ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 10, No. 6Copyright © 1980, Institute for Clinical Science, Inc.

Clinical Manifestations of Hypothalamic Tumors*

ADOLFO D. GARNICA, M.D., M ICHAEL L. N ETZLO FF, M .D.,fand A. L. ROSENBLOOM, M.D.

Department o f Pediatrics, University o f Florida College o f Medicine,

Gainesville, FL 32610 and

f Department o f Human Development, Michigan State University

East Lansing, MI 88823

ABSTRACT

The regulatory function of the central nervous system encompasses di­verse endocrine, metabolic, and behavioral processes. Many of these origi­nate, 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

Until recently, no endocrine disorder directly attributable to hypothalamic dys­function had been recognized, and the majority of endocrine-metabolic homeo­static processes were acknowledged to be under the control of the anterior pitui­tary.48,49 However, in 1901 Frohlich re­ported a patient with a suprasellar tumor, hypogonadism and obesity, which Erd- heim su g g ested w ere the re su lt of hypothalamic injury caused by the tumor rather than a primary effect of the tumor itself.19,22 Clinical observations of pitui­tary dysfunction following hypothalamic injury have now defined a clear relation­ship betw een hypothalamus and pitui-

f Supported in part by N IH G rant No. 1K04 NS00409-01.

tary.4,7,31 A secretory function for certain hypothalamic neurons was postulated in 1928 and subsequently confirmed by the demonstration of hormone synthesis in the supraoptic and paraventricular nu­clei.28,53 Moreover, observations on the effects of environm ent on the menstrual cycles of women and the study of repro­ductive cycles in animals have shown a functional connection betw een central nervous system and pituitary.18,52 The role of the brain as a major endocrine tissue, through which the integration of neuro­endocrine function occurs, is now gener­ally acknowledged, and the concept of the hypothalamic neurosecretory neurons as “ neuroendocrine transducers” linking neural activity with endocrine-metabolic regulation is now accepted.28,48,49,52

Considering, therefore, the significance of the central nervous system and the

4740091-7370/80/1100-0474 $01.80 © Institute for Clinical Science, Inc.

CLINICAL MANIFESTATIONS OF HYPOTHALAMIC TUMORS 475

hypothalamus, specifically, in neuroen­docrine function, the varied clinical man­ifesta tions of cen tra l nervous system neoplasm s are not surprising. Indeed, studies of patients with central nervous system tumors provided the first clues as to the function of the hypothalamus.4,7 Of all intracranial tumors, those in the region of the hypothalamus present a complex array of signs, symptoms, and chemical abnormalities reflecting the involvement o f hypo thalam ic n u c le a r groups and pathways ,4,7> 30,31,32>35,45

Basic ConsiderationsT he functional endocrine un it, the

hypothalamic-neurohypophyseal system, includes the paraventricular and supra­optic nuclei, the median eminence, the pituitary stalk, the neurophypophysis, the hypophysiotropic area, and the portal system su p p ly in g the ad en o h y p o ­physis.28,48,49,52 An extensive hormonal control of adenohypophyseal secretory function is exerted by the central nervous system through the m ediation of neuro­horm ones elaborated from specialized nerve cells of the hypophysiotropic area and released into the pituitary via the hypothalamohypophyseal portal system under the control of synapses with higher hypothalam ic and th ird v en trica l re ­gions.28,49 The posterior pitu itary hor­m ones, vasopressin and oxytocin, are synthesized and secreted by cells of the supraoptic and paraventricular nuclei of anterior hypothalamus.

Seven hypophysiotropic factors have now been identified, including growth hor­m one releasing factor, thyro tropin re­leasing hormone, corticotropin releasing factor, gonadotropin releasing hormone, prolactin inhibitory factor, somatrotropin release inhibitory hormone, and melano­cyte inhibitory factor.28,49 The neurosec­retory cells of the hypothalam us are term ed “peptidergic” because their sec­retory products, including the hypophys­iotropic hormones, are peptides.28,49 Pep­

tidergic pathways originate primarily in the m id-brain , are d istr ib u ted to the hypothalam us, basal ganglia, forebrain and spinal cord, and influence the secre­tion of the hypophysiotropic hormones, the functions of drinking and eating, the control of body temperature, and displays of arousal and “affect.” 45,49 (Table I.)

Endocrine Hypothalamic Functions

A relationship betw een growth distur­bances and hypothalam ic disease has been recognized since early this century. Patients studied after interruption of their hypothalam ic-pituitary connections by pituitary stalk section demonstrate sub­normal growth hormone response.38 Fur­therm ore, animal studies implicate the ventromedial-arcuate region of the medial basal hypothalam us in the neuroendo­crine regulation of growth hormone secre­tion (table I).16'38-39 This region and the

TABLE I

Functions of the Hypothalamus

Function Hypothalamic Factor

Endocrine Posterior pituitary Water balance Milk ejection, uterine contraction

Anterior pituitary Growth

Gonadotropic

Thyrotropic

Adrenocorticotropic

Mammary development, reproductive

Melanocyte stimulation

Non-endocrine State of Consciousness CognitionEmotional behavior Autonomic balance Thermor egu1ation Caloric balance

*Not releasing factors. These are hormonesproduced in the hypothalamus. They are stored and released from the posterior pituitary.

Vasopressin*Oxytocin*

GH releasing factor Somatotropin release Inhibitory hormone

Gonadotropin Releasing hormone

Thyrotropin Releasing hormone

Corticotropin Releasing factor

Prolactin Inhibitory factor

Melanocyte Inhibitory factor

476 CARNICA, NETZLO FF AND ROSENBLOOM

adjacent lateral hypothalamus also func­tion as the final integrative center for homeostatic regulation of energy balance and food intake.16,38 Growth hormone se­cretion is regulated by the stimulatory and inhibitory influences of growth hormone releasing factor and growth hormone re­lease inhibitory hormone.16,28,38,39 Nearly norm al basal se c re tio n , in c lu d in g pulsatile release, can be maintained by the isolated hypothalamus.

Animal studies, however, indicate that additional inpu ts to the m edial basal hypothalamus also may have excitatory or inhibitory influences.16,38 Phasic changes in growth hormone secretion are thought to be m ediated by higher brain centers. Physical and psychological stresses have been shown to affect its release, and pulsatile bursts of growth hormone secre­tion have been observed in subjects at rest in the absence of changes in the levels of plasma metabolites known to influence growth hormone secretion.16,38

Current concepts of menstrual regula­tion characterize the brain as an endocrine organ controlling the interaction of ovary, pituitary and hypothalamus.48,52,60 The ul­timate site of control of this system is th o u g h t to be the cen tra l nervous system-hypothalamic complex, subject to feedback control of ovarian hormones. Pituitary gonadotropin secretion is con­trolled by input from the hypothalamus subject to cyclic feedback provided by ovarian s te ro id s , w hich in flu en ce gonadotropin secretion by positive and negative feedback m echanism s.60 E s­trogen-binding neurons are p resent in hypothalamic and extra-hypothalamic re­g ions.37,60 T he hypothalam ic arcuate nucleus-median eminence unit appears to be critical to the control of p itu itary gonadotropin secretion, and the cyclic re­lease of gonadotropin is influenced by a feedback provided by ovarian estradiol. In extra-hypothalam ic areas, estrogen- binding neurons are present in the inter­stitial nucleus of the stria terminalis, the

m edial am ygdaloid nucleus, the fore­brain, and the brain stem. Estrogen sensi­tive areas in these extrahypothalamic re­gions are postulated to exert m odulating in flu en ces on rep ro d u c tiv e cyclicity th ro u g h the reg u la tio n o f m ood and behavior.37,52,60

The hom eostatic regulation of body water and osmolality depend on interac­tions among thirst, drinking behavior, and antidiuretic hormone (ADH) release.45,48 Hormones produced by the magnocellu- lar neurons of the hypothalamic supraop­tic and periventricular nuclei ensure that a normal serum osmolality is m aintained even when the hypothalamus is isolated from the rest of the brain. ADH is trans­ported from the hypothalamus to the m e­dian em inence and neurophypophysis, from which it is released into the blood.48 Baseline secretion from the neurosecre­tory cells is modulated by input from os­moreceptors or volume receptors.45,48

Non-endocrine Hypothalamic Function

The hypothalamus influences at least six non-endocrine functions, including state of consciousness, cognition, emo­tional behavior and affect, autonomic bal­ance, thermoregulation, and caloric bal­ance (table I).45 An anterior hypothalamic sleep center and posterior wake center have been postu lated on the basis of stud ies in hum ans dem onstrating b e ­havioral unresponsiveness with anterior hypothalam ic stim ulation and arousal w ith poste rio r hypothalam ic stim ula­tion.14,23,58 Destruction of the same struc­tures in animals induces wakefulness or variable degrees of sensorial depression resp e c tiv e ly .23,41,45,58 T he behav ioral com ponents of hypothalam ic function include an influence on the intensity of be­havior, the production of behavior appro­priate to affective state and the coordina­tion of motor, autonomic and endocrine components of behavior.4,45,47,54 A mem­ory function for the hypothalamus is im­

CLINICAL MANIFESTATIONS OF HYPOTHALAMIC TUMORS 4 7 7

plied by animal studies demonstrating a necessity for ventromedian hypothalamic integrity for the acquisition of short term memory.13,43,45 In humans, memory loss has been correlated with neoplastic dam­age to the mammilary body.30,45,59

The hypothalam us has been charac­terized as the “head ganglion of the au­tonom ic nervous system ,” w ith para­sympathetic tone under the control of the p re-op tic a n te rio r hypo thalam us and sympathetic tone under control of the pos­terior hypothalamus.4,40,45 This concept, however, is accurate only insofar as the hypothalamus functions in the integration of more posteriorly originating autonomic influences. Thus, stimulation of the an­terior hypothalam us results in a para­sympathetic response because of the large num ber of descending, parasympathetic pathways in the region. Stimulation of the posterior hypothalam us yields a sym­pathetic response attributable in part to the diffuse sympathetic reticular core lo­cated in the region. Despite its capacity for autonomic response, therefore, the p red o m in an t fu n c tio n o f the h y p o ­thalam us is coordination.45 In the ab­sence of normal hypothalamic function, base lin e autonom ic activ ity is m ain­tained, but complex, homeostatic coordi­nation of autonomic and behavioral re­sponses is lost.

The role of the hypothalamus in ther­moregulation was recognized as early as 1885, and the concept of an anterior heat dissipating center and posterior heat pro­ducing center was proposed in 1913.45,46 The hypothalamus coordinates and acti­vates appropriate heat dissipating or pro­ducing mechanisms through the integra­tion of physiologic responses, affective sensations of thermal discomfort and be­havioral responses.45 Available evidence in d ica tes th a t the p reo p tic an te rio r hypothalamus generates thermal signals to the posterior hypothalamus where the effector signals for physiologic, affective and behavioral responses originate.

Hypothalamic Tumors

D isorders of the hypothalam us may produce abnormalities of endocrine and metabolic function through involvement of hypothalamic nuclei or hypothalamic pathw ays. Extra-hypothalam ic central nervous system disease may resu lt in similar dysfunction by altering the input to the hypothalamus. Although many le­sions can affect the hypothalamus, the most frequent are tumors.4,7,32 Because many of them are of the developm ental origin, the m ajority of tum or-re la ted hypothalamic dysfunction occurs in pa­tients under the age of 25 years.20,40,44,48 Tumors of the parasellar region constitute approximately 15 percent of childhood central nervous system tumors.20 Of these, craniopharyngioma represents approxi­mately n ine percent; pituitary tumors, three percent; optic glioma, two percent; teratoma, two percent; and pinealoma, less than one percent.20

Intrinsic tumors of the hypothalamus should be differentiated from extrinsic tumors which affect hypothalamic func­tio n .40 T he in tr in s ic tum ors in c lu d e various gliomas such as astrocytom as, spongioblastomas and glioblastomas, in addition to harartomas and, rarely, infun- dibulomas (table II). The extrinsic tumors include craniopharyngiomas, optic glio­mas, pineal cysts, pinealomas, and hema­tomas.4,7,32,40 Suprasellar cysts or p ine­alomas may invade the hypothalamus.

In the hypothalamus, as in most regions of the brain, slowly growing lesions may

TABLE II

Central Nervous System Tumors Affecting Hypothalamic Function

Hypothalamic Extra-hypothalamic(Intrinsic) (Extrinsic)G1iomas Cr an iopharyng ioma

Astrocytoma Optic gliomaGlioblastoma PinealomaSpongioblastoma Pineal cyst

Hamartoma HematomaInfundibuloma

478 GARNICA, NETZLO FF AND ROSENBLOOM

achieve considerable size before causing symptoms, while rapidly developing le­sions, even if small, produce significant symptomatology.45 Hypothalamic tumors m ost fre q u e n tly p roduce a lte ra tio n s in e n d o c rin e and m etabo lic p roc ­esses.4,7,32,40 Chronic lesions tend to inter­fere with complex functions requiring the integration of neural information from multiple regions of the brain, and their translation into effector mechanisms such as cognition, caloric balance, fluid bal­ance or endocrine regulation.45 Signs and symptoms of chronic processes are charac­teristically less severe, progress slowly, and often spare at least part of the in­volved anatomic region. Unilateral dam­age seldom causes symptoms or perm a­nent dysfunction in man since either side of the hypothalam us can m aintain the functions regulated by a specific region. T he re la tiv e ly h igh freq u en cy of n e u ro e n d o c rin e ab n o rm alitie s w ith hypothalamic disease can at least partially be attributed to the juxtaposition of paired

TABLE III

Signs and Symptoms of Parasellar Tumors

Age-RelatedPrepubertal: Headache

Vomiting Sexual precocity

Young adults: Sexual infantilismGrowth deficiency Impotence Amenorrhea Loss of libido Obesity

Adults: HeadacheVisual disturbances Hair loss Asthenia

General (Age-unrelated)Frequent: Headache

Visual disturbances Oculomoter dysfunction Endocrine dysfunction

Less frequent: SeizuresFacial painDisturbance of consciousness Temperature instability Blood pressure instability

n e u ro se c re to ry trac ts in th e m ed ian em inence.45

N eoplasm s in the reg ion o f the hypothalamus and pituitary often present with disturbances in visual perception or oculomotor function, headache or endo­crine dysfunction (table HI).33,44,56 Less frequently, the presenting complaints in­clude seizures, facial pain, and distur­bances of consciousness. Am ong the tum ors involv ing this region, cran io ­pharyngiomas and hypothalamic gliomas are most commonly associated with hor­monal disturbances.4,31,32,48 In contrast, endocrine disturbances are less prom i­n e n t in p a tien ts w ith op tic g liom as, meningiomas and suprasellar cysts.4,48

The sym ptom atology observed w ith hypothalamic tumors can be classified ac­cording to the region affected. Diabetes insip idus and hypogonadism are most commonly associated with lesions affect­ing the anterior hypothalamus, including optic glioma, craniopharyngioma, ectopic pinealoma, meningioma of the sphenoid ridge, and infundibuloma (table IV).32,40 In contrast, lesions affecting the posterior hypothalam us, including ham artom as, pinealomas, and ependymomas, are most com m only assoc ia ted w ith sexual precocity.32,40

Among the cases of hypothalamic dis­ease review ed by Bauer, the most fre­quent clinical abnormalities were diabe­tes insipidus and gonadal dysfunction, while thyroid and adrenocortical dysfunc­tion occurred less often.7 Similar findings w ere o b se rv ed in p a tie n ts w ith c ran iopharyng iom a or h y po thalam ic gliomas by Korsgaard et al who reported subnormal gonadotropin secretion in all patients, growth hormone deficiency in 55 percent, adrenocortical hypofunction in 44 percen t and hypothyroidism in 22 percent.31

Craniopharyngiom as produce symp­toms by compressing the hypothalamus or pituitary and disturbing their function. Before p u b e rty , the m ost p ro m in en t

CLIN ICA L M A NIFESTATION S O F H Y PO TH A LA M IC TUMORS 479

sym ptom s seen w ith this tum or are h ead ­ache an d v o m itin g .4, 7,31,32,40,48 Y oung adults dem onstrate prim arily sexual in ­fa n ti l is m , p o o r g ro w th , im p o te n c e , am enorrhea, failing libido, and obesity. O lder adults p resen t w ith headache, vis­ual d isturbances, hair loss, and asthenia. D is tu rb a n c e s o f co n sc io u sn e ss , b o d y te m p e ra tu re o r b lo o d p re s s u re an d polyuria m ay occur.4,45 Sexual precocity occurs rarely.48

Gliom as o f the optic nerve or chiasm and /o r hypothalam us p resen t m ost prom ­inen tly w ith visual d isturbances b u t may also dem onstrate d iabetes insip idus, obe­sity, and lethargy.4,7,32,33 Gliomas o f the th ird ven tric le m ay be associated w ith o b e s ity , h y p o g o n a d ism , d ia b e te s i n ­s ip id u s , sex u a l p re c o c ity , au to n o m ic sym ptom s, tem p era tu re instability , d is­tu rb e d co n sc io u sn ess , an d b eh av io ra l abnorm alities 7’25,31,32,40,45,48 Korsgaard e t al found tha t patien ts w ith optic glioma or sup rase lla r cyst dem onstra ted e ith er norm al endocrine function or im paired g ro w th h o rm o n e a n d g o n a d o tro p in secretion.31

D isturbances o f w ater balance are the m o st w e ll d e s c r ib e d d is o rd e rs o f hypothalam ic function.45,48 T he role of the supraoptic and paraventricular nucle i in AD H synthesis and th e ir re la tionsh ip to neu ro h y p o p h y sis are w ell estab lish ed . T he capacity of nearly any pathologic in ­tracranial process to produce ADH insuf­ficiency, or d iabetes insip idus, has been attribu ted to the anatom ic vulnerability of th e su p rao p tico n eu ro h y p o p h y sia l sys­tem 2 (table V). H ow ever, studies indicate tha t the developm en t of irreversib le d i­abetes insip idus requires a loss of at least 90 p ercen t o f the AD H secreting cells, and im plies tha t a perm anen t loss can resu lt o n ly from d ire c t h y p o th a la m ic d a m ­age.12,25,45 Dysgerm inom a, an infiltrating neop lasm o f the hypothalam us, is said to b e the tum or m ost com m only associated w ith d iabetes insip idus.44 Functional ab­n o rm alitie s o f p o s te rio r p itu ita ry hor-

TABLE IV

Relationship of Endocrine Symptomatology to Hypothalamic Region Affected

ClinicalRegion Presentation Tumor

Anterior Diabetes insipidus Optic gliomaHypogonadi sm Cr an iopharyng ioma

Dysgerminoma Meningioma, sphenoid ridge

Infundibuloma Posterior Sexual precocity Hamartoma

PinealomaEpendymoma

m ones resu lting from intrasellar lesions a re u su a lly m ild and often ca n n o t b e detected .

A variation of ADH insufficiency, es­sential hypernatrem ia, is characterized by hypernatrem ia w ithout fluid deficiency, partial A D H deficiency, p reserv ed renal tu b u la r re s p o n s iv e n e s s to A D H , in ­adequate secretion of ADH in response to osm otic s tim u li, and ab se n ce o f d e f i­c ien c y o f th irs t .4,35,45,55 Such p a tie n ts characteristically m anifest no sym ptom other than a lack of thirst, b u t m ay re ta in habitual drinking, although the volum e ingested may be inadequate to m aintain a no rm al o sm ola lity . W ith in c re a se s in serum sodium above norm al, such pa­tien ts p rogressively d ev e lo p w eakness

TABLE V

Endocrine Disturbances Related to Hypothalamic Dysfunction

Posterior Pituitary (Neurohypophysis) Diabetes insipidus Inappropriate ADH secretion Essential hypernatremia

Anterior Pitui tary (Adenohypophysis) Gonadal dysfunction Sexual precocity Sexual infantilism (hypogonadism)

Growth Disturbance Growth deficiency Growth excess (gigantism)

Adrenocortical insufficiency Hypothyroidism Galactorrhea

480 GARNICA, N E T Z L O F F AND ROSENBLOOM

and fever, m uscle tenderness and cram p­ing, fatigue, ataxia, and even paralysis. M en ta l sy m p to m s in c lu d e le th a rg y , anorexia, depression , paranoia, an d irrita­bility. Sodium concentrations above 180 m E q p e r dl m ay lead to con fusion or stupor, and even death. A bsence o f th irst is essential to the production of essential hypernatrem ia, as an intact th irs t response w ould resu lt in d iabetes in sip idus.45 Al­th o u g h m any p a tie n ts w ith e s s e n tia l h y p e rn a trem ia dem o n stra te no cen tra l nervous system lesion, a few have been found to have tum ors localized to the preoptic anterior hypothalam us and tub- eral region.45,57

A relatively uncom m on m anifestation of parasellar tum or is the syndrom e of in a p p ro p r ia te A D H sec re tio n w h ich in c lu d es serum h y p o n a trem ia , hypo- osmolality, abnorm ally high serum con­c e n tra tio n s of im m u n o reac tiv e A D H , norm al renal excretion of sodium , and an in ap p ro p ria te ly h ig h u rin e osm olality w ithout clinical ev idence o f body fluid dep le tion .15,26,45 T he inappropria te ADH secretion characteristic o f this condition has b een attribu ted to com pression of irri­tation of the hypothalam us.

G onadal d y sfu n c tio n is a re la tiv e ly com m on a b n o rm a lity o b s e rv e d w ith hypothalam ic tum ors. Sexual precocity usually im plies a lesion of the posterior hypothalam us and /o r p ineal gland, w hile hypogonadism is usually associated w ith les io n s o f th e an te r io r h y p o th a lam u s (table IV). Sexual precocity has been attri­b u ted to the d irec t neoplastic involve­m ent of the hypothalam us.7,31,32 An esti­m ated tw o-thirds of the cases o f sexual precocity caused by destructive lesions are associated w ith tum ors caudal to the m edian em inence, com m only hypo thal­am ic h am arto m a or te ra to m a .4,32,44,48 Ham artom as are noninvasive tum ors of d evelopm enta l origin consisting o f e n ­c a p su la ted n o d u le s o f n e rv o u s tis su e attached to the posterior hypothalam us b e tw een the an terior portion of the mam-

m ilary bodies and the posterio r region of the tu b e r cinereum .44,48 H am artom as may produce signs and sym ptom s of sexual precocity before dam age to the surround­ing tissues has occurred, in some instances as early as the age o f th ree m onths.

A lthough neurologic sym ptom s are rare at the tim e sexual precocity is first noted, the m ajority o f patien ts develop progres­sive m anifestations of hypothalam ic in ­v o lv em en t, in c lu d in g h y d ro c e p h a lu s , h e a d a c h e , v isu a l d is tu rb a n c e , p a p i l ­ledem a, obesity, seizures, and behavioral changes lead ing to death before the age of20 years.48 Sexual precocity has also been o b s e rv e d in a s s o c ia tio n w ith p in e a l tum ors ex tending beyond the p ineal re­gion, the m ost com m on being a teratom a c o m p o se d o f w e ll -d if f e re n tia te d t i s ­sues.44,48 T hey may also p roduce clinical ev idence of hypothalam ic invo lvem ent including d iabetes insip idus, polyphagia, obesity, som nolence or behavioral d istur­bances as a resu lt of the tum or causing structural changes in the hypothalam us. A lthough the p ineal gland and surround­ing region are the m ost com m on sites of pinealom as, they m ay also be found in the area of the in fundibulum w here they pro­duce d iab ete s in s ip id u s, v isual d is tu r­bances, and sexual p reco c ity .4,7,31,32,48 T hey may also occur in o ther bra in sites w here th ey may be re ferred to as ectopic pinealom as, a m isnom er. T hey are tera­tom as o f n o n -p in ea l o rig in , s im ila r to those occuring in the p in ea l region b u t are m ore app ropria te ly d esig n ated dysger- minomas. Craniopharyngiomas may induce sexual precocity w ithout associated de­ficiencies o f o ther p itu itary horm ones, al­th o u g h th e y u s u a lly c a u se h y p o ­pitu itarism by destruction o f the pituitary s talk an d v e n tra l h y p o th a la m u s .4,32,48 Gliomas and astrocytom as involving the parasellar or tem poral lobe regions have also b e e n r e p o r te d to c a u se sex u a l precocity.

H ypogonadism secondary to gonado­tro p in d e f ic ie n c y m ay d e v e lo p on a

CLINICAL M A NIFESTATION S O F H Y POTHALA M IC TUM ORS 481

neurogenic basis.1 A lthough such cases are no t associated usually w ith dem onstra­b le structu ra l d isease of the parasellar region, a sm all proportion has b een re­ported w ith neoplasm s. Possibly the m ost w e ll-k n o w n o f th e se is th e B abinski- F ro lic h sy n d ro m e , w h ich co n sis ts o f hypogenitalism and obesity and is gener­ally though t to resu lt from lesions involv­in g th e b a sa l h y p o th a la m u s a n d th e m edian em in en ce .3,13,19,22 T he original report was o f an individual with a cranio­pharyngiom a, b u t the condition may be asso c ia ted w ith o th e r d iso rd e rs .22,45,48 Dam age to the ventrom edial region re ­su lts in g o n ad o tro p in d e fic ien cy . Al­though hypogonadism is frequen tly as­sociated w ith hypothalam ic obesity, it can be separated from it experim entally by le ­sions restric ted to the m edian em inence.45

Galactorrhea, ano ther endocrine disor­d e r o f c e n tra l o rig in , is g en e ra lly a s ­sociated w ith am enorrhea.21,32,48,50 It can be seen secondary to anatom ic lesions in ­v o lv in g th e h y p o th a lam u s , in c lu d in g transection of the p itu itary stalk, m eta­static carcinom a or prim ary tum ors of the p itu ita ry or h y p o th a lam u s.48 T h e p re ­sum ed pathogenesis of this condition is an in terference w ith areas concerned w ith the production of prolactin inhibitory fac­tor, w hich results in an increase in prolac­tin secretion by the pituitary. Franks e t al found increased serum prolactin levels in 70 p ercen t of th e ir patients w ith “ func- t io n le s s ” p i tu ita ry tu m o rs p r io r to surgery.21

G row th fa ilu re is th e m ost com m on m anifesta tion o f grow th horm one defi­ciency in childhood, and hypothalam ic disorders are a w ell-recognized cause of grow th horm one defic iency . H ow ever, few er than one-fourth of growth horm one d efic ien t p a tien ts have b ee n show n to have organic hypothalam ic or hypophy­sea l le s io n .11, 16,31,40,48 O f th e tu m o rs c a u s in g g ro w th h o rm o n e d e f ic ie n c y , craniopharyngiom a is the m ost common; o ther tum ors are uncom m on.16

G row th horm one excess may also occur, causing gigantism in childrem or acromeg­aly in adults.16,38,56 Classically, acrom eg­aly and gigantism have been considered to b e caused by eosinophilic adenom as of the an terior pituitary. H ow ever, the ob­servation tha t som e patients w ith chronic grow th horm one hypersecre tion do not have adenohypophyseal tum ors suggests that chronic grow th horm one h y persecre­tion and som atotrope proliferation m ay resu lt from a defect in the hypothalam ic control of grow th horm one secretion .38,56 It is now ap p a ren t th a t th e signs and sym ptoms of growth horm one h y persecre­tion , accom pan ied by e lev a ted p lasm a growth horm one levels, may long p recede any ev idence of p itu itary adenom a and may be re la ted to a prim ary hypothalam ic disturbance causing an inappropria te se­cretion o f growth horm one re leasing fac­tor. Several cases of hypothalam ic tum or w ith e leva ted growth horm one levels are com m only found in the d iencephalic syn­drom e of early infancy, a condition alm ost invariably associated w ith gliom a o f the an terior hypothalam us.38,40,43,45

N on-endocrine D isturbances

T he d ien cep h alic syndrom e was d e ­scrib ed o rig inally as a com bination of severe emaciation, nystagmoid eye move­m ents, and inappropria te affective be-

TABLE VI

Non-Endocrine Disturbances Related to Hypothalamic Dysfunction

Disturbances of Consciousness Emotional Disturbances Weight Disturbances (Caloric Balance) Anorexia nervosa Obesity

Thermoregulatory Dysfunction Hyperthermia Hypothermia

Autonomic Dysfunction Blood pressure instability Autonomic "seizures"

Complex Disturbances or Syndromes Diencephalic syndrome Hypothalamic syndrome (acute lymphoblastic leukemia)

482 GARNICA, N E T Z L O F F AND ROSENBLOOM

havior in infants b e tw een th e ages o f 12 a n d 18 m o n th s , m o st co m m o n ly a s­sociated w ith an invasive tum or of the hypothalam us or one involving the an­te r io r h y p o th a lam u s (tab le V I ).24-45-51 Tum ors of the d iencephalon in infants m ay p r e s e n t w ith e m a c ia tio n an d euphoria or, less com m only, autonom ic seizures.48 T he hypothalam us is usually d e s tro y e d co m p le te ly by th e tim e o f death, b u t studies indicate tha t the tum ors a r ise in th e o p tic ch iasm or a n te r io r hypothalam us and are confined to the an­terior an d tuberal regions a t the onse t of sym ptom s.43,48 A ffected in fan ts usually are alert, cheerfu l and hyperactive, m ain­tain a good appetite and grow to an age- appropriate height, desp ite severe w ast­ing.48,51

Although the m echanism of the em acia­tion has not b een characterized, these ob­servations suggest that it is not m erely a consequence of hypophagia or one com­p onen t o f general grow th failure.45 T he decrease in subcutaneous fat has b een postu lated to be re la ted to hypothalam ic d y sfu n c tio n , p o s s ib ly in v o lv in g a fat m o b iliz in g su b s ta n c e as y e t u n id e n ­tified .34,48 E ndocrine studies have been found to be norm al except for elevated g row th h o rm o n e , w h ich is com m only found in this d isorder.38,40,45 T he finding o f high grow th horm one levels in patients w ith sy m p to m a tic h y p o g ly c e m ia and em aciation has prom pted the im plication o f the lipolytic properties o f grow th hor­m o n e as a fa c to r c a u s in g e m a c ia ­tion 34-38>40>45

A lthough affected patien ts usually do no t survive beyond th e ir second birthday, the few th a t do often undergo a qualitative transform ation in sym ptom atology.24 W ith con tinued good appetite and intake, the child may develop hypothalam ic obesity, a finding rarely seen in infants younger than two years of age. Irritab ility m ay re­place the euphoria characteristic of the earlier m onths, and the prognosis for sur­vival is greatly im proved.45 W hether the

change in sym ptom atology is due to the m etabolic changes occurring at that age or the grow th characteristics of the tum or is unclear. I t is no t know n w hy the im m a­tu re , in fan tile h y po tha lam us p roduces sym ptom s d ifferen t from those seen in the o lder ch ild and adult. T he few reported adu lts w ith h y p o th a lam ic d isease and em aciation have dem onstrated anorexia and hypophagia and, by the tim e of au­topsy, th e responsib le lesion has usually destroyed the en tire hypothalam us.45

A lthough anorexia nervosa is usually assum ed to be a psychogenic d isorder, patients with this condition may dem on­strate abnorm alities o f hypothalam ic func­tion, th e etiology of w hich are no t d e ­fined .9,18,45,60 T he characteristic anorexia, w eight loss, am enorrhea, and decreased lu te in iz ing horm one/fo llicle stim ulating horm one (L H /FSH ) levels are associated w ith decreased secretion of gonadotropin re le a s in g h o rm o n e from th e h ypo- thalm us,9,60 M ost patien ts exam ined at au­topsy have had m orphologically norm al b ra in s , a lth o u g h ra re cases o f poo rly localized hypothalam ic tum ors have been reported .17,36

In the repo rt o f M enezes e t al, abnor­m alities o f body w eigh t occurred in 75 p ercen t of patien ts .40 A lthough m ore than 50 p ercen t failed to gain w eight, four pa­tien ts p re sen ted w ith excessive w eight g a in a s s o c ia te d w ith n o rm a l l in e a r growth. O besity is a w ell-know n m anifes­tation of hypothalam ic tum or, especially in patien ts beyond the infant age group, and it is o ften a sso c ia ted w ith h y p o ­gonadism .13,45,47 T he neoplasm m ost com­m only im p lica ted in th is syndrom e is craniopharyngiom a, as in the original re ­po rt o f Frolich , b u t the syndrom e may be associated w ith o ther lesions.13,22,45

The B abinski-Frolich syndrom e w hich consists of hypogenitalism and obesity is generally thought to resu lt from lesions involving the basal hypothalam us and the m edian em in en ce .3,13,22,45,48 D am age to the ventrom edial region results in obe­

CLINICAL M A NIFESTATION S O F H Y PO TH A LA M IC TUMORS 4 8 3

sity, w hile destruction o f the m edian em i­n e n c e re s u lts in g o n a d o tro p in d e f i­ciency.45 M ost patien ts w ith hypothalam ic o b e s ity , in c lu d in g th o se w ith th e B ab insk i-F ro lich syndrom e, have b een dem onstrated at autopsy to have lesions in v o lv in g th e m a jo rity o f th e h y p o ­th a la m u s , a lth o u g h th e p o s te r io r h y p o th a la m u s h as f r e q u e n tly b e e n spared .45' 47 O ccasional cases have been associated w ith severe, b ilateral leukem ic in f i l tr a t io n o f th e p e r iv e n tr ic u la r hypothalam us, especially the ventrom ed­ial region.6,27 M arked hyperphagia, obe­sity and aggressive behavior in a young w om an w ere show n to b e associated w ith a ham artom a com pletely and specifically d e s tro y in g th e v e n tro m e d ia l h y p o ­th a lam u s.47 In d iv id u a ls w ith hyp o th al­amic obesity differ from norm als and from those w ith essen tial obesity in th a t they consum e m ore calories than they expend only du ring th e period o f w eight gain.45 O nce a new set-point is achieved, the ex­ce ss iv e a p p e ti te su b sid es , u n le ss the etiologic lesion progresses.

T he hypothalam us is also subject to in ­volvem ent by non-central nervous system n eo p lasm s. Tw o w e ll-reco g n ized syn­drom es caused by cellu lar infiltration of the hypothalam us and surrounding struc­tures are know n to occur in patients w ith H and-Schuller-C hristian disease or acute leukem ia. T he hypothalam ic involvem ent in H and-Schu ller-C hristian d isease has b een characterized as a d isorder affecting th e hy p o th a lam u s, p itu ita ry stalk , and posterior p itu itary b u t sparing the anterior p itu itary .50 D iabetes insip idus is the most com m on m anifestation of the histiocytic infiltration of the hypothalam us seen with H a n d -S c h u lle r-C h ris tia n d isease , b u t g row th ho rm o n e d efic ien cy , h y p o th y ­ro id ism , h y p o g o n a d o trô p ism , hypo- a d ren o co rtica lism , an d h y p e rp ro la c ti­n e m ia h av e a lso b e e n r e p o r te d .10,50 Sym ptom atic hypothalam ic involvem ent in acute lym phoblastic leukem ia occurs uncom m only, p resen tin g initially w ith a

m arked increase in appetite and w eight gain un re la ted to corticosteroid therapy and progressing to signs and sym ptom s of increased intracranial pressure associated w ith diffuse, pronounced leukem ic infil­tration of the hypothalam ic tissues, par­ticularly at the level of the ventrom edial nucleus.6,27 L eukem ic involvem ent is less com m only associated w ith hypogonadism and behavioral abnorm alities.6,27

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