Clinical Manifestations of Hypothalamic Tumors*

ADOLFO D. GARNICA, M.D., MICHAEL L. NETZLOFF, M.D.,f and A. L. ROSENBLOOM, M.D.

Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610 and f Department of Human Development, Michigan State University East Lansing, MI 88823

ABSTRACT The regulatory function of the central nervous system encompasses di verse endocrine, metabolic, and behavioral processes. Many of these origi nate, are integrated, or are coordinated through hypothalamic pathways or nuclei. Thus, tumors affecting areas projecting to the hypothalamus, tumors of the hypothalamus, and tumors invading or compressing the hypothalamus can produce abnormalities of hypothalamic function.

Introduction tary.4,7,31 A secretory function for certain hypothalamic neurons was postulated in Until recently, no endocrine disorder 1928 and subsequently confirmed by the directly attributable to hypothalamic dys demonstration of hormone synthesis in function had been recognized, and the the supraoptic and paraventricular nu majority of endocrine-metabolic homeo clei.28,53 Moreover, observations on the static processes were acknowledged to be effects of environment on the menstrual under the control of the anterior pitui cycles of women and the study of repro tary.48,49 However, in 1901 Frohlich re ductive cycles in animals have shown a ported a patient with a suprasellar tumor, functional connection between central hypogonadism and obesity, which Erd- nervous system and pituitary.18,52 The role heim suggested were the result of of the brain as a major endocrine tissue, hypothalamic injury caused by the tumor through which the integration of neuro rather than a primary effect of the tumor endocrine function occurs, is now gener itself.19,22 Clinical observations of pitui ally acknowledged, and the concept of the tary dysfunction following hypothalamic hypothalamic neurosecretory neurons as injury have now defined a clear relation “neuroendocrine transducers” linking ship between hypothalamus and pitui- neural activity with endocrine-metabolic regulation is now accepted.28,48,49,52 f Supported in part by NIH Grant No. 1K04 Considering, therefore, the significance NS00409-01. of the central nervous system and the 474 0091-7370/80/1100-0474 $01.80 © Institute for Clinical Science, Inc. CLINICAL MANIFESTATIONS OF HYPOTHALAMIC TUMORS 475 hypothalamus, specifically, in neuroen tidergic pathways originate primarily in docrine function, the varied clinical man the mid-brain, are distributed to the ifestations of central nervous system hypothalamus, basal ganglia, forebrain neoplasms are not surprising. Indeed, and spinal cord, and influence the secre studies of patients with central nervous tion of the hypophysiotropic hormones, system tumors provided the first clues as the functions of drinking and eating, the to the function of the hypothalamus.4,7 Of control of body temperature, and displays all intracranial tumors, those in the region of arousal and “affect.”45,49 (Table I.) of the hypothalamus present a complex array of signs, symptoms, and chemical Endocrine Hypothalamic Functions abnormalities reflecting the involvement of hypothalamic nuclear groups and A relationship between growth distur pathways ,4,7> 30,31,32>35,45 bances and hypothalamic disease has been recognized since early this century. Basic Considerations Patients studied after interruption of their hypothalamic-pituitary connections by The functional endocrine unit, the pituitary stalk section demonstrate sub hypothalamic-neurohypophyseal system, normal growth hormone response.38 Fur includes the paraventricular and supra thermore, animal studies implicate the optic nuclei, the median eminence, the ventromedial-arcuate region of the medial pituitary stalk, the neurophypophysis, the basal hypothalamus in the neuroendo hypophysiotropic area, and the portal crine regulation of growth hormone secre system supplying the adenohypo tion (table I).16'38-39 This region and the physis.28,48,49,52 An extensive hormonal control of adenohypophyseal secretory T A B L E I function is exerted by the central nervous system through the mediation of neuro Functions of the Hypothalamus hormones elaborated from specialized nerve cells of the hypophysiotropic area Function Hypothalamic Factor and released into the pituitary via the Endocrine hypothalamohypophyseal portal system Posterior pituitary under the control of synapses with higher Water balance Vasopressin* Milk ejection, Oxytocin* hypothalamic and third ventrical re uterine contraction gions.28,49 The posterior pituitary hor Anterior pituitary Growth GH releasing factor mones, vasopressin and oxytocin, are Somatotropin release synthesized and secreted by cells of the Inhibitory hormone Gonadotropic Gonadotropin supraoptic and paraventricular nuclei of Releasing hormone Thyrotropic Thyrotropin anterior hypothalamus. Releasing hormone Seven hypophysiotropic factors have Adrenocorticotropic Corticotropin Releasing factor now been identified, including growth hor Mammary development, Prolactin mone releasing factor, thyrotropin re reproductive Inhibitory factor Melanocyte stimulation Melanocyte leasing hormone, corticotropin releasing Inhibitory factor factor, gonadotropin releasing hormone, Non-endocrine State of Consciousness prolactin inhibitory factor, somatrotropin Cognition release inhibitory hormone, and melano Emotional behavior Autonomic balance cyte inhibitory factor.28,49 The neurosec Thermor egu1ation retory cells of the hypothalamus are Caloric balance termed “peptidergic” because their sec *Not releasing factors. These are hormones retory products, including the hypophys produced in the hypothalamus. They are stored iotropic hormones, are peptides.28,49 Pep and released from the posterior pituitary. 476 CARNICA, NETZLOFF AND ROSENBLOOM adjacent lateral hypothalamus also func medial amygdaloid nucleus, the fore tion as the final integrative center for brain, and the brain stem. Estrogen sensi homeostatic regulation of energy balance tive areas in these extrahypothalamic re and food intake.16,38 Growth hormone se gions are postulated to exert modulating cretion is regulated by the stimulatory and influences on reproductive cyclicity inhibitory influences of growth hormone through the regulation of mood and releasing factor and growth hormone re behavior.37,52,60 lease inhibitory hormone.16,28,38,39 Nearly The homeostatic regulation of body normal basal secretion, including water and osmolality depend on interac pulsatile release, can be maintained by tions among thirst, drinking behavior, and the isolated hypothalamus. antidiuretic hormone (ADH) release.45,48 Animal studies, however, indicate that Hormones produced by the magnocellu- additional inputs to the medial basal lar neurons of the hypothalamic supraop hypothalamus also may have excitatory or tic and periventricular nuclei ensure that inhibitory influences.16,38 Phasic changes a normal serum osmolality is maintained in growth hormone secretion are thought even when the hypothalamus is isolated to be mediated by higher brain centers. from the rest of the brain. ADH is trans Physical and psychological stresses have ported from the hypothalamus to the me been shown to affect its release, and dian eminence and neurophypophysis, pulsatile bursts of growth hormone secre from which it is released into the blood.48 tion have been observed in subjects at rest Baseline secretion from the neurosecre in the absence of changes in the levels of tory cells is modulated by input from os plasma metabolites known to influence moreceptors or volume receptors.45,48 growth hormone secretion.16,38 Current concepts of menstrual regula Non-endocrine Hypothalamic Function tion characterize the brain as an endocrine organ controlling the interaction of ovary, The hypothalamus influences at least pituitary and hypothalamus.48,52,60 The ul six non-endocrine functions, including timate site of control of this system is state of consciousness, cognition, emo thought to be the central nervous tional behavior and affect, autonomic bal system-hypothalamic complex, subject to ance, thermoregulation, and caloric bal feedback control of ovarian hormones. ance (table I).45 An anterior hypothalamic Pituitary gonadotropin secretion is con sleep center and posterior wake center trolled by input from the hypothalamus have been postulated on the basis of subject to cyclic feedback provided by studies in humans demonstrating be ovarian steroids, which influence havioral unresponsiveness with anterior gonadotropin secretion by positive and hypothalamic stimulation and arousal negative feedback mechanisms.60 Es with posterior hypothalamic stimula trogen-binding neurons are present in tion.14,23,58 Destruction of the same struc hypothalamic and extra-hypothalamic re tures in animals induces wakefulness or gions.37,60 The hypothalamic arcuate variable degrees of sensorial depression nucleus-median eminence unit appears to respectively.23,41,45,58 The behavioral be critical to the control of pituitary components of hypothalamic function gonadotropin secretion, and the cyclic re include an influence on the intensity of be lease of gonadotropin is influenced by a havior, the production of behavior appro feedback provided by ovarian estradiol. priate to affective state and the coordina In extra-hypothalamic areas, estrogen- tion of motor, autonomic and endocrine binding neurons are present in the inter components of behavior.4,45,47,54 A mem stitial nucleus of the stria terminalis, the ory function for the hypothalamus is im CLINICAL MANIFESTATIONS OF HYPOTHALAMIC TUMORS 4 7 7 plied by animal studies demonstrating a Hypothalamic Tumors necessity for ventromedian hypothalamic integrity for the acquisition of short term Disorders of the hypothalamus may memory.13,43,45 In humans, memory loss produce abnormalities of endocrine and has been correlated with neoplastic dam metabolic function through involvement age to the mammilary body.30,45,59 of hypothalamic nuclei or hypothalamic pathways. Extra-hypothalamic central The hypothalamus has been charac nervous system disease may result in terized as the “head ganglion of the au similar dysfunction by altering the input tonomic nervous system,” with para to the hypothalamus. Although many le sympathetic tone under the control of the sions can affect the hypothalamus, the pre-optic anterior hypothalamus and most frequent are tumors.4,7,32 Because sympathetic tone under control of the pos many of them are of the developmental terior hypothalamus.4,40,45 This concept, origin, the majority of tumor-related however, is accurate only insofar as the hypothalamic dysfunction occurs in pa hypothalamus functions in the integration tients under the age of 25 years.20,40,44,48 of more posteriorly originating autonomic Tumors of the parasellar region constitute influences. Thus, stimulation of the an approximately 15 percent of childhood terior hypothalamus results in a para central nervous system tumors.20 Of these, sympathetic response because of the large craniopharyngioma represents approxi number of descending, parasympathetic mately nine percent; pituitary tumors, pathways in the region. Stimulation of the three percent; optic glioma, two percent; posterior hypothalamus yields a sym teratoma, two percent; and pinealoma, pathetic response attributable in part to less than one percent.20 the diffuse sympathetic reticular core lo Intrinsic tumors of the hypothalamus cated in the region. Despite its capacity should be differentiated from extrinsic for autonomic response, therefore, the tumors which affect hypothalamic func predominant function of the hypo tion.40 The intrinsic tumors include thalamus is coordination.45 In the ab various gliomas such as astrocytomas, sence of normal hypothalamic function, spongioblastomas and glioblastomas, in baseline autonomic activity is main addition to harartomas and, rarely, infun- tained, but complex, homeostatic coordi dibulomas (table II). The extrinsic tumors nation of autonomic and behavioral re include craniopharyngiomas, optic glio sponses is lost. mas, pineal cysts, pinealomas, and hema The role of the hypothalamus in ther tomas.4,7,32,40 Suprasellar cysts or pine moregulation was recognized as early as alomas may invade the hypothalamus. 1885, and the concept of an anterior heat In the hypothalamus, as in most regions dissipating center and posterior heat pro of the brain, slowly growing lesions may ducing center was proposed in 1913.45,46 The hypothalamus coordinates and acti vates appropriate heat dissipating or pro T A B L E II ducing mechanisms through the integra Central Nervous System Tumors tion of physiologic responses, affective Affecting Hypothalamic Function sensations of thermal discomfort and be havioral responses.45 Available evidence Hypothalamic Extra-hypothalamic (Intrinsic) (Extrinsic) indicates that the preoptic anterior G1iomas Cr an iopharyng ioma Astrocytoma Optic glioma hypothalamus generates thermal signals Glioblastoma Pinealoma to the posterior hypothalamus where the Spongioblastoma Pineal cyst Hamartoma Hematoma effector signals for physiologic, affective Infundibuloma and behavioral responses originate. 478 GARNICA, NETZLOFF AND ROSENBLOOM

achieve considerable size before causing neurosecretory tracts in the median symptoms, while rapidly developing le eminence.45 sions, even if small, produce significant Neoplasms in the region of the symptomatology.45 Hypothalamic tumors hypothalamus and pituitary often present most frequently produce alterations with disturbances in visual perception or in endocrine and metabolic proc oculomotor function, headache or endo esses.4,7,32,40 Chronic lesions tend to inter crine dysfunction (table HI).33,44,56 Less fere with complex functions requiring the frequently, the presenting complaints in integration of neural information from clude seizures, facial pain, and distur multiple regions of the brain, and their bances of consciousness. Among the translation into effector mechanisms such tumors involving this region, cranio as cognition, caloric balance, fluid bal pharyngiomas and hypothalamic gliomas ance or endocrine regulation.45 Signs and are most commonly associated with hor symptoms of chronic processes are charac monal disturbances.4,31,32,48 In contrast, teristically less severe, progress slowly, endocrine disturbances are less promi and often spare at least part of the in nent in patients with optic gliomas, volved anatomic region. Unilateral dam meningiomas and suprasellar cysts.4,48 age seldom causes symptoms or perma The symptomatology observed with nent dysfunction in man since either side hypothalamic tumors can be classified ac of the hypothalamus can maintain the cording to the region affected. Diabetes functions regulated by a specific region. insipidus and hypogonadism are most The relatively high frequency of commonly associated with lesions affect neuroendocrine abnormalities with ing the anterior hypothalamus, including hypothalamic disease can at least partially optic glioma, craniopharyngioma, ectopic be attributed to the juxtaposition of paired pinealoma, meningioma of the sphenoid ridge, and infundibuloma (table IV).32,40 In contrast, lesions affecting the posterior T A B L E III hypothalamus, including hamartomas, Signs and Symptoms of Parasellar Tumors pinealomas, and ependymomas, are most commonly associated with sexual Age-Related precocity.32,40 Prepubertal: Headache Vomiting Among the cases of hypothalamic dis Sexual precocity ease reviewed by Bauer, the most fre

Young adults: Sexual infantilism quent clinical abnormalities were diabe Growth deficiency tes insipidus and gonadal dysfunction, Impotence Amenorrhea while thyroid and adrenocortical dysfunc Loss of libido Obesity tion occurred less often.7 Similar findings were observed in patients with Adults: Headache Visual disturbances craniopharyngioma or hypothalamic Hair loss gliomas by Korsgaard et al who reported Asthenia subnormal gonadotropin secretion in all General (Age-unrelated) patients, growth hormone deficiency in 55 Frequent: Headache Visual disturbances percent, adrenocortical hypofunction in Oculomoter dysfunction 44 percent and hypothyroidism in 22 Endocrine dysfunction percent.31 Less frequent: Seizures Facial pain Craniopharyngiomas produce symp Disturbance of consciousness toms by compressing the hypothalamus or Temperature instability Blood pressure instability pituitary and disturbing their function. Before puberty, the most prominent CLINICAL MANIFESTATIONS OF HYPOTHALAMIC TUMORS 479 symptoms seen with this tumor are head T A BLE IV ache an d v o m itin g .4, 7,31,32,40,48 Y oung Relationship of Endocrine Symptomatology adults demonstrate primarily sexual in to Hypothalamic Region Affected fantilism, poor growth, impotence, Clinical amenorrhea, failing libido, and obesity. Region Presentation Tumor Older adults present with headache, vis ual disturbances, hair loss, and asthenia. Anterior Diabetes insipidus Optic glioma Disturbances of consciousness, body Hypogonadi sm Cr an iopharyng ioma Dysgerminoma temperature or blood pressure and Meningioma, sphenoid ridge polyuria may occur.4,45 Sexual precocity Infundibuloma occurs rarely.48 Posterior Sexual precocity Hamartoma Pinealoma Gliomas of the optic nerve or chiasm Ependymoma and/or hypothalamus present most prom inently with visual disturbances but may also demonstrate diabetes insipidus, obe mones resulting from intrasellar lesions sity, and lethargy.4,7,32,33 Gliomas of the are usually mild and often cannot be third ventricle may be associated with detected. obesity, hypogonadism, diabetes in A variation of ADH insufficiency, es sipidus, sexual precocity, autonomic sential hypernatremia, is characterized by symptoms, temperature instability, dis hypernatremia without fluid deficiency, turbed consciousness, and behavioral partial ADH deficiency, preserved renal abnorm alities 7’25,31,32,40,45,48 Korsgaard tubular responsiveness to ADH, in et al found that patients with optic glioma adequate secretion of ADH in response to or suprasellar cyst demonstrated either osmotic stimuli, and absence of defi normal endocrine function or impaired ciency of thirst.4,35,45,55 Such patients growth hormone and gonadotropin characteristically manifest no symptom secretion.31 other than a lack of thirst, but may retain Disturbances of water balance are the habitual drinking, although the volume most well described disorders of ingested may be inadequate to maintain a hypothalamic function.45,48 The role of the normal osmolality. With increases in supraoptic and paraventricular nuclei in serum sodium above normal, such pa ADH synthesis and their relationship to tients progressively develop weakness neurohypophysis are well established. The capacity of nearly any pathologic in tracranial process to produce ADH insuf T A B L E V ficiency, or diabetes insipidus, has been Endocrine Disturbances Related attributed to the anatomic vulnerability of to Hypothalamic Dysfunction the supraopticoneurohypophysial sys Posterior Pituitary (Neurohypophysis) tem 2 (table V). However, studies indicate Diabetes insipidus that the development of irreversible di Inappropriate ADH secretion Essential hypernatremia abetes insipidus requires a loss of at least 90 percent of the ADH secreting cells, and Anterior Pitui tary (Adenohypophysis) Gonadal dysfunction implies that a permanent loss can result Sexual precocity only from direct hypothalamic dam Sexual infantilism (hypogonadism) age.12,25,45 Dysgerminoma, an infiltrating Growth Disturbance Growth deficiency neoplasm of the hypothalamus, is said Growth excess (gigantism) to be the tumor most commonly associated Adrenocortical insufficiency Hypothyroidism with diabetes insipidus.44 Functional ab Galactorrhea normalities of posterior pituitary hor- 480 GARNICA, NETZLOFF AND ROSENBLOOM and fever, muscle tenderness and cramp milary bodies and the posterior region of ing, fatigue, ataxia, and even paralysis. the tuber cinereum.44,48 Hamartomas may Mental symptoms include lethargy, produce signs and symptoms of sexual anorexia, depression, paranoia, and irrita precocity before damage to the surround bility. Sodium concentrations above 180 ing tissues has occurred, in some instances mEq per dl may lead to confusion or as early as the age of three months. stupor, and even death. Absence of thirst Although neurologic symptoms are rare is essential to the production of essential at the time sexual precocity is first noted, hypernatremia, as an intact thirst response the majority of patients develop progres would result in diabetes insipidus.45 Al sive manifestations of hypothalamic in though many patients with essential volvement, including hydrocephalus, hypernatremia demonstrate no central headache, visual disturbance, papil nervous system lesion, a few have been ledema, obesity, seizures, and behavioral found to have tumors localized to the changes leading to death before the age of preoptic anterior hypothalamus and tub- 20 years.48 Sexual precocity has also been eral region.45,57 observed in association with pineal A relatively uncommon manifestation tumors extending beyond the pineal re of parasellar tumor is the syndrome of gion, the most common being a teratoma inappropriate ADH secretion which composed of well-differentiated tis includes serum hyponatremia, hypo- sues.44,48 They may also produce clinical osmolality, abnormally high serum con evidence of hypothalamic involvement centrations of immunoreactive ADH, including diabetes insipidus, polyphagia, normal renal excretion of sodium, and an obesity, somnolence or behavioral distur inappropriately high urine osmolality bances as a result of the tumor causing without clinical evidence of body fluid structural changes in the hypothalamus. depletion.15,26,45 The inappropriate ADH Although the pineal gland and surround secretion characteristic of this condition ing region are the most common sites of has been attributed to compression of irri pinealom as, they may also be found in the tation of the hypothalamus. area of the infundibulum where they pro Gonadal dysfunction is a relatively duce diabetes insipidus, visual distur common abnormality observed with bances, and sexual precocity.4,7,31,32,48 hypothalamic tumors. Sexual precocity They may also occur in other brain sites usually implies a lesion of the posterior where they may be referred to as ectopic hypothalamus and/or pineal gland, while pinealomas, a misnomer. They are tera hypogonadism is usually associated with tomas of non-pineal origin, similar to lesions of the anterior hypothalamus those occuring in the pineal region but are (table IV). Sexual precocity has been attri more appropriately designated dysger- buted to the direct neoplastic involve minomas. Craniopharyngiomas may induce ment of the hypothalamus.7,31,32 An esti sexual precocity without associated de mated two-thirds of the cases of sexual ficiencies of other pituitary hormones, al precocity caused by destructive lesions though they usually cause hypo are associated with tumors caudal to the pituitarism by destruction of the pituitary median eminence, commonly hypothal stalk and ventral hypothalamus.4,32,48 amic hamartoma or teratoma.4,32,44,48 Gliomas and astrocytomas involving the Hamartomas are noninvasive tumors of parasellar or temporal lobe regions have developmental origin consisting of en also been reported to cause sexual capsulated nodules of nervous tissue precocity. attached to the posterior hypothalamus Hypogonadism secondary to gonado between the anterior portion of the mam- tropin deficiency may develop on a CLINICAL MANIFESTATIONS OF HYPOTHALAMIC TUMORS 481 neurogenic basis.1 Although such cases Growth hormone excess may also occur, are not associated usually with demonstra causing gigantism in childrem or acromeg ble structural disease of the parasellar aly in adults.16,38,56 Classically, acromeg region, a small proportion has been re aly and gigantism have been considered ported with neoplasms. Possibly the most to be caused by eosinophilic adenomas of well-known of these is the Babinski- the anterior pituitary. However, the ob Frolich syndrome, which consists of servation that some patients with chronic hypogenitalism and obesity and is gener growth hormone hypersecretion do not ally thought to result from lesions involv have adenohypophyseal tumors suggests ing the basal hypothalamus and the that chronic growth hormone hypersecre median eminence.3,13,19,22 The original tion and somatotrope proliferation may report was of an individual with a cranio result from a defect in the hypothalamic pharyngioma, but the condition may be control of growth hormone secretion.38,56 associated with other disorders.22,45,48 It is now apparent that the signs and Damage to the ventromedial region re symptoms of growth hormone hypersecre sults in gonadotropin deficiency. Al tion, accompanied by elevated plasma though hypogonadism is frequently as growth hormone levels, may long precede sociated with hypothalamic obesity, it can any evidence of pituitary adenoma and be separated from it experimentally by le may be related to a primary hypothalamic sions restricted to the median eminence.45 disturbance causing an inappropriate se Galactorrhea, another endocrine disor cretion of growth hormone releasing fac der of central origin, is generally as tor. Several cases of hypothalamic tumor sociated with amenorrhea.21,32,48,50 It can with elevated growth hormone levels are be seen secondary to anatomic lesions in commonly found in the diencephalic syn volving the hypothalamus, including drome of early infancy, a condition almost transection of the pituitary stalk, meta invariably associated with glioma of the static carcinoma or primary tumors of the anterior hypothalamus.38,40,43,45 pituitary or hypothalamus.48 The pre sumed pathogenesis of this condition is an Non-endocrine Disturbances interference with areas concerned with The diencephalic syndrome was de the production of prolactin inhibitory fac scribed originally as a combination of tor, which results in an increase in prolac severe emaciation, nystagmoid eye move tin secretion by the pituitary. Franks et al ments, and inappropriate affective be- found increased serum prolactin levels in 70 percent of their patients with “func- T A B L E VI tionless” pituitary tumors prior to Non-Endocrine Disturbances Related surgery.21 to Hypothalamic Dysfunction Growth failure is the most common

manifestation of growth hormone defi Disturbances of Consciousness ciency in childhood, and hypothalamic Emotional Disturbances Weight Disturbances (Caloric Balance) disorders are a well-recognized cause of Anorexia nervosa growth hormone deficiency. However, Obesity Thermoregulatory Dysfunction fewer than one-fourth of growth hormone Hyperthermia deficient patients have been shown to Hypothermia Autonomic Dysfunction have organic hypothalamic or hypophy Blood pressure instability Autonomic "seizures" seal le s io n .11, 16,31,40,48 O f th e tu m o rs Complex Disturbances or Syndromes causing growth hormone deficiency, Diencephalic syndrome Hypothalamic syndrome craniopharyngioma is the most common; (acute lymphoblastic leukemia) other tumors are uncommon.16 482 GARNICA, NETZLOFF AND ROSENBLOOM havior in infants between the ages of 12 change in symptomatology is due to the and 18 months, most commonly as metabolic changes occurring at that age or sociated with an invasive tumor of the the growth characteristics of the tumor is hypothalamus or one involving the an unclear. It is not known why the imma terior hypothalamus (table VI).24-45-51 ture, infantile hypothalamus produces Tumors of the diencephalon in infants symptoms different from those seen in the may present with emaciation and older child and adult. The few reported euphoria or, less commonly, autonomic adults with hypothalamic disease and seizures.48 The hypothalamus is usually emaciation have demonstrated anorexia destroyed completely by the time of and hypophagia and, by the time of au death, but studies indicate that the tumors topsy, the responsible lesion has usually arise in the optic chiasm or anterior destroyed the entire hypothalamus.45 hypothalamus and are confined to the an Although anorexia nervosa is usually terior and tuberal regions at the onset of assumed to be a psychogenic disorder, symptoms.43,48 Affected infants usually patients with this condition may demon are alert, cheerful and hyperactive, main strate abnormalities of hypothalamic func tain a good appetite and grow to an age- tion, the etiology of which are not de appropriate height, despite severe wast fined.9,18,45,60 The characteristic anorexia, ing.48,51 weight loss, amenorrhea, and decreased Although the mechanism of the emacia luteinizing hormone/follicle stimulating tion has not been characterized, these ob hormone (LH/FSH) levels are associated servations suggest that it is not merely a with decreased secretion of gonadotropin consequence of hypophagia or one com releasing hormone from the hypo- ponent of general growth failure.45 The thalmus,9,60 Most patients examined at au decrease in subcutaneous fat has been topsy have had morphologically normal postulated to be related to hypothalamic brains, although rare cases of poorly dysfunction, possibly involving a fat localized hypothalamic tumors have been mobilizing substance as yet uniden reported.17,36 tified.34,48 Endocrine studies have been In the report of Menezes et al, abnor found to be normal except for elevated malities of body weight occurred in 75 growth hormone, which is commonly percent of patients.40 Although more than found in this disorder.38,40,45 The finding 50 percent failed to gain weight, four pa of high growth hormone levels in patients tients presented with excessive weight with symptomatic hypoglycemia and gain associated with normal linear emaciation has prompted the implication growth. Obesity is a well-known manifes of the lipolytic properties of growth hor tation of hypothalamic tumor, especially mone as a factor causing emacia in patients beyond the infant age group, tion 34-38>40>45 and it is often associated with hypo Although affected patients usually do gonadism.13,45,47 The neoplasm most com not survive beyond their second birthday, monly implicated in this syndrome is the few that do often undergo a qualitative craniopharyngioma, as in the original re transformation in symptomatology.24 With port of Frolich, but the syndrome may be continued good appetite and intake, the associated with other lesions.13,22,45 child may develop hypothalamic obesity, The Babinski-Frolich syndrome which a finding rarely seen in infants younger consists of hypogenitalism and obesity is than two years of age. Irritability may re generally thought to result from lesions place the euphoria characteristic of the involving the basal hypothalamus and the earlier months, and the prognosis for sur m edian em inence.3,13,22,45,48 D am age to vival is greatly improved.45 Whether the the ventromedial region results in obe CLINICAL MANIFESTATIONS OF HYPOTHALAMIC TUMORS 4 8 3

sity, while destruction of the median emi marked increase in appetite and weight nence results in gonadotropin defi gain unrelated to corticosteroid therapy ciency.45 Most patients with hypothalamic and progressing to signs and symptoms of obesity, including those with the increased intracranial pressure associated Babinski-Frolich syndrome, have been with diffuse, pronounced leukemic infil demonstrated at autopsy to have lesions tration of the hypothalamic tissues, par involving the majority of the hypo ticularly at the level of the ventromedial thalamus, although the posterior nucleus.6,27 Leukemic involvement is less hypothalamus has frequently been commonly associated with hypogonadism spared.45'47 Occasional cases have been and behavioral abnormalities.6,27 associated with severe, bilateral leukemic infiltration of the periventricular R eferences hypothalamus, especially the ventromed 1. A n d e r s o n , E., H a y m a k e r , W . , and ial region.6,27 Marked hyperphagia, obe Rappaport, H.: Seminiferous tubule failure associated with degenerative change in the sity and aggressive behavior in a young hypothalamus. Amer. Pract. 1:40-45, 1950. woman were shown to be associated with 2. Av io l i, L. V., E a r l e y , L. E., and K a s h im a , H . a hamartoma completely and specifically K.: Chronic and sustained hypernatremia, ab sence of thirst, diabetes insipidus and adreno- destroying the ventromedial hypo corticotropin insufficiency resulting from thalamus.47 Individuals with hypothal widespread destruction of the hypothalamus. amic obesity differ from normals and from Ann. Intern. Med. 56:131-140, 1962. 3. B a b in s k i, J.: Tumeur du corps pituitaire sans those with essential obesity in that they acromegalie et avec arret de developement des consume more calories than they expend organes genitaux. Rev. Neurol. (Paris) 8:531- only during the period of weight gain.45 533, 1900. 4. B a i l e y , P.: Tumors involving the hypo Once a new set-point is achieved, the ex thalamus and their clinical manifestations. The cessive appetite subsides, unless the Hypothalamus, vol. XX. Res. Publ. Assoc. Nerv. etiologic lesion progresses. Ment. Dis. New York, Hafner Publishing Co., 1940, p. 723. The hypothalamus is also subject to in 5. B a r d , P.: A diencephalic mechanism for the volvement by non-central nervous system expression of rage with special reference to the neoplasms. Two well-recognized syn sympathetic nervous system. Amer. J. Physiol. 84:490-515, 1928. dromes caused by cellular infiltration of 6. Bastrup-M adsen, P. and G reisen, O.: the hypothalamus and surrounding struc Hypothalamic obesity in acute leukemia. Acta tures are known to occur in patients with Haematol. 29:109-116, 1963. 7. B a u e r , H. G.: Endocrine and metabolic condi Hand-Schuller-Christian disease or acute tions related to pathology in the hypothalamus: leukemia. The hypothalamic involvement A review. J. Nerv. Ment. Dis. 21:323-338,1959. in Hand-Schuller-Christian disease has 8. Beck, P., Parker, M. L., and Daughaday, W. H.: Paradoxical hypersecretion of growth hor been characterized as a disorder affecting mone in response to glucose. J. Clin. Endoc. the hypothalamus, pituitary stalk, and 26:463-469, 1966. posterior pituitary but sparing the anterior 9. B ell, E. T., H arkness, R. A., and L oraine, J. A.: Gonadotrophin and oestrogen excretion in pituitary.50 Diabetes insipidus is the most patients with anorexia nervosa. J. Psychosom. common manifestation of the histiocytic R es. 9:79, 1965. infiltration of the hypothalamus seen with 10. B ernard, J. D. and A g u i l a r , M. J.: Localized hypothalamic histiocytosis X. Arch. Neurol. Hand-Schuller-Christian disease, but 20:368-372, 1969. growth hormone deficiency, hypothy 11. B ie r ic h , J. R.: On the aetiology of hypopitui- roidism, hypogonadotrôpism, hypo- tary dwarfism. Growth and Growth Hormone, 2nd International Symposium. Pecile, A., and adrenocorticalism, and hyperprolacti Mueller, E. E., eds. Amsterdam, Excerpta nemia have also been reported.10,50 Medica, 1972, pp. 408-414. Symptomatic hypothalamic involvement 12. Braverm an, L. E., M a n c i n i , J. P., and M cGoldrick, D. M.: Hereditary idiopathic di in acute lymphoblastic leukemia occurs abetes insipidus. Ann. Intern. Med. 63:503- uncommonly, presenting initially with a 508, 1965. 4 8 4 CARNICA, NETZLOFF AND ROSENBLOOM

13. B r a y , G . A. and G allagher, T. F ., J r . : Man 30. K illeffer, F. A. and S t e r n , W. E.: Chronic ifestations of hypothalamic obesity in man: A effects of hypothalamic injury. Report of a case comprehensive investigation of eight patients of near total hypothalamic destruction resulting and a review of the literature. Medicine from removal of a craniopharyngioma. Arch. 54:301-330, 1975. Neurol. 22: 419-219, 1970. 14. B r i e r l e y , J. B.: The neuropathology of am 31. Korsgaard, O., Lindholm, J., and nesic states. Amnesia. Whitty, C. W. M. and Rasmussen, P.: Endocrine function in patients Zangwill, O. L., ed. London, Butterworths, with suprasellar and hypothalamic tumors. Acta 1966, pp. 150-180. Endocr. 83: 1-8, 1976. 15. BriSM A N , R. and Chutorian, A. M.: Inappro 32. K rieger, D. T.: The hypothalamus and priate antidiuretic hormone secretion. neuroendocrine pathology. Hosp. Pract. Hypothalamic glioma in a child. Arch. Neurol. 7:127-138, 1971. 23:63-69, 1970. 33. Krieger, H. P.: Sellarandjuxtasellardisease: A 16. C r y e r , P. E. and Daughaday, W. H.: Growth neurologic viewpoint. Hosp. Pract. 12:95-103, hormone. Clinical Neuroendocrinology. Mar 1979. tini, L. and Besser, G. M., eds. New York, 34. K urtz, R. G., R o z in , P., and Teitelbaum , P.: Academic Press, 1977, pp. 243-277. Ventromedial hypothalamic hyperphagia in the 17. D a l y , J. J. and Nabarro, J. D. N.: hypophysectomized weanling rat. J. Comp. Clinicopathological Conference. A case of Physiol. Psychol. 80:19-25, 1972. anorexia. Brit. Med. J. 2:158-163, 1973. 35. Lascelles, P. T. and L e w is , P. D .: Hypodipsia 18. de la Fuente, J. R. and Rosenbaum, A. H.: and hypernatremia associated with Psychoendocrinology. Mayo Clin. Proc. hypothalamic and suprasellar lesions. Brain 54:109-118, 1979. 95:249-264, 1972. 19. E r d h e i m , J.: Uber hypophysenganggesch- 36. Lewin, K., M attingly, D., and M i l l s , R. R.: wulste und hircholesteatome. Sitz. Akad. Wis- Anorexia nervosa associated with hypothalamic sen. Wien. 113:537-716, 1904. tumor. Brit. Med. J. 2:630, 1972. 20. F a r w e l l , J. R., D o h r m a n n , G. J. and 37. McEwen, B. S.: The brain as a target organ of 122:95-104, F l a n n e r y , ]. T.: Central nervous system endocrine hormones. Hosp. Pract. tumors in children. Cancer 40:3123-3132, 1975. 1977. 38. M artin, J. B.: Neural regulation of growth hormone secretion. New Eng. J. M e d . 21. F r a n k s , S., N a b a r r o , J. D. N ., and J a c o b s, H. S.: Prevalence and presentation of hyperprolac 288:1384-1393, 1973. tinemia in patients with functionless pituitary 39. M artin, J. B., Brazeau, P., Tannenbaum, G. tumors. Lancet 7:778, 1977. S., W illoughby, J. O., E p e lb a u m , J., T e r r y , L. C., and Durand, D.: Neuroendocrine or 2 2 . F r O H L IC H , A.: Ein fall von tumor der ganization of growth hormone regulation in the hypophysis ceribri ohne akromegalie. Wien. hypothalamus. Reichlin, S., Baldessarini, R. J., Kim. Rundsch. 15:883-886, 906-908, 1901. and Martin, J. B., eds. New York, Raven Press, 23. F u l t o n , J. F . and B a i l e y , P.: Tumors in the 1978, pp. 3 2 9 -3 5 7 . region of the third ventricle: Their diagnosis 40. M enzees, A. H., B ell, W. E., and P erret, G. and relation to pathological sleep. J. Nerv. E.: Hypothalamic tumors in children. Childs Ment. Dis. 69:1-25, 1929. Brain 3:265-280, 1977. 24 . G a m s t o r p , I., K j e l l m a n , B., and P a l m g r e n , 41. Nauta, W. J. H.: Hypothalamic regulation of B.: Diencephalic syndromes of infancy. J. sleep in rats. Experimental study. J. Pediat. 70:383-390, 1967. Neurophysiol. 9:285-316, 1946. 25. G r e e n , J. P., B u c h a n a n , G. C ., A l v o r d , E . C., 42. O l d s , M. E. and O l d s , J.: Effects of lesions in a n d Sw a n s o n , A. G.: Hereditary and idiopathic the medial forebrain bundle on self-stimulation types of diabetes insipidus. Brain 90:707-714, behavior. Amer. J. Physiol. 217:1253-1264, 1967. 1969. 26. G r e i s s , K. C., M o s e s , A. M ., and K r i e g e r , D. 43. P e l c , S.: The diencephalic syndrome in in T.: Pituitary adenoma associated with inappro fants. A review in relation to optic nerve glioma. priate anti-diuretic hormone secretion. Acta Eur. Neurol. 7:321-334, 1972. Endocrinol. 76:59-66, 1974. 44. Page, L. K.: Surgical management of 27. Greydanus, D. E., B u r g e r t , O. E., and hypothalamic neoplasms. Hormones and GILCHRIST, G. S.: Hypothalamic syndrome in Cancer. Charylulu, K. K. N. and Sudarsanam, children with acute lymphocytic leukemia. A., eds. New York, Stratton International Medi Mayo Clin. Proc. 53:217-220, 1978. cal Books Corp., 1976, pp. 6 9 -8 5 . 28. G uillem in, R.: The expanding significance of 45. P lu m , F . and Van U itert, R.: Nonendocrine hypothalamic peptides, or is endocrinology a diseases and disorders of the hypothalamus. branch of neuroendocrinology. Rec. Prog. The Hypothalamus. Reichlin, S., Baldessarini, Horm. Res. 33:1-28, 1977. R. J., and Martin, J. B., eds. New York, Raven 29. K ahn , E. and Crosby, E. C.: Korsakoffs syn Press, 1978, pp. 1-1 4 . drome associated with surgical lesions involv 46. Ranson, S. W.: Regulation of body tempera ing the mammillary bodies. Neurology ture. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 22:117-125, 1972. 20:342-399, 1940. CLINICAL MANIFESTATIONS OF HYPOTHALAMIC TUMORS 4 8 5

47. R e e v e s , A. G. and P l u m , F.: Hyperphagia, rage 55. S r i d h a r , C . B., C a l v e r t , G . D ., a n d and dementia accompanying a ventromedial I b b e r t s o n , H. K.: Syndrome of hypernatremia, hypothalamic neoplasm. Arch. Neurol. hypodipsia and partial diabetes insipidus: A 20:616-624, 1969. new interpretation. J. Clin. Endocr. Metab. 48. R e i c h l in , S.: Neuroendocrinology. Textbook 38:890-901, 1974. of Endocrinology. Williams, R . H ., ed. 56. T a y l o r , A. L.: Endocrinologic disturbances in Philadelphia, W. B. Saunders Co., 1972, pp. hypothalamic-pituitary neoplasms. Hormones 774-831. and Cancer. Charylulu, K. K. N. and Sudar- 49. R E IC H L IN , S.: Introduction. The Hypo sanam, A., eds. New York, Stratton Interna thalamus. Reichlin, S., Baldessarini, R . J., tional Medical Book Corp., 1976, pp. 87-95. and Martin, J. B., New York, Raven Press, 1978, 57. V e jja jiv a , A., Sit p r ija , V., and Sh u a n g s h o t i, pp. 1-14. S .: Chronic sustained hypernatremia and 50. R o t h m a n , J. G., Sn y d e r , P. J., and U t i g e r , R. hypovolemia in hypothalamic tumor. Neurol D.: Hypothalamic endocrinopathy in Hand- ogy 19:161-166, 1969. Schuller-Christian disease. Ann. Int. Med. 58. W a l t e r , W . G ., G r i f f i t h s , G . M., and 88:512-513, 1978. N e r v in , S.: The electroencephalogram in a 51. R u s s e l , A.: A diencephalic syndrome of emaci case of pathological sleep due to hypothalamic ation in infancy and childhood. Arch. Dis. tumor. Brit. Med. J. 1:107-109, 1939. Child. 26:274, 1951. 59. W il l ia m s , M. and P e n n y p a c k e r , J.: Memory 52. Sc h a l l y , A. V.: Aspects of hypothalamic regu disturbances in third ventricle tumors. J. lation of the pituitary gland. Science202:18-28, Neurol. Neurosurg. Psychiat. 17:115-123, 1978. 1954. 53. Sc h a r r e r , E. and Sc h a r r e r , B.: Secretory 60. Ye n , S. C.: Neuroendocrine aspects of the regu cells within the hypothalamus. Res. Publ. As lation of cyclic gonadotropin release in women. soc. Nerv. Ment. Dis. 20:170-194, 1940. Prog. Repro. Biol., vol. 2. Clinical Reproductive 54. Sp i e g e l , E. D. and W y c is , H. T.: Multiplicity Neuroendocrinology. Hubinont, P. O., Her- of subcortical localization of various functions. mite, M. L., and Robyn, C., eds. Basel, S. J. Nerv. Ment. Dis. 147:45-48, 1968. Karger, 1977, pp. 150-175.