia, rage, and dementia accompanying a ventromedial hypothalamic neoplasm. Arch Neurol 1969;20:616\x=req-\ 624. 3. Bray GA, Gallagher TF: Manifestations of hypothalamic obesity in man: A comprehensive investigation of eight patients and a review of the literature. Medicine 1975;54:301-330. 4. Boshes B: Syndromes of the diencephalon, in Vinken PJ, Bruyn GW (eds): Handbook of Clinical Neurology. Amsterdam, North Holland Publishing Co, 1969, vol 2, pp 432-468. 5. Martin JB, Reichlin S, Brown GM: Clinical Neuroendocrinology. Philadelphia, FA Davis Co, 1977, pp 247-273. 6. Powley TL, Opsahl CA, Cox JE, et al: The role of the hypothalamus in energy homeostasis, in Morgane PJ, Panksepp J (eds): Handbook of the Hypothalamus. New York, Marcel Dekker Inc, 1981, vol 3, pp 211-298.

7. Gold RM:

of

the

ventromedial

Hypothalamic obesity:
nucleus.

The myth Science

1973;182:488-490. 8. Dinarello CA, Wolff SM: Pathogenesis of fever in man. N Engl J Med 1978;298;607-612. 9. Duguid H, Simpson RG, Stowers JM: Accidental hypothermia. Lancet 1961;2:1213-1219. 10. Read AE, Emslie-Smith D, Gough KR, et

al: Pancreatitis and accidental hypothermia. Lancet 1961;2:1219-1221. 11. Revlev JB: Hypothermia: Pathophysiology, clinical settings, and management. Ann Intern Med 1978;89:519-527. 12. Fox H, Buckley HC: Pathologic factors involved in infertility, in Blaustein A (ed): Pathology of the Female Genital Tract. New York, Springer-Verlag, 1982, pp 828-837. 13. Besedovsky H, Sorkin E, Felix D, et al: Hypothalamic changes during the immune response. Eur J Immunol 1977;7:323-325. 14. Cross RJ, Markesbery WR, Brooks WH, et al: Hypothalamic-immune interactions: I. The acute 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 anatomical basis for impairment and facilitation. Ann Neurol 1982;12:56-61. 16. Cross RJ, Markesbery WR, Brooks WH, et al: Hypothalamic immune interaction: Effect of hypophysectomy on neuromodulation. J Neurol Sci 1982;53:557-566. 17. Raisman B, Brown-Guent K: The suprachiasmatic syndrome: Endocrine and behavioral abnormalities following lesions of the suprachiasmatic nuclei in the female rat. Proc R Soc Lond Biol 1977;198:297-314. 18. Moore RY: The suprachiasmatic nucleus, circadian rhythms and regulation of brain peptides, 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 of circadian rhythms. Physiol Rev 1979;59:449-526.

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