Global Hypothalamic Syndromes
A variety of lesions can invade and destroy all or a large part of the hypothalamus. These include sarcoid and other granulomatous diseases, an idiopathic inflammatory disease, and germ-cell and other tumors. The hypothalamus is involved in approximately 5 percent of cases of sarcoidosis, sometimes as the primary manifestation of the disease, but more often in combination with facial palsy and hilar lymphadenopathy. The lesion may be visible by MRI (see Fig. 32-2).
Tumors that involve the hypothalamopituitary axis include metastatic carcinoma, lymphoma, craniopharyngioma, and a variety of germ-cell tumors. The last category (reviewed by Jennings et al) includes germinomas, teratomas, embryonal carcinoma, and choriocarcinoma. They develop during childhood, tend to invade the posterior hypothalamus, and are accompanied in some instances by an increase in serum alpha-fetoprotein or the beta subunit of chorionic gonadotropin. A unique syndrome of gelastic epilepsy is caused by a hamartoma of the hypothalamus (see Chap. 16).
Among the inflammatory conditions, infundibuloneurohypophysitis, or infundibulitis, is a cryptogenic inflammation of the neurohypophysis and pituitary stalk, with thickening of these parts by infiltrates of lymphocytes (mainly T cells) and plasma cells (Imura et al). It is thought to be an autoimmune disorder. Histiocytosis X—a group of diseases comprising Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma—implicates multiple organs, including the hypothalamus and neighboring structures and leptomeninges (often causing cells to appear in the cerebrospinal fluid [CSF]). These conditions of children pursue an indolent course. The cell type is a proliferating histiocyte. The obscure infiltrative and inflammatory condition, Erdheim-Chester disease, can also involve this region sometimes with proptosis, but is primarily a bone disease.
Partial Hypothalamic Syndromes
This is a state of polyuria with dilute urine and polydipsia that results in the loss of action of antidiuretic hormone. As long ago as 1913, Farini of Venice and von den Velden of Dusseldorf (quoted by Martin and Reichlin) independently discovered that diabetes insipidus was associated with destructive lesions of the hypothalamus. They showed, moreover, that in patients with this disorder, the polyuria could be corrected by injections of extracts of the posterior pituitary. Ranson elucidated the anatomy of the neurohypophysis; the Scharrers traced the posterior pituitary secretion to granules in the cells of the supraoptic and paraventricular nuclei and followed their passage to axon terminals in the posterior lobe of the pituitary. As mentioned in the introductory section, DuVigneaud and colleagues determined the chemical structure of the two neurohypophyseal peptides, vasopressin and oxytocin, of which these granules were composed.
As already stated, the usual cause of DI is a lack of vasopressin (ADH) as a result of a lesion of the neurohypophysis. This leads to a reduction in its action in the kidneys, where it normally promotes the absorption of water. As a consequence, there is diuresis of low-osmolar urine (polyuria), reduction in blood volume, and increased thirst and drinking of water (polydipsia) in an attempt to maintain osmolality. A congenital abnormality of renal tubular epithelium or destruction of the epithelium has a similar effect—nephrogenic DI. DI is also of interest to the neurologist because of its association with lithium toxicity, which impairs renal tubular water absorption.
Among the established causes of acquired DI, the most important are brain tumors, infiltrative granulomatous diseases, head injury, and intracranial surgical trauma (which has become less frequent with the transsphenoidal approach to pituitary tumors). In a series of 135 cases of persistent DI reported by Moses and Stretten, 25 percent were idiopathic, 15 percent complicated primary brain tumors, 24 percent were postoperative (mostly after hypophysectomy or surgery for craniopharyngioma), 18 percent were caused by head trauma, and fewer than 10 percent were associated with intracranial histiocytosis, metastatic cancer, sarcoidosis, and ruptured aneurysm. Granulomatous infiltration of the base of the brain by sarcoid, eosinophilic granuloma, Letterer-Siwe disease, or Hand-Schüller-Christian disease, is a more frequent cause of DI in young patients. Of the primary tumors, glioma, hamartoma and craniopharyngioma, granular cell tumor (choristoma), large chromophobe adenomas, and pinealoma are notable. The primary tumors can present with DI alone, whereas the granulomatous infiltrating processes generally exhibit other systemic manifestations before polydipsia and polyuria appear. Metastatic tumors originating in the lung or breast or leukemic and lymphomatous infiltration may also cause DI, sometimes in conjunction with pituitary disturbances and impairment of vision. The mild global hypothalamic dysfunction that often follows brain irradiation for glioma may occasionally include DI as a feature. The most extreme cases of hypothalamic destruction occur in brain death, in which DI is a regular component, although it is not always evident at the time brainstem reflexes are lost.
Pituitary tumors are infrequently associated with DI unless they become massive and invade the stalk of the pituitary and the infundibulum. This anatomic relationship was substantiated in past years by surgical sections of the stalk for metastatic carcinoma and for retinitis proliferans, which result in DI only if the section is high enough to produce retrograde degeneration of supraoptic neurons.
Among the idiopathic forms of DI, there also exists a congenital type of hypothalamic DI, of which only a small number of familial cases have been described. The disorder is evident at an early age and persists throughout life owing to a developmental defect of the supraoptic and paraventricular nuclei and smallness of the posterior lobe of the pituitary. This defect has been related in some cases to a point mutation in the vasopressin-neurophysin-glycopeptide gene. It may be combined with other genetic disorders such as diabetes mellitus, optic atrophy, deafness (Wolfram syndrome), and Friedreich ataxia.
Acquired idiopathic DI may occur at any age, most often in childhood or early adult life and more often in males, and by definition has no apparent cause. Other signs of hypothalamic or pituitary disease are lacking in 80 percent of such patients, but steps must be taken to exclude other disease processes by repeating endocrine and radiologic studies periodically. In some cases of idiopathic DI, there are serum antibodies that react with the supraoptic neurons, raising the question of an autoimmune disorder. In a few such instances, postmortem examination has disclosed a decreased number of neurons in the supraoptic and paraventricular nuclei. Also, anorexia nervosa is often associated with mild DI.
Finally, it should be mentioned that certain drugs used in neurologic practice—for example, carbamazepine—may be the cause of reversible DI (excessive secretion of ADH is more common in relation to this drug) and, as mentioned, lithium regularly causes DI, even at times at the upper range of its therapeutic serum concentration.
In all these conditions, the severity and permanence of the DI are determined by the nature of the lesion. In cases of acute onset, three phases have been delineated: First, a severe DI lasting days; then, as the neurohypophysis degenerates, a reduction in severity of DI or even the opposite, hyponatremia from excessive hormone, as a result of the release of stored ADH and, finally, a persistent pattern, usually lifelong. The neurohypophyseal axons can regenerate, allowing for some degree of recovery even after years.
Diagnosis of Diabetes Insipidus
This is always suggested by the passage of large quantities of dilute urine accompanied by polydipsia and polyuria lasting throughout the night. The thirst mechanism and drinking usually prevent dehydration and hypovolemia, but if the patient is stuporous or the thirst mechanism is inoperative, severe dehydration and hypernatremia can occur, leading to coma, seizures, and death. In an unresponsive patient careful measurement of fluid output and input are needed to expose the disorder.
A low urine osmolality and specific gravity are found in DI, in conjunction with high serum osmolality and sodium values. Osmotic dehydration as a cause of the polydipsia–polyuria syndrome, such as occurs with the glycosuria of diabetes mellitus must, of course, be excluded. A period of 6 to 8 h of dehydration increases urinary osmolality in a person with normal kidneys and neurohypophysis; it is this change in urine concentration that is most useful in the differential diagnosis of polyuria, particularly in distinguishing compulsive water drinkers from those with DI; in the latter group, urinary volume and serum electrolytes normalize with dehydration. Proof that the patient has a central cause of DI and not nephrogenic unresponsiveness to vasopressin is obtained by injecting 5 U of vasopressin (Pitressin) subcutaneously; this will diminish urine output and increase osmolality when there is a central cause of DI. Diagnosis is also aided by the radioimmunoassay for plasma ADH; ADH is usually reduced to less than 1.0 pg/mL in patients with central DI (normal: 1.4 to 2.7 pg/mL).
Treatment of Diabetes Insipidus
Vasopressin tannate in oil, synthetic vasopressin nasal spray, and a long-acting analogue of arginine vasopressin (desmopressin [DDAVP]) administered by nasal insufflation (10 to 20 mg or 0.1 to 0.2 mL) are used to control chronic DI. The nasal form is generally preferred because of its long antidiuretic action and few side effects. In unconscious patients, aqueous vasopressin, 5 to 10 U given subcutaneously, is effective for 3 to 6 h; DDAVP, 1 to 4 mg subcutaneously, is effective for 12 to 24 h. These drugs must be given repeatedly, guided by urine output and osmolality (we have given these drugs intravenously in critical situations). The brief duration of action of the medication is advantageous in postoperative states and after head injury, for it allows the recognition of recovery of neurohypophyseal function and the avoidance of water intoxication. If a longer duration of treatment is anticipated, one uses vasopressin tannate in oil (2.5 U), the action of which persists for 24 to 72 h. In the unconscious patient, great care must be taken in the acute stages to replace the fluid lost in the urine, but not to the point of water intoxication. These problems can be avoided by matching the amount of intravenous fluids to the urinary volume and by evaluating serum and urine osmolalities every 8 to 12 h. This pertains even if a patient is receiving concurrent ADH analogues. For patients with partial preservation of ADH function, chlorpropamide, clofibrate, or carbamazepine can be used to stimulate release of the hormone.
Syndrome of Inappropriate Antidiuretic Hormone Secretion
As mentioned, blood volume and osmolality are normally maintained within narrow limits by the secretion of ADH and the thirst mechanism. A reduction in osmolality of even 1 percent stimulates osmoreceptors in the hypothalamus to decrease ADH and to suppress thirst and drinking; increased osmolality and reduced blood volume do the opposite. Normally, blood osmolality is about 282 mmol/kg and is maintained within a very narrow range. Release of ADH begins when osmolality reaches 287 mmol/kg (the "osmotic threshold"). At this point, plasma ADH levels are 2 pg/mL and increase rapidly as the osmolality rises. The response of ADH secretion to hyperosmolality is not the same for all plasma solutes; in contrast to hypernatremia, for example, hyperosmolality induced by elevations in urea nitrogen or endogenous glucose produce minimal or no elevations in ADH.
Derangement of this delicately regulated mechanism, taking the form of dilutional hyponatremia and water retention without edema, is observed under a variety of clinical circumstances in which the plasma ADH is above normal or inappropriately normal despite plasma hypoosmolality. The term inappropriate secretion of antidiuretic hormone (SIADH) was applied to this syndrome by Schwartz and Bartter because of its similarity to that produced in animals by the chronic administration of ADH. The same syndrome can arise from ectopic production of the hormone by tumor tissue. In such cases, the thirst mechanism is not inhibited by decreased osmolality, and continued drinking further increases blood volume and reduces its solute concentration; ADH levels are found to be persistently elevated. The physiologic hallmarks of this condition are a concentrated urine, usually with an osmolality above 300 mOsm/L, and low serum osmolality and sodium concentrations. Because of the dilutional effects, urea nitrogen and uric acid are reduced in the blood and serve as markers for excessive total body water. Tissue edema is not seen because sodium excretion in the urine is maintained by suppression of the renin–angiotensin system and by an increase in atrial natriuretic peptide secretion (see below).
SIADH is observed frequently with a variety of cerebral lesions (infarct, tumor, hemorrhage, meningitis, encephalitis) that do not involve the hypothalamus directly and with many types of local hypothalamic diseases (trauma, surgery, vascular lesions). In most cases, it tends to be a transient feature of the underlying illness. The acute dysautonomia of Guillain-Barré syndrome is a common neurologic cause of SIADH; it is ostensibly the result of the neuropathy affecting the afferent nerves from volume receptors in the right atrium and jugular veins. (Hyponatremia is particularly likely to occur in such patients on positive-pressure ventilation.) The increased thoracic pressure induced by positive-pressure ventilation promotes SIADH in susceptible patients. Acute porphyric episodes have the same effect. Neoplasms, particularly small cell tumors, and sometimes inflammatory lesions of the lung, may elaborate an ADH-like substance, and certain drugs—such as carbamazepine, chlorpromazine, chlorothiazide, chlorpropamide, clofibrate, nonsteroidal antiinflammatory agents, and vincristine—also stimulate ADH release and may lead to hyponatremia. In some cases, no cause or associated disease is apparent.
A fall in serum sodium to 125 mEq/L usually has few clinical effects, although signs of an associated neurologic disease, such as a previous stroke or a subdural hematoma, may worsen. Sodium levels of less than 120 mEq/L are attended by nausea and vomiting, inattentiveness, drowsiness, stupor, and generalized seizures. There may be asterixis. As is characteristic of most metabolic encephalopathies, the more rapid the decline of the serum sodium, the more likely there will be accompanying neurologic symptoms.
The rapid restitution of serum sodium to normal or above-normal levels carries a risk of producing an osmotic demyelination (also called central pontine myelinolysis; see Chap. 40). Our usual procedure in patients with serum sodium concentrations of 117 to 125 mEq/L is to slowly correct the sodium concentration by restricting water to 400 to 800 mL/d and to verify the desired urinary loss of water by checking the patient's weight and serum sodium until it reaches approximately 130 mEq/L. If there is drowsiness, confusion, or seizures that cannot be confidently attributed to the underlying neurologic illness, or if the serum sodium is in the range of 100 to 115 mEq/L, isotonic or 3 percent NaCl should be infused over 3 to 4 h and furosemide 20 to 40 mg administered to prevent fluid overload. A safe clinical rule is to raise the serum sodium by no more than 12 mEq/L in the first 24 h and by no more than 20 mEq/L in 48 h so as to prevent myelinolysis.
Neurogenic (Cerebral) Salt Wasting (Nelson Syndrome)
A moderate reduction in the serum sodium concentration is a common finding in patients with acute intracranial diseases and postoperatively in neurosurgical patients. Originally it was described as a "cerebral salt-wasting" syndrome by Peters and colleagues and later was erroneously identified with the then newly described Schwartz-Bartter syndrome of SIADH. In recent years it has again come to be recognized as being a result of natriuresis and not of water retention caused by ADH secretion. As Nelson and colleagues demonstrated many years ago, neurosurgical patients with hyponatremia have a reduction in blood volume, suggesting sodium loss rather than water retention. This distinction has important clinical implications because the use of fluid restriction with the intention to treat SIADH can have disastrous results if a state of volume contraction exists from salt wasting.
One leading hypothesis concerning the mechanism of hyponatremia in these cases is secretion of another oligopeptide, atrial natriuretic factor (ANF) that is found mainly in the walls of the cardiac atria but also in neurons surrounding the third ventricle in the anteroventral hypothalamic region. Physiologically, ANF activity opposes that of ADH in the kidney tubules and also has a potent inhibitory effect on ADH release from the hypothalamus; i.e., it causes a natriuresis (see review by Samson). ANF, like some other neural peptides, is secreted in bursts, and the natriuresis is evident only if total urinary sodium content is measured over many hours or days.
The role of ANF in causing the hyponatremia that follows subarachnoid hemorrhage is controversial (see Wijdicks et al and Diringer et al for opposing views), but it is our experience that the hyponatremia in this condition is the result mainly of salt loss, not water retention. Because fluid restriction after subarachnoid hemorrhage may precipitate cerebral ischemia from vasospasm, the proper approach is to maintain normal intravascular volume with intravenous fluids and to correct hyponatremia by infusion of normal saline.
In addition to head trauma, salt wasting has also been reported with cerebral tumors, after pituitary surgery, and in the dysautonomia of Guillain-Barré syndrome, conditions that have also been associated at times with SIADH. As already stated, in each of these disorders, should the patient be hyponatremic, it is desirable to determine the intravascular volume and the urine sodium output before instituting treatment.
Other Disturbances of Antidiuretic Hormone and Thirst
Conditions have been described in which the osmoreceptor control of ADH and of thirst appear to be dissociated. As reported by Hayes and coworkers, one of our colleagues' patients repeatedly developed severe hypernatremia (levels as high as 180 to 190 mEq/L), at which time he became confused and stuporous. Although the patient was able to initiate a release of ADH, his thirst mechanism was nonfunctional. Only when the patient was compelled to drink water at regular intervals did his serum sodium fall. Robertson and others have described similar cases with abnormalities of thirst. These have been reported under the title of "central" or "essential" hypernatremia.
Loss of function of the anterior pituitary gland may result from disease of the pituitary itself or from hypothalamic disease. In either event, it leads to a number of clinical abnormalities, each predicated on the deficiency of one or more hormones that depend on the pituitary trophic factors described earlier. The condition of panhypopituitarism represents the more serious illness in that it requires supplementation with multiple hormones. Hypopituitarism may have its onset in childhood, either as an inherited process that affects individual or multiple hormones or as a secondary process caused by a destructive lesion of the pituitary or the hypothalamus from tumor, e.g., craniopharyngioma. Later in life the causes vary, but the most common are pituitary surgery, infarct of the gland from a rapidly growing adenoma (pituitary apoplexy, see "Pituitary Apoplexy" in Chap. 31), involutional changes that occur at the end of pregnancy (Sheehan syndrome), cranial irradiation for cerebral tumors other than those in the pituitary fossa, lymphocytic hypophysitis, and granulomatous and neoplastic invasion.
The clinical features of pituitary failure vary, but impairments of thyroid function tend to be more prominent than those of adrenal failure. The neurologic accompaniments of pituitary failure depend on the underlying cause; Lamberts and colleagues have reviewed the endocrinologic aspects and a detailed discussion can be found in Harrison's Principles of Internal Medicine.
Other Hypothalamic Syndromes
Apart from DI and SIADH, there are a variety of other special clinical phenomena resulting from disease of the hypothalamus. These usually occur not in isolation but in various combinations, comprising a number of rare, but well-characterized, syndromes.
This term refers to the abnormally early onset of androgen secretion and spermatogenesis in boys and of estrogen secretion and cyclic ovarian secretion in girls. It is associated with the premature development of secondary sexual characteristics. The occurrence of precocious puberty always calls for a neurologic as well as an endocrine investigation. In the male, one searches for evidence of a teratoma of the pineal gland or mediastinum or an androgenic tumor of the testes or adrenals. In the female with early development of secondary sexual characteristics and menstruation, one seeks other evidence of hypothalamic disease, as well as an estrogen-secreting ovarian tumor.
A hamartoma of the hypothalamus (part of von Recklinghausen disease, or of polyostotic fibrous dysplasia of McCune-Albright syndrome) is a leading cause of precocious puberty in both boys and girls; in a number of such cases, so-called gelastic seizures have been conjoined (Breningstall, see "Complex Partial Seizures" in Chap. 16). Neurologic study entails CT and MRI imaging of the hypothalamus, ovaries, and adrenals.
Several genetic conditions can lead to failure of puberty. Kallman syndrome is a type of hypogonadotropic hypogonadism that is associated with anosmia. GnRH-secreting neurons formed in the olfactory placode migrate across the cribriform plate into the olfactory bulb and ultimately reside in the hypothalamus. In Kallman syndrome, the olfactory bulb does not develop normally, leading to loss of hypothalamic control of FSH and LH release, and failure of puberty to initiate, as well as anosmia. Several causative X-linked and autosomal dominant gene mutations have been discovered.
Prader-Willi syndrome, discussed in Chap. 38, is associated with hypogonadism and incomplete sexual development along with other endocrine abnormalities affecting growth and satiety. The Bardet-Biedl syndrome is a heterogenous disorder affecting multiple organ systems. Variable growth retardation, obesity, and diabetes mellitus are seen, along with hypogonadism and anosmia. The causative mutations affect ciliary function at several sites.
Adiposogenital Dystrophy (Froehlich Syndrome)
Under this title, in 1901, Froehlich first described the association of obesity and gonadal underdevelopment. He related the disorder to a pituitary tumor. But a few years later, Erdheim recognized that the same syndrome could be a manifestation of a lesion (a suprasellar cyst in his case) involving or restricted to the hypothalamus. Later it was determined that obesity and hypogonadism could occur together or separately and were often combined with a loss of vision and unprovoked rage, aggression, or antisocial behavior. DI may be added. In some patients, the clinical state is characterized by abulia, apathy, and reduced verbal output. The usual causes of the Froehlich syndrome are craniopharyngioma, adamantinoma, and glioma, but many other tumors have been reported (pituitary adenoma, cholesteatoma, lipoma, meningioma, glioma, angiosarcoma, and chordoma). The condition bears clinical similarities to the Prader-Willi syndrome, in which hypothalamic abnormalities are not found, as discussed in Chap. 38.
Hypothalamic Disorders Associated with Alterations in Weight
Neuroanatomic studies have localized a satiety center in the ventromedial nucleus of the hypothalamus and an appetite center in the ventrolateral nucleus. Lesions in the lateral hypothalamus may result in a failure to eat and, in the neonate, failure to thrive; lesions in the medial hypothalamus may result in overeating and obesity. Bray and Gallagher, who analyzed 8 cases of the latter type, concluded that the critical lesion was bilateral destruction of the ventromedial regions of the hypothalamus. Most of the reported cases of this type have been caused by tumors, particularly craniopharyngioma, and some to trauma, inflammatory disease, and hydrocephalus (Suzuki et al). In a case that was subject to clinicopathologic correlation, Reeves and Plum found that a hamartoma had destroyed the medial eminence and the ventromedial nuclei bilaterally but spared the lateral hypothalamus. Hyperphagia and rage reactions were the main clinical features; the associated polydipsia and polyuria were due to extension of the tumor to the anterior hypothalamus. It is evident that in only a tiny fraction of people can obesity be traced to a hypothalamic lesion. Of overriding importance are genetic factors, such as the number of lipocytes that one inherits and their ability to store fat.
A disorder of infants has been described under the name diencephalic syndrome. Progressive and ultimately fatal emaciation (failure to thrive), despite normal or near-normal food intake, in an otherwise alert and cheerful infant is the main clinical feature. The lesion has usually proved to be a low-grade astrocytoma of the anterior hypothalamus or optic nerve (Burr et al).
Extrahypothalamic parts of the brain, if diseased, may also be associated with increased food-seeking behavior, food ingestion, and weight gain. Examples are involvement of limbic structures, as in the Klüver-Bucy syndrome and basal frontal lobe lesions leading to gluttony. Indeed, the primacy of hypothalamic lesions in causing pathologic weight gain has been challenged in a review of published cases by Uher and Treasure.
Anorexia Nervosa and Bulimia
The special syndromes called anorexia nervosa and bulimia have been difficult to classify and are mentioned in this chapter only because they are associated with alterations in several hypothalamic functions, including appetite, temperature control, and menstruation. In all likelihood, these alterations are not the result of a primary dysfunction of hypothalamic nuclei but are secondary to the extreme weight loss, which is the primary feature of the disease. However, a causal link between these idiopathic diseases and hypothalamic dysfunction has been suggested by the rare patients with an anorexia nervosa syndrome who were later found to have hypothalamic tumors (Bhanji and Mattingly; Berek et al; and Lewin et al).
Anorexia nervosa and bulimia are probably best regarded as disorders of behavior, in this case an obsession with thinness; consequently, they are discussed with the psychiatric disorders (see Chap. 56). But the developmental nature of the disease (arising in early adolescence), its virtual absence in men, and the hypothalamic alterations mentioned above do not allow the dismissal of a primary disorder of the brain's appetite centers.
Presumably, in most instances of growth retardation, there is a deficiency of GHRH or of GH per se. In the Prader-Willi syndrome (obesity, hypogonadism, hypotonia, mental retardation, and short stature), Bray and Gallagher found the deficiency to be one of GHRH. In certain congenital and developmental diseases, the hypothalamus appears to be incapable of releasing GH. This appears to be the case in the de Morsier septooptic defect of the brain (median facial cleft, cavum septum pellucidum, optic defect), as Stewart and colleagues found an isolated deficiency of GH. In children with idiopathic hypopituitarism in whom stunting of growth is associated with other endocrine abnormalities, the deficiency is probably in the synthesis or release of GHRH. In some dwarfs (Laron dwarf, Seckel bird-headed dwarf), there are extremely high levels of circulating GH, suggesting either a defect in the GH molecule or an unresponsiveness of target organs. Many patients with the more severe forms of mental retardation are subnormal in height and weight, but the explanation for this has not been ascertained. It has not been reducible to changes in the level of GHRH or GH.
Of course, the vast majority of unusually short children who are otherwise healthy do not have a recognizable defect in GH or GHRH. Often their parents are short. The therapeutic use of GH in such children is a controversial matter. The hormone effects a spurt in growth during the first year of its administration, but whether it significantly influences growth in the long term is still under investigation. There is concern about the risk of transmitting prion or viral diseases through administration of the biologically derived hormone; this problem is obviated if a genetically produced hormone is used.
In gigantism, most of the reported cases have been caused by pituitary adenomas that secrete an excess of GH. This must occur prior to closure of the epiphyses. Hypersecretion of GH after closure of the epiphyses results in acromegaly. The notion of a purely hypothalamic form of gigantism or acromegaly (hypothalamic acromegaly) has been affirmed by Asa and associates, who described 6 patients with hypothalamic gangliocytomas that produced GHRH. The possibility of an ectopic source of GH must also be considered. The mentally retarded individuals with gigantism described by Sotos and coworkers were found to have no abnormalities of GHRH, GH, or somatomedin.
Disturbances of Temperature Regulation
Bilateral lesions in the anterior parts of the hypothalamus, specifically of temperature-sensitive neurons in the preoptic area, may result in hyperthermia. The heat-dissipating mechanisms of the body, notably vasodilatation and sweating, are impaired. This effect has followed operations or other trauma in the region of the floor of the third ventricle but we have seen it most often after massive rupture of an anterior communicating artery aneurysm. The temperature rises to 41°C (106°F) or higher and remains at that level until death some hours or days later, or it drops abruptly with recovery. Acetylsalicylic acid has little effect on central hyperthermia; the only way to control it is by active evaporative cooling of the body while administering sedation. A less-dramatic example of the loss of natural circadian temperature patterns is seen in patients with postoperative damage in the suprachiasmatic area (Cohen and Albers) and suprachiasmatic metastasis (Schwartz et al). These types of lesions are invariably associated with other disorders of intrinsic rhythmicity, including sleep and behavior. It should be emphasized, however, that instances of "central fever" are rare, and unexplained fever of moderate degree should not be attributed to an existing or putative brain lesion.
Hyperthermia is also part of the malignant hyperthermia syndrome, in which, in a limited number of cases, there is an inherited (autosomal dominant) susceptibility to develop hyperthermia and muscle rigidity in response to inhalation anesthetics and skeletal muscle relaxants ("Malignant Hyperthermia" in Chap 54). In some of these instances, it has been found to be caused by a defective ryanodine receptor. Closely related is the neuroleptic malignant syndrome, which is the result of an idiosyncratic reaction to neuroleptic drugs ("Neuroleptic Malignant Syndrome" in Chap. 43). Wolff and colleagues have described a syndrome of periodic hyperthermia, associated with vomiting, hypertension, and weight loss and accompanied by an excessive excretion of glucocorticoids; the symptoms had no apparent explanation, although there was a symptomatic response to chlorpromazine.
Lesions in the posterior part of the hypothalamus have had a different effect; i.e., they often produce hypothermia (a persistent temperature of 35°C [95°F] or less) or poikilothermia (equilibration of body and environmental temperatures). The latter may pass unnoticed unless the patient's temperature is taken after lowering and raising the room temperature. Somnolence, confusion, and hypotension may be associated. Spontaneous periodic hypothermia, probably first described by Gowers, has been found in association with a cholesteatoma of the third ventricle (Penfield) and with agenesis of the corpus callosum (Noel et al). Episodically, there are symptoms of autonomic disturbance—salivation, nausea and vomiting, vasodilatation, sweating, lacrimation, and bradycardia; the rectal temperature may fall to 30°C (86°F), and seizures may occur. Penfield referred to these attacks incorrectly as "diencephalic epilepsy." Between attacks, which last a few minutes to an hour or two, neurologic abnormalities are usually not discernible and temperature regulation is normal.
Chronic hypothermia is a more familiar state than hyperthermia, being recorded in cases of severe hypothyroidism, hypoglycemia, and uremia; after prolonged immersion or exposure to cold; and in cases of intoxication with barbiturates, phenothiazines, or alcohol. It tends to be more frequent among elderly patients, who are often found to have an inadequate thermoregulatory mechanism.
Cardiovascular Disorders with Hypothalamic Lesions
Ranson demonstrated a number of autonomic effects upon stimulation of the hypothalamus; these effects as well as hypertension were recorded in Penfield's case of "diencephalic epilepsy." Since Byer and colleagues' description of large, upright T waves and prolonged QT intervals in patients with stroke, it has been appreciated that acute lesions of the brain—particularly subarachnoid hemorrhage and head trauma—may be accompanied by changes in the electrocardiogram (ECG) as well as by supraventricular tachycardia, ectopic ventricular beats, and ventricular fibrillation. Most of the same effects can be induced by very high levels of circulating norepinephrine and corticosteroids. Considering the numerous catastrophic lesions of the brain as well as extreme emotional states that can provoke arrhythmias and other changes in the ECG, the hypothalamus, with its limbic connections and ability to mount a massive sympathoadrenal discharge, is the likely source of these autonomic changes. Cropp and Manning found that the changes seen in the ECG, particularly "cerebral T waves" and other reversible repolarization abnormalities, could occur almost instantaneously (too quickly for attribution to circulating factors) during surgery for a cerebral aneurysm. Again, the hypothalamus is implicated, but as yet no direct evidence links this structure to direct cardiac control.
In experimental animals, lesions placed in or near the tuberal nuclei induce superficial erosions or ulcerations of the gastric mucosa in the absence of hyperacidity (Cushing ulcers). Gastric lesions of similar type are seen in patients with several types of acute intracranial disease (particularly subdural hematoma and other effects of head injury, cerebral hemorrhages, and tumors). In seeking causative lesions, as in patients dying with cardiac changes after head injury or subarachnoid hemorrhage, one searches in vain for a lesion in the various hypothalamic nuclei. A functional disorder in this region is nonetheless suspected.
"Neurogenic" Pulmonary Edema
Following the original observations by Maire and Patton in humans, numerous cases of massive and often fatal pulmonary edema have been described in relation to catastrophic intracranial lesions—head injury, subarachnoid and intracerebral hemorrhage, bacterial meningitis, and status epilepticus being the usual ones. A sudden elevation in intracranial pressure is involved in most cases, usually accompanied by a brief bout of extreme systemic hypertension but without obvious left ventricular failure—which is one reason the pulmonary edema has been attributed to a "neurogenic" rather than a cardiogenic cause. Also, it has been shown that experimental lesions in the caudal hypothalamus are capable of producing this type of pulmonary edema, but almost always with the interposed event of brief and extreme systemic hypertension.
Both the pulmonary edema and hypertensive response can be prevented by sympathetic blockade at any level, suggesting that the adrenergic discharge and the hypertension it causes are essential for the development of pulmonary edema. The rapid rise in vascular resistance and systemic blood pressure is similar to the pressor reaction obtained by destruction of the nucleus of the tractus solitarius, as described in Chap. 26, making understandable the few instances of neurogenic edema that have followed acute lesions in the medullary tegmentum (as was seen in one of our patients [Brown et al]). At issue is whether the hypothalamus exerts a direct sympathetic influence on the pulmonary vasculature, allowing a leakage of protein-rich edema fluid, or if the edema is the result of sudden and massive overloading of the pulmonary circulation by a shift of fluid from the systemic vasculature. The latter theory, essentially one of momentary right-heart failure, is currently favored but does not explain all aspects of the syndrome. Likewise, the role of circulating catecholamines and adrenal steroids has not been fully elucidated. These issues have been summarized in the text on neurologic intensive care by Ropper and colleagues.
Disorders of Consciousness and Personality
Since Ranson's experimental work in monkeys, it has been appreciated that acute lesions in the posterior and lateral parts of the hypothalamus may be associated with stupor, although it has always been difficult to determine the precise structures that were involved. One can be certain that permanent coma from small lesions in the caudal diencephalon (thalamus) may occur in the absence of any changes in the hypothalamus and, conversely, that chronic hypothalamic lesions may be accompanied by no more than drowsiness or confusion or no mental change at all. In one of our cases, involving an infundibuloma entirely confined to the hypothalamus, the patient lay for weeks in a state of torpor, drowsy and confused. His blood pressure was low, his body temperature was 34°C (93.2°F) to 35°C (95°F), and he had diabetes insipidus. When aroused, he was aggressive, like the patient of Reeves and Plum (see earlier).
Among the cases of acquired changes in personality and sleep patterns from ventral hypothalamic disease that we have seen, a few have been impressive because of a tendency to a hypomanic, hypervigilant state with insomnia, lasting days on end, and an impulsiveness and disinhibition suggestive of involvement of the frontal connections to the hypothalamus. In one recent case we examined following removal of a craniopharyngioma, a delirious, agitated state lasted 3 weeks during which the patient's attention could not be captured for even a moment. These and other cognitive disorders with hypothalamic lesions are difficult to interpret and are usually transient. Often the lesions are acute or postoperative and involve adjacent areas, making it impossible to attribute them to the hypothalamus alone.
Periodic Somnolence and Bulimia (Kleine-Levin Syndrome)
Kleine in 1925 and Levin in 1936 described an episodic disorder characterized by somnolence and overeating. For days or weeks, the patients, mostly adolescent boys, sleep 18 or more hours a day, waking only long enough to eat and attend to toilet needs. They appeared dull, often confused, and restless, and were sometimes troubled by hallucinations. The hypothalamus has been implicated on the basis of these symptoms, but without definite pathologic confirmation. We have had some experience with patients having this disorder; a further discussion can be found in "Kleine-Levin Syndrome" in Chap. 19.
Neuroendocrine Syndromes Related to the Adrenal Glands (See also Chap. 30)
Cushing Disease and Cushing Syndrome
The clinical features of Cushing disease, first described in Cushing's monograph in 1932, are familiar to everyone in medicine: truncal obesity with reddish purple cutaneous striae over the abdomen and other parts; dryness and pigmentation of the skin and fragility of skin vessels; excessive facial hair and baldness; cyanosis and mottling of the skin of the extremities; osteoporosis and thoracic kyphosis; proximal muscular weakness; hypertension; glycosuria; and a number of psychologic disturbances. Adrenal hyperplasia secondary to a basophil adenoma of the pituitary (pituitary basophilia was Cushing's term) was the established pathology in Cushing's cases. It is to the pituitary form of hyperadrenalism that the term Cushing disease has been applied. But the same combination of abnormalities may be associated with chronically increased production of cortisol from a primary adrenal tumor, ectopic production of ACTH by carcinoma of the lung or other carcinomas, and most commonly, with the prolonged administration of glucocorticoids (prednisone, methylprednisolone, or ACTH). For these latter conditions, all but the last being associated with secondary adrenal hyperplasia, the term Cushing syndrome is appropriate. Some components of the syndrome may be lacking or less conspicuous than in florid Cushing disease; diagnosis is then facilitated by measurements of ACTH and cortisol in the blood and urine. Cushing syndrome of ectopic type differs clinically from primary pituitary Cushing disease with respect to its more rapid development and greater degrees of proximal limb weakness, skin pigmentation, hypokalemia, hypertension, and glycosuria. Plasma concentrations of ACTH are usually above 20 pg/ml and may exceed 50 pg/ml in the ectopic type and are not suppressed by dexamethasone.
In Orth's review of 630 cases of Cushing syndrome of endogenous cause, 65 percent were caused by hyperpituitarism (Cushing disease), 12 percent by ectopic production of ACTH, 10 percent by an adrenal adenoma, and 8 percent by adrenal carcinoma.
In Cushing disease, either hyperplasia of pituitary cells or a better-defined basophil or chromophobe adenoma produces ACTH, which stimulates the adrenals. Unlike the usual pituitary tumors, the corticotroph (basophil) type are usually microadenomas (<1 cm) and enlarge the sella in only 20 percent of cases. However, it is now appreciated by MRI or high-resolution CT through the sella, that either micro- or macroadenomas are the cause in approximately 80 percent of cases, higher than in the aforementioned series by Orth and all studies prior to the inception of modern brain imaging. There are only a few cases in which a hypothalamic tumor such as a gangliocytoma has caused Cushing syndrome.
For diagnostic purposes, measurement of the excretion of cortisol over 24 h in the urine is the most expeditious test and superior to serum sampling because of fluctuations in the serum levels of ACTH. If a 24-h urine collection is not feasible, it is advisable to obtain two or three daily urine determinations, as the values may vary from day to day in Cushing syndrome and patients are frequently unable to save all their urine. The normal value for urinary excretion of cortisol is approximately 12 to 40 mg in 24 h, but some assays that measure additional metabolites of the hormone may allow normal values up to 100 mg. This should be followed by low- or high-dose dexamethasone suppression testing. A test using high doses of dexamethasone (2 mg every 6 h orally for 2 d, or a single dose of 8 mg at midnight) is the most dependable screening method for separating Cushing disease from ectopic secretion of ACTH. In the latter condition, the urinary excretion of cortisol is not suppressed by the administration of dexamethasone, whereas there is a reduction of 90 percent in urinary excretion in 60 to 70 percent of patients with Cushing disease.
Treatment is governed by the cause of the syndrome. A pituitary adenoma, if not extending out of the sella and encroaching on the optic chiasm (microadenoma), is ideally treated by transsphenoidal pituitary microsurgery, as discussed in Chap. 31. The alternative is focused proton beam or gamma radiation, but the long latency of response to these forms of treatment, 6 months or more, makes them less desirable. If such indirect methods of treatment are used, hypercortisolism may be suppressed in the interim by adrenal enzyme inhibitors such as ketoconazole, metapyrone, or aminoglutethimide. The rate of cure for pituitary microadenoma by transsphenoidal surgery approaches 80 percent, although operative complications—CSF leakage, transient diabetes insipidus, visual abnormalities, meningitis—occur in as many as 10 percent of patients. In approximately 20 percent of patients, removal of the tumor is incomplete and symptoms persist or recur. In such circumstances reoperation is often undertaken, with total excision of the gland and a consequent requirement for extensive hormone replacement in many cases. As an alternative, radiotherapy may be used after failed surgery. If there is an urgent need to suppress the effects of hypercortisolism, bilateral adrenalectomy is effective but has obvious limitations.
Depending on the functional status of the pituitary after any mode of successful treatment, replacement therapy may be needed for a variable period or for the patient's lifetime.
Adrenocortical Insufficiency (Addison Disease)
The classic form of adrenal insufficiency, described by Addison in the nineteenth century, is a result of primary disease of the adrenals. It is characterized by pigmentation of the skin and mucous membranes, nausea, vomiting, and weight loss, as well as muscle weakness, languor, and a tendency to faint. Since Addison's time, hypotension, hyperkalemia, hyponatremia, and low serum cortisol concentrations have come to be recognized as important laboratory features.
In the past, the most common cause of primary adrenal disease was tuberculosis. Now, most cases are designated as idiopathic and thought to represent an autoimmune disorder, often associated with Hashimoto thyroiditis and diabetes mellitus and rarely with other polyglandular autoimmune endocrine disorders. A less-frequent cause is a hereditary metabolic disease of the adrenals—in combination with a demyelinating disease of brain, spinal cord, and nerves and occurring predominantly in males (adrenoleukodystrophy; see Chap. 37). In primary adrenal disease, plasma concentrations of cortisol are low, in response to which the concentrations of ACTH rise. Adrenal insufficiency of whatever cause is a life-threatening condition; there is always a danger of collapse and even death, particularly during periods of infection, surgery, injury, and the like. Lifelong replacement therapy is usually required, with a glucocorticoid (cortisone, 25 to 50 mg, or prednisone, 7.5 to 15 mg daily) and a mineralocorticoid, such as fludrocortisone acetate (Florinef), 0.05 to 0.2 mg daily.
When adrenal insufficiency is secondary to disease of the pituitary, ACTH is low or absent and cortisol secretion is markedly reduced, but aldosterone levels are sustained. Hyperpigmentation is notably absent; it is the elevation of ACTH that causes melanoderma, such as occurs, for example, in patients subjected to bilateral adrenalectomy. Hypothalamic lesions, principally involving the paraventricular nuclei, may also cause adrenal insufficiency, but less frequently than do pituitary lesions.