Neurology_Adams

Neurology_Adams. Unlike other hormones secreted by the hypothalamus, which stimulate the release of pituitary hormones, dopamine released from the hypothalamus actually inhibits the release of prolactin from lactotrophic cells of the anterior pituitary. Dopamine is released by neurons in the region of the arcuate nucleus into the hypophyseal portal system of the median eminence. It is responsive to sensory stimuli from the nipples, via pathways in the spinal cord and brainstem, accounting for the effect of suckling on milk production. Nipple stimulation is also an important influence on oxytocin secretion, as described later. The normal blood levels of prolactin are 5 to 25 ng/mL. Tumors that compress the pituitary stalk disrupt the inhibitory action of dopamine on prolactin secretion, accounting for clinical manifestations such as galactorrhea and reproductive dysfunction. This mechanism also explains galactorrhea that occurs with administration of dopamine-blocking medications such as haloperidol.


Neurology_Adams

Neurology_Adams. The Neurohypophysis: Vasopressin and Oxytocin The oligopeptides vasopressin and oxytocin are elaborated by cells of the supraoptic and paraventricular nuclei and are transported, via their axons, through the stalk of the pituitary to its posterior lobe, where these substances are stored. Together, these elements constitute the neurohypophysis (posterior pituitary), which develops as an evagination of the floor of the third ventricle. Some of the vasopressin-containing nerve endings also terminate on cells of origin of the autonomic nervous system and on the capillary plexus of the hypophyseal portal circulation, through which they influence the secretion of CRH and GH. The peptide components of vasopressin and oxytocin, whose chemical nature was determined by DuVigneaud, are almost identical, differing from one another by only two amino acids.


Neurology_Adams

Neurology_Adams. Vasopressin, acting on the V2 receptors in kidney tubules, serves as the antidiuretic hormone (ADH) and, complemented by thirst mechanisms, maintains the osmolality of the blood. Plasma osmolality modifies vasopressin secretion by acting directly on the supraoptic and paraventricular neurons as well as separate osmoreceptors in the hypothalamus. If serum osmolality falls below 280 mOsm/L, the release of ADH is completely inhibited. Antidiuresis is maximal when plasma levels of vasopressin reach 5 pg/mL. This system is most effective in maintaining homeostasis when serum osmolality is in the range between 280 and 295 mOsm/L.


Neurology_Adams

Neurology_Adams. Alterations in blood volume and pressure also affect vasopressin release through neural mechanisms originating in the baroand mechanoreceptors of the aortic arch, carotid sinus, and right atrium. Afferent signals from these regions are conveyed in the vagus and glossopharyngeal nerves, which synapse in the nucleus of the tractus solitarius; the precise pathways leading to the hypothalamus have not been delineated, however. With severe hypotension, ADH release will continue even if there is a low serum osmolality; the effects of blood pressure predominate over osmolarity as a stimulus. Vasopressin secretion is also influenced by nonosmotic factors. Nausea, for example, is associated with a rise in the levels of the hormone, as much as 100-fold. Hypoglycemia also has an effect, but less pronounced. Drugs such as morphine, nicotine, alcohol, and certain chemotherapeutic agents (cyclophosphamide) also cause release of the stored peptide. Pain, emotional stress, and exercise have long been


Neurology_Adams

Neurology_Adams. Drugs such as morphine, nicotine, alcohol, and certain chemotherapeutic agents (cyclophosphamide) also cause release of the stored peptide. Pain, emotional stress, and exercise have long been thought to cause release of vasopressin, but it is unclear whether this is a direct effect or is mediated through hypotension or nausea.


Neurology_Adams

Neurology_Adams. Oxytocin initiates uterine contraction and promotes lactation. Its release is stimulated by distention of the cervix, labor, breastfeeding, and estrogen. The effects of oxytocin are inhibited by alcohol. Role of the Hypothalamus in Sexual Development (See Also Chap. 27) The hypothalamus also plays a critical role in the development of human sexuality and its expression, a theme elaborated further in the next chapter. The suprachiasmatic nucleus and the number of neurons it contains are considerably larger in men than in women, a dimorphism that becomes evident during postnatal development. Studies by LeVay have suggested that the interstitial nucleus of the hypothalamus is smaller in homosexual males compared to heterosexual males, although the biologic evidence has been sharply challenged (Byne) and more research is needed to understand the implications of the reported association. These issues are addressed further in the section on sexual development in Chap. 27.


Neurology_Adams

Neurology_Adams. The intimate relationship of the hypothalamus with sexual development is exemplified by the appearance during puberty of hypertrophic neurons in the infundibular area that are rich in estrogen receptors; it has been proposed that some of the symptoms of menarche are timed and mediated by the specific pattern of genetic expression in these hypothalamic neurons (Karapanou). With aging, and more so in Alzheimer disease, the neuronal population in this region decreases markedly; the sleep disturbances of senescence and some aspects of the “sundowning” syndrome (confusion and delirium occurring in the evening) have also been attributed to this cell loss. Regulation of Sympathetic and Finally, the central role of the hypothalamus in the regulation of both sympathetic and parasympathetic activities must be emphasized. This key aspect of hypothalamic function is discussed in the preceding chapter. The Pineal Gland and Melatonin


Neurology_Adams

Neurology_Adams. The Pineal Gland and Melatonin The pineal body is a small glandular structure (about 9 mm in diameter) that projects from the dorsal diencephalon and lies just posterior to the third ventricle. Given its central location in the brain, in the past the pineal body figured prominently in philosophic and religious writings; for Descartes, it was the seat of the soul. When this idea was discredited, the pineal gland was relegated to the status of a vestigial organ. The identification of melatonin, the pineal hormone—followed by recognition of its role in maintaining biologic, circadian rhythms—revived scientific interest in the structure.


Neurology_Adams

Neurology_Adams. It is the cyclic secretion of melatonin that appears to be the most important activity of the pineal gland. Melatonin secretion, however, is more accurately regarded as a linked manifestation of the circadian rhythm than as its controlling mechanism. The main cellular element of the gland, the pinealocyte, is thought to derive from neural photoreceptors in lower vertebrates. The latter cells, structurally analogous to retinal cones, transduce light directly into neural impulses and contribute to circadian entrainment of hormonal rhythms in these animals. In humans, the pineal no longer possesses the ability to transduce light directly. However, it retains its influence upon the circadian light–dark cycle, relying on inputs that originate in the retina, synapse in the suprachiasmatic nucleus, pass through descending sympathetic tracts to the intermediolateral cell columns and superior cervical ganglia, and then ascend to innervate noradrenergic terminals on the pinealocytes. Special


Neurology_Adams

Neurology_Adams. pass through descending sympathetic tracts to the intermediolateral cell columns and superior cervical ganglia, and then ascend to innervate noradrenergic terminals on the pinealocytes. Special retinal ganglion cells that contain melanopsin and are intrinsically photosensitive (called ipRGCs) have large receptive fields and physiologic response properties that make them well-suited to detect overall levels of ambient light (Berson). Darkness elicits a release of norepinephrine from these photoreceptors, ultimately stimulating the synthesis and release of melatonin. During daylight the retinal photoreceptor cells are hyperpolarized, norepinephrine release is inhibited, and melatonin secretion is suppressed. The serum concentration of the hormone peaks between 2 and 4 a.m. and gradually falls thereafter. An approximate circadian rhythmicity to melatonin release is preserved in continuous darkness. In humans, the clinical changes that occur with lesions of the suprachiasmatic nucleus


Neurology_Adams

Neurology_Adams. falls thereafter. An approximate circadian rhythmicity to melatonin release is preserved in continuous darkness. In humans, the clinical changes that occur with lesions of the suprachiasmatic nucleus cannot be separated from those that occur with lesions of the pineal gland.


Neurology_Adams

Neurology_Adams. Like other neuroendocrine cells, pinealocytes release peptides that are produced in the cell’s Golgi apparatus and packaged in secretory granules. Whether this is the main mechanism for melatonin release is unclear, as these cells can use an alternative ependymal type of vacuolar secretion. The entire gland is invested by a rich vasculature to receive and circulate the released peptide (in some mammals the blood flow per gram of pineal tissue is surpassed only by that of the kidney). The biochemistry and physiology of melatonin have been extensively reviewed by Brzezinski.


Neurology_Adams

Neurology_Adams. In humans, a regular feature of pineal pathology is the accumulation of calcareous deposits in structures termed acervuli (“brain sand”). These have a more complex composition than simply calcium; they are actually composed of carbonate-containing hydroxyapatite that is linked to calcium and other metals. A review of the mineralization of the pineal can be found in the text by Haymaker and Adams. These concretions are formed within vacuoles of pinealocytes and released into the extracellular space. The mineralization of the pineal body provides a convenient marker for its position in plain films and other neuroimaging studies.


Neurology_Adams

Neurology_Adams. It is of significance that pineal tumors do not secrete melatonin; in contrast, the loss of melatonin may be used as a marker for the completeness of surgical pinealectomy. Most interest in the past several years has centered on melatonin as a soporific agent and its potential to reset sleep rhythms. Its concentration in depressive illnesses, especially in the affected elderly, is also decreased. The subject of pineal tumors is discussed later and is contained in Chap. 31, with discussion of other brain tumors. Hypothalamic syndromes may either be global, in which all or many hypothalamic functions are disordered, often in combination with signs of disease in contiguous structures, or they may be partial, in which there is selective loss of hypothalamic–hypophyseal function attributable to a discrete lesion of the hypothalamus and often resulting in a deficiency or overproduction of a single hormone.


Neurology_Adams

Neurology_Adams. A variety of lesions can involve and impair all or a large part of the hypothalamus. These include inflammatory disorders including sarcoidosis and neoplastic disorders. The hypothalamus is involved in approximately 5 percent of cases of sarcoidosis, often in combination with facial palsy and hilar lymphadenopathy but sometimes as the primary manifestation of the disease (see Fig. 31-2). Infundibuloneurohypophysitis is a cryptogenic inflammation of the neurohypophysis and pituitary stalk, with thickening of these parts by infiltrates of lymphocytes and plasma cells (Imura et al). Histiocytosis X is a group of diseases comprising Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma that usually implicates multiple organs, especially the hypothalamus, neighboring structures, and the leptomeninges. Histopathologic analysis demonstrates proliferating histiocyte. The obscure infiltrative and inflammatory condition,


Neurology_Adams

Neurology_Adams. Erdheim-Chester disease, can also involve this region, and usually involves the orbit, sometimes with proptosis, but is primarily a bone disease. 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. 15). Irradiation for tumors in the hypothalamic region can also contribute to hypothalamic dysfunction (Mechanick). Disorders of Sodium and Fluid Homeostasis


Neurology_Adams

Neurology_Adams. This is a state of production of excessively dilute urine that results from 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 substance secreted by the posterior pituitary 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.


Neurology_Adams

Neurology_Adams. As already stated, the usual cause of diabetes insipidus DI is a lack of vasopressin (ADH) secretion resulting from a lesion of the neurohypophysis. This leads to a reduction of absorption of water in the renal tubules. As a consequence, there is diuresis of low-osmolar urine, 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 ultimately has a similar effect, but is termed nephrogenic DI. Notably, this type of DI may be provoked by lithium toxicity.


Neurology_Adams

Neurology_Adams. Among the established causes of acquired central 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


Neurology_Adams

Neurology_Adams. 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 may occur only hours after brainstem reflexes are lost, or it may not be apparent at all.


Neurology_Adams

Neurology_Adams. 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, which resulted in DI only if the section was high enough to produce degeneration of supraoptic neurons. Among the idiopathic forms of DI, there also exists a congenital 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 with a hypoplastic 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 the syndrome of diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome), and with Friedreich ataxia.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Finally, it should be mentioned that certain drugs used in neurologic practice—for example, carbamazepine— may be the cause of reversible DI (although excessive secretion of ADH is more common in relation to this drug). As mentioned earlier, lithium regularly causes DI, at serum concentration levels that are supratherapeutic or, at times, within the upper therapeutic range. 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 hyponatremia from excessive release of stored ADH; and finally, a persistent pattern that is usually lifelong. The neurohypophyseal axons can regenerate, allowing for some degree of recovery after months or years.


Neurology_Adams

Neurology_Adams. Diagnosis of diabetes insipidus The diagnosis is 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.


Neurology_Adams

Neurology_Adams. 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 water intoxication, urinary volume and serum electrolytes normalize with water restriction. Proof that the patient has a central cause of DI and not nephrogenic unresponsiveness to vasopressin is obtained by injecting 5 U of vasopressin subcutaneously; this will diminish urine output and increase urine osmolality when there is a central cause of DI. Diagnosis is also aided by the radioimmunoassay for plasma ADH; ADH


Neurology_Adams

Neurology_Adams. U of vasopressin subcutaneously; this will diminish urine output and increase urine 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).


Neurology_Adams

Neurology_Adams. Treatment of diabetes insipidus A long-acting analogue of arginine vasopressin (desmopressin [DDAVP]) administered by nasal insufflation (10 to 20 mg or 0.1 to 0.2 mL) is the most commonly used treatment to control chronic DI. Vasopressin tannate in oil and a synthetic vasopressin nasal spray have also been used. The nasal form of DDAVP 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 (in rare, critical situations, these drugs are given intravenously). 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. In the unconscious patient, great care must be taken in the acute stages to replace the fluid lost in the urine, but


Neurology_Adams

Neurology_Adams. of recovery of neurohypophyseal function and the avoidance of water intoxication. 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. For patients with partial preservation of ADH function, chlorpropamide, clofibrate, or carbamazepine can be used to stimulate release of the hormone.


Neurology_Adams

Neurology_Adams. Syndrome of Inappropriate Antidiuretic As described above, 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.


Neurology_Adams

Neurology_Adams. 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 syndrome of inappropriate 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, continued drinking further increases blood volume and reduces its solute concentration, and ADH levels are found to be persistently elevated. The physiologic hallmarks of this condition are concentrated urine, usually with an osmolality above 300 mOsm/L, and low serum osmolality and sodium concentrations. Because of the dilutional effects, the


Neurology_Adams

Neurology_Adams. physiologic hallmarks of this condition are concentrated urine, usually with an osmolality above 300 mOsm/L, and low serum osmolality and sodium concentrations. Because of the dilutional effects, the concentrations of 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 increased atrial natriuretic peptide secretion (see below).


Neurology_Adams

Neurology_Adams. SIADH is observed frequently with a variety of cerebral lesions that do not involve the hypothalamus directly (infarct, tumor, hemorrhage, meningitis, encephalitis) 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. Of interest, hyponatremia is particularly likely to occur in such patients on positive-pressure ventilation because increased thoracic pressure provides an additional stimulus to SIADH. Acute porphyric episodes have the same effect. Neoplasms, particularly small cell tumors, and inflammatory lesions of the lung such as sarcoidosis may elaborate an ADH-like substance and produce this syndrome. Certain drugs—such as carbamazepine,


Neurology_Adams

Neurology_Adams. Neoplasms, particularly small cell tumors, and inflammatory lesions of the lung such as sarcoidosis may elaborate an ADH-like substance and produce this syndrome. Certain drugs—such as carbamazepine, chlorpromazine, chlorothiazide, chlorpropamide, clofibrate, nonsteroidal anti-inflammatory agents, and vincristine—also stimulate ADH release and may lead to hyponatremia. In some cases, no cause or associated disease is apparent.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. Treatment of SIADH If hyponatremia has been of several days or more duration, the rapid restitution of serum sodium to normal or above-normal levels carries a risk of producing 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. In order to avoid osmotic demyelination, a safe clinical rule is to raise the serum sodium by no more than 12 mEq/L in the


Neurology_Adams

Neurology_Adams. 3 to 4 h and furosemide 20 to 40 mg administered to prevent fluid overload. In order to avoid osmotic demyelination, 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.


Neurology_Adams

Neurology_Adams. 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. Later it was erroneously identified as SIADH, until the pathophysiological understanding of this disorder subsequently returned to the concept of natriuresis rather than 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 fluid restriction, which is used to treat SIADH, can have disastrous results when a patient has volume depletion associated with salt wasting.


Neurology_Adams

Neurology_Adams. 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. ANF activity causes natriuresis. It physiologically opposes that of ADH in the kidney tubules and it also strongly inhibits ADH release from the hypothalamus (see review by Samson). Like some other neural peptides, ANF is secreted in bursts, and the natriuresis it produces may be evident only if total urinary sodium content is measured over many hours or days.


Neurology_Adams

Neurology_Adams. 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 all also been associated 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.


Neurology_Adams

Neurology_Adams. 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, rare patients have been reported to repeatedly developed severe hypernatremia (levels as high as 180 to 190 mEq/L), presenting with confusion and stupor. Although the patient reported 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 causing a type of “central” or “essential” hypernatremia. Disorders of Sexual Development Related to Hypothalamic Dysfunction (See Also Chap. 27)


Neurology_Adams

Neurology_Adams. Disorders of Sexual Development Related to Hypothalamic Dysfunction (See Also Chap. 27) This term refers to the abnormally early onset of androgen secretion and spermatogenesis in boys and of cyclic estrogen secretion, and sometimes ovulation, in girls. It is associated with the premature development of secondary sexual characteristics. The occurrence of precocious puberty should prompt both neurologic and endocrine investigations. 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 or an estrogen-secreting ovarian tumor.


Neurology_Adams

Neurology_Adams. A hamartoma of the hypothalamus is a leading cause of precocious puberty in both boys and girls. These lesions can be associated with Neurofibromatosis type 1 (von Recklinghausen disease) or the polyostotic fibrous dysplasia of McCune-Albright syndrome). The clinical presentation of these lesions can include so-called gelastic seizures, with involuntary fits of laughing (Breningstall, see “Complex Partial Seizures” in Chap. 15). Failure of Puberty 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 and the hypothalamus fails to regulate FSH and LH release. Several causative X-linked and autosomal dominant gene mutations have been discovered.


Neurology_Adams

Neurology_Adams. Prader-Willi syndrome, discussed in Chap. 37, 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.


Neurology_Adams

Neurology_Adams. In 1901, Froehlich first described this condition characterized by obesity and gonadal underdevelopment, relating the disorder to a pituitary tumor. A few years later Erdheim recognized that the same syndrome could be a manifestation of a lesion involving or restricted to the hypothalamus. In some patients, the clinical state is characterized by loss of vision, aggression, abulia, apathy, and reduced verbal output. DI may be another clinical feature. The usual causes of the Froehlich syndrome are craniopharyngioma and glioma, but many other tumors have been reported (pituitary adenoma, cholesteatoma, lipoma, meningioma, angiosarcoma, and chordoma). The condition bears some clinical similarities to the Prader-Willi syndrome, as discussed in Chap. 37.


Neurology_Adams

Neurology_Adams. Neuroanatomic studies have localized an appetite center in the ventrolateral nucleus and a satiety center in the ventromedial nucleus of the hypothalamus. 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 by trauma, inflammatory disease, and hydrocephalus (Suzuki et al). Reeves and Plum studied one case with prominent hyperphagia in which a hamartoma had destroyed the medial eminence and the ventromedial nuclei bilaterally sparing the lateral hypothalamus. It is evident, however, that in only a tiny fraction of people can obesity be traced to a hypothalamic lesion. Of overriding


Neurology_Adams

Neurology_Adams. and the ventromedial nuclei bilaterally sparing the lateral hypothalamus. It is evident, however, 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.


Neurology_Adams

Neurology_Adams. A diencephalic syndrome that occurs in infants describes a progressive and ultimately fatal emaciation (failure to thrive), despite normal or near-normal food intake, in an otherwise alert and cheerful infant. The lesion has usually proves 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.


Neurology_Adams

Neurology_Adams. The syndromes of 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 do not stem from a primary dysfunction of hypothalamic nuclei, but rather are a result of the extreme weight loss that 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).


Neurology_Adams

Neurology_Adams. 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 Anderson and Chap. 47). But the developmental nature of the disease (arising in early adolescence), its virtual absence in men, and the hypothalamic alterations mentioned previously do not allow the dismissal of a primary disorder of the brain’s appetite centers (Scheithauser). Abnormalities of Growth


Neurology_Adams

Neurology_Adams. Some instances of growth retardation relate to a deficiency of either GHRH or GH. 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 other 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), where 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 (Brazeau). 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


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Neurology_Adams. 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.


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Neurology_Adams. 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 affects 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.


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Neurology_Adams. In gigantism, most 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 six 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. Systemic Effects and Other Disorders of Hypothalamic Disease Disturbances of Temperature Regulation


Neurology_Adams

Neurology_Adams. 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 either remains at that level until death occurs or 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


Neurology_Adams

Neurology_Adams. 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 relatively rare, and unexplained fever of moderate degree should not be attributed to an existing or putative brain lesion unless other causes have been evaluated.


Neurology_Adams

Neurology_Adams. Hyperthermia is also part of the malignant hyperthermia syndrome, in which extreme hyperthermia and muscle rigidity occurs in response to inhalation anesthetics and skeletal muscle relaxants (also discussed in Chap. 45). In some of these instances, it has been found to be caused by a mutation in the gene encoding the ryanodine receptor. The typical inheritance pattern is autosomal dominant but penetrance is incomplete; some affected members may develop congenital central core myopathy. Closely related is the neuroleptic malignant syndrome, which is the result of an idiosyncratic reaction to neuroleptic drugs (also discussed in Chap. 41). 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.


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Neurology_Adams. Lesions in the posterior part of the hypothalamus have had a different effect; that is, 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. Between attacks, which last a few minutes to an hour or two, neurologic abnormalities are usually not discernible and temperature regulation is


Neurology_Adams

Neurology_Adams. may fall to 30°C (86°F), and seizures may occur. Between attacks, which last a few minutes to an hour or two, neurologic abnormalities are usually not discernible and temperature regulation is normal.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. In a series of experiments with monkeys, Ranson demonstrated a number of autonomic effects upon stimulation of the hypothalamus. Subsequently, Byer and colleagues described large, upright T waves and prolonged QT intervals in patients with stroke, and since then it has been appreciated that other acute lesions of the brain—particularly subarachnoid hemorrhage and head trauma—may be accompanied by supraventricular tachycardia, ectopic ventricular beats, ventricular fibrillation, and other changes in the electrocardiogram. 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. Most of the same effects can also be induced by very high levels of circulating norepinephrine and corticosteroids. Extreme emotional states can also provoke arrhythmias and other changes in the ECG. The


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Neurology_Adams. of the same effects can also be induced by very high levels of circulating norepinephrine and corticosteroids. Extreme emotional states can also 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 the autonomic changes in these various clinical situations.


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Neurology_Adams. Gastric Complications of Hypothalamic Dysfunction 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 in patients, for example those with head injury or subarachnoid hemorrhage, one searches in vain for a lesion in the various hypothalamic nuclei. An organic disorder in this region is nonetheless suspected.


Neurology_Adams

Neurology_Adams. 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—most commonly head injury, subarachnoid and intracerebral hemorrhage, bacterial meningitis, or status epilepticus. A sudden elevation in intracranial pressure is involved in most cases, usually accompanied by a brief bout of extreme systemic hypertension 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.


Neurology_Adams

Neurology_Adams. Both the pulmonary edema and hypertensive response can be prevented by sympathetic blockade, 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. 25, making understandable the few instances of neurogenic edema that have followed acute lesions in the medullary tegmentum (Brown). 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


Neurology_Adams

Neurology_Adams. 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.


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Neurology_Adams. Disorders of Consciousness and Personality Since Ranson’s experimental work, 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 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, confusion or no mental change at all.


Neurology_Adams

Neurology_Adams. Among the cases of acquired changes in personality and sleep patterns from ventral hypothalamic disease that we have seen, a few have shown an impressive tendency toward a hypomanic, hypervigilant state with insomnia, lasting days on end, accompanied by an impulsiveness and disinhibition suggestive of involvement of the frontal connections to the hypothalamus. In one patient we examined following removal of a craniopharyngioma, a delirious, agitated state lasted 3 weeks during which time 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.


Neurology_Adams

Neurology_Adams. 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 appear dull, often confused, and restless, and are sometimes troubled by hallucinations. The hypothalamus has been implicated on the basis of these symptoms, but without definite pathologic confirmation. Further discussion can be found in Chap. 18.


Neurology_Adams

Neurology_Adams. 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 is a serious illness that 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, for example, 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 Chap. 30), involutional changes that occur at the end of pregnancy (Sheehan syndrome), cranial irradiation for cerebral tumors other than those in the pituitary


Neurology_Adams

Neurology_Adams. adenoma (pituitary apoplexy, see Chap. 30), 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.


Neurology_Adams

Neurology_Adams. 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. Neuroendocrine Syndromes Related to the Adrenal Glands (See Also Chap. 30)


Neurology_Adams

Neurology_Adams. Neuroendocrine Syndromes Related to the Adrenal Glands (See Also Chap. 30) The clinical features of Cushing disease, first described in Cushing’s monograph in 1932, are familiar to virtually 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 this pituitary form of hyperadrenalism that the term Cushing disease has been applied.


Neurology_Adams

Neurology_Adams. The same combination of abnormalities, however, 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. Clinical presentation may vary and some components of the syndrome may be lacking or less conspicuous; 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 (at times exceeding 50 pg/mL)


Neurology_Adams

Neurology_Adams. and greater degrees of proximal limb weakness, skin pigmentation, hypokalemia, hypertension, and glycosuria. Plasma concentrations of ACTH are usually above 20 pg/mL (at times exceeding 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.


Neurology_Adams

Neurology_Adams. In Cushing disease, either hyperplasia of pituitary cells or a basophil or chromophobe adenoma produces excessive ACTH, which stimulates the adrenals. Corticotroph (basophil) adenomas 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 microor macroadenomas are the cause in approximately 80 percent of cases of Cushing syndrome, higher than in the aforementioned series by Orth. There are only a few cases in which a hypothalamic tumor such as a gangliocytoma has caused Cushing syndrome.


Neurology_Adams

Neurology_Adams. 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 considerably. 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 lowor 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; in contrast, 60 to 70 percent of patients with


Neurology_Adams

Neurology_Adams. from ectopic secretion of ACTH. In the latter condition, the urinary excretion of cortisol is not suppressed by the administration of dexamethasone; in contrast, 60 to 70 percent of patients with Cushing disease show a 90 percent reduction in urinary cortisol excretion.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


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Neurology_Adams. 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. 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.


Neurology_Adams

Neurology_Adams. 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 and the serum ACTH level rises as a consequence. 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, and extreme injury. Lifelong replacement therapy is usually required with a glucocorticoid (cortisone, 25 to 50 mg, or prednisone, 7.5 to 15 mg daily) and a


Neurology_Adams

Neurology_Adams. during periods of infection, surgery, and extreme injury. 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.


Neurology_Adams

Neurology_Adams. 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. Anderson AE: Practical Comprehensive Treatment of Anorexia Nervosa and Bulimia. Baltimore, Johns Hopkins University Press, 1985. Aronin N, DiFiglea M, Leeman SE: Substance P. In: Krieger DT, Brownstein NJ, Martin JB (eds): Brain Peptides. New York, Wiley, 1983, pp 783–804.


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Neurology_Adams. Aronin N, DiFiglea M, Leeman SE: Substance P. In: Krieger DT, Brownstein NJ, Martin JB (eds): Brain Peptides. New York, Wiley, 1983, pp 783–804. Asa SL, Scheithauer BW, Bilbau J, et al: A case of hypothalamic acromegaly: A clinico-pathologic study of 6 patients with hypothalamus gangliocytomas producing growth hormone releasing factor. J Clin Endocrinol Metab 58:796, 1984. Berek K, Aichner F, Schmutzhard E, et al: Intracranial germ cell tumour mimicking anorexia nervosa. Klin Wochenschr 69:440, 1991. Berson DM, Dunn FA, Takao M: Phototransduction by retinal ganglion cells that set the circadian clock. Science 295:1070, 2002. Bhanji S, Mattingly D: Medical Aspects of Anorexia Nervosa. London, Wright, 1988. Bray GA, Gallagher TF Jr: Manifestations of hypothalamic obesity in man: A comprehensive investigation of eight patients and a review of the literature. Medicine (Baltimore) 54:301, 1975.


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Neurology_Adams. Bray GA, Gallagher TF Jr: Manifestations of hypothalamic obesity in man: A comprehensive investigation of eight patients and a review of the literature. Medicine (Baltimore) 54:301, 1975. Brazeau P, Vale W, Bargus R, et al: Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77, 1973. Breningstall GN: Gelastic seizures, precocious puberty and hypothalamic hamartoma. Neurology 35:1180, 1985. Brown RH, Beyerl BD, Iseke R, Lavyne MH: Medulla oblongata edema associated with neurogenic pulmonary edema. J Neurosurg 64:494, 1986. Brzezinski A: Melatonin in humans. N Engl J Med 336:186, 1997. Burr IM, Slonim AE, Danish RK: Diencephalic syndrome revisited. J Pediatr 88:429, 1976. Byer E, Ashman R, Toth LA: Electrocardiogram with large upright T-wave and long Q-T intervals. Am Heart J 33:796, 1947.


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Neurology_Adams. Byer E, Ashman R, Toth LA: Electrocardiogram with large upright T-wave and long Q-T intervals. Am Heart J 33:796, 1947. Byne W: The biological evidence challenged. In: The Editors of Scientific American Magazine (eds): The Scientific American Book of the Brain. New York, Lyons Press, 1999, pp 181–194. Cohen RA, Albers HE: Disruption of human circadian and cognitive regulation following a discrete hypothalamic lesion: A case study. Neurology 41:726, 1991. Cropp CF, Manning GW: Electrocardiographic change simulating myocardial ischemia and infarction associated with spontaneous intracranial hemorrhage. Circulation 22:24, 1960. Cushing H: Basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilia). Bull Johns Hopkins Hosp 50:137, 1932. Diringer M, Ladenson PW, Stern BJ, et al: Plasma atrial natriuretic factor and subarachnoid hemorrhage. Stroke 19:1119, 1988.


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Neurology_Adams. Hopkins Hosp 50:137, 1932. Diringer M, Ladenson PW, Stern BJ, et al: Plasma atrial natriuretic factor and subarachnoid hemorrhage. Stroke 19:1119, 1988. DuVigneaud V: Hormones of the posterior pituitary gland: Oxytocin and vasopressin. Harvey Lect 50:1, 1954–1955. Erdheim J: Über Hypophysengangs Geschwülste und Hirn Cholesteatome. Sitzungs DK Akad d Wissensch. Math Natur WC Wien 113:537, 1904. Euler US, Gaddum JH: An unidentified depressor substance in certain tissue abstracts. J Physiol 612:74, 1931. Gowers WR. The borderland of epilepsy: faints, vagal attacks, vertigo, migraine, sleep symptoms, and their treatment. Philadelphia: Blackiston’s, p. 18, 1907. Froehlich A: Ein Fall von Tumor der Hypophysis cerebri ohne Akromegalie. Wien Klin Wochenschr 15:883, 1901. Hayes R, McHugh PR, Williams H: Absence of thirst in hydrocephalus. N Engl J Med 269:277, 1963.


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Neurology_Adams. Hayes R, McHugh PR, Williams H: Absence of thirst in hydrocephalus. N Engl J Med 269:277, 1963. Haymaker W, Adams RD: The pineal gland, in Histology and Histopathology of the Nervous System. Springfield, IL, Charles C Thomas, 1982, pp 1801–2023. Imura H, Nakoa K, Shimatsu A, et al: Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus. N Engl J Med 329:683, 1993. Jennings MT, Gelman R, Hochberg FH: Intracranial germ-cell tumors: Natural history and pathogenesis. J Neurosurg 63:155, 1985. Karapanou O, Papadimitriou A: Determinants of menarche. Reprod Biol Endocrinol 8:115, 2010. Lamberts SWJ, DeHerder WW, Van der Lely AJ: Pituitary insufficiency. Lancet 352:127, 1998. Leeman SE, Mroz EA: Substance P. Life Sci 15:2033, 1974. LeVay S: A difference in the hypothalamic structure between heterosexual and homosexual men. Science 253:1034, 1991. Lewin K, Mattingly D, Mills RR: Anorexia nervosa associated with hypothalamic tumour. Br Med J 2:629, 1972.


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Neurology_Adams. Lewin K, Mattingly D, Mills RR: Anorexia nervosa associated with hypothalamic tumour. Br Med J 2:629, 1972. Martin JB, Reichlin S: Clinical Neuroendocrinology, 2nd ed. Philadelphia, Davis, 1987. Mechanick JI, Hochberg FH, LaRocque A: Hypothalamic dysfunction following whole-brain radiation. J Neurosurg 65:490, 1986. Maire FW, Patton HD. Neural structures involved in the genesis of preoptic pulmonary edema, gastric erosions, and behavior changes. Am J Physiol. 1956;184:345–350. Moses AM, Stretten DHP: Disorders of the neurohypophysis. In: Braunwald E, Fauci A, Kasper D, et al (eds): Harrison’s Principles of Internal Medicine, 14th ed. New York, McGraw-Hill, 1998, p 1924. Nauta WJH, Haymaker W: Hypothalamic nuclei and fiber connections. In: Haymaker W, Anderson E, Nauta WJH (eds): The Hypothalamus. Springfield, IL, Charles C Thomas, 1969, pp 136–209.


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Neurology_Adams. Nauta WJH, Haymaker W: Hypothalamic nuclei and fiber connections. In: Haymaker W, Anderson E, Nauta WJH (eds): The Hypothalamus. Springfield, IL, Charles C Thomas, 1969, pp 136–209. Nelson PB, Seif SM, Maroon JC, Robinson AG: Hyponatremia in intracranial disease: Perhaps not the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). J Neurosurg 55:938, 1981. Noel P, Hubert JP, Ectors M, et al: Agenesis of the corpus callosum associated with relapsing hypothermia. Brain 96:359, 1973. Orth DN: Cushing’s syndrome. N Engl J Med 332:791, 1995. Penfield W: Diencephalic autonomic epilepsy. Arch Neurol Psychiatry 22:358, 1929. Peters JP, Welt LG, Sims EAH, et al: A salt wasting syndrome associated with cerebral disease. Trans Assoc Am Physicians 63:57, 1950. Ranson SW: Somnolence caused by hypothalamic lesions in the monkey. Arch Neurol Psychiatry 41:1, 1939.


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Neurology_Adams. Ranson SW: Somnolence caused by hypothalamic lesions in the monkey. Arch Neurol Psychiatry 41:1, 1939. Reeves AG, Plum F: Hyperphagia, rage and dementia accompanying a ventromedial hypothalamic neoplasm. Arch Neurol 20:616, 1969. Reichlin S: Neuroendocrinology. In: Wilson JD, Foster DW (eds): Williams Textbook of Endocrinology, 8th ed. Philadelphia, Saunders, 1992, pp 135–219. Robertson GL: Posterior pituitary. In: Selig P, Baxter JD, Broadus AE, Frohman LA (eds): Endocrinology and Metabolism, 2nd ed. New York, McGraw-Hill, 1987, pp 338–385. Ropper AH, Gress DR, Diringer MN, et al: Pulmonary aspects of neurological intensive care, cardiovascular aspects of neurological intensive care. In: Ropper AH (ed): Neurological and Neurosurgical Intensive Care. Baltimore, Lippincott Williams & Wilkins, 2004, pp 52–104. Samson WK: Atrial natriuretic factor and the central nervous system. Endocrinol Metab Clin North Am 16:145, 1987.


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Neurology_Adams. Samson WK: Atrial natriuretic factor and the central nervous system. Endocrinol Metab Clin North Am 16:145, 1987. Scheithauer BW, Kovacs KT, Jariwala LK, et al: Anorexia nervosa: An immunohistochemical study of the pituitary gland. Mayo Clin Proc 63:23, 1988. Schwartz WB, Bartter FC: The syndrome of inappropriate secretion of antidiuretic hormone. Am J Med 42:790, 1967. Schwartz WJ, Busis NA, Hedley-Whyte T: A discrete lesion of the ventral hypothalamus and optic chiasm that disrupted the daily temperature rhythm. J Neurol 233:1, 1986. Sotos JF, Dodge PR, Muirhead D, et al: Cerebral gigantism in childhood. N Engl J Med 271:109, 1964. Speidel CC: Gland-cells of internal secretion in the spinal cord of the skates. Papers from the Department of Marine Biology of the Carnegie Institution of Washington 13:1–31, 1919.


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Neurology_Adams. Speidel CC: Gland-cells of internal secretion in the spinal cord of the skates. Papers from the Department of Marine Biology of the Carnegie Institution of Washington 13:1–31, 1919. Stewart C, Castro-Magana M, Sherman J, et al: Septo-optic dysplasia and median cleft face syndrome in a patient with isolated growth hormone deficiency and hyperprolactinemia. Am J Dis Child 137:484, 1983. Suzuki N, Shinonaga M, Hirata K, et al: Hypothalamic obesity due to hydrocephalus caused by aqueductal stenosis. J Neurol Neurosurg Psychiatry 53:1102, 1990. Swaab DF: The human hypothalamus: Basic and clinical aspects. Part I, Nuclei of the human hypothalamus; Part II, Neuropathology of the human hypothalamus and adjacent structures. In: Aminoff MJ, Boller F, Swaab DF (eds): Handbook of Clinical Neurology, Volumes 79 and 80, Series 3. Amsterdam, Elsevier, 2003. Uher R, Treasure J: Brain lesions and eating disorders. J Neurol Neurosurg Psychiatry 76:852, 2005.


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Neurology_Adams. Uher R, Treasure J: Brain lesions and eating disorders. J Neurol Neurosurg Psychiatry 76:852, 2005. Wijdicks EF, Ropper AH, Hunnicutt EJ, et al: Atrial natriuretic factor and salt wasting after aneurysmal subarachnoid hemorrhage. Stroke 22:1519, 1991. Wolff SM, Adler RC, Buskirk ER, et al: A syndrome of periodic hypothalamic discharge. Am J Med 36:956, 1964. Figure 26-1. Diagram of the hypothalamic–pituitary axis. Indicated on the left is the hypothalamic–neurohypophyseal system, consisting of supraoptic and paraventricular neurons, axons of which terminate on blood vessels in the posterior pituitary (neurohypophysis). The hypothalamic–adenohypophyseal system is illustrated on the right. Tuberoinfundibular neurons, the source of the hypothalamic regulatory hormones, terminate on the capillary plexus in the median eminence. (Courtesy of Dr. J.B. Martin.) Chapter 26 The Hypothalamus and Neuroendocrine Disorders Development of the Nervous System


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Neurology_Adams. Chapter 26 The Hypothalamus and Neuroendocrine Disorders Development of the Nervous System In this chapter and the next one on aging, we consider the effects of growth, maturation, and aging on the nervous system. These are discussed in some detail because certain aspects of neurologic diseases are meaningful only when viewed against the background of these natural age-linked changes. Developmental diseases of the nervous system, for example, malformations, genetic defects, and other forms of damage that are acquired in the intrauterine period of life, are considered in Chap. 37.


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Neurology_Adams. The establishment of a biologic timescale of human development requires observation of a large number of normal individuals of known ages and testing them for measurable items of behavior. Because of individual variations in the tempo of development, it is equally important to study the growth and development of any one individual over a prolonged period. If these observations are to be correlated with stages of neuroanatomic development, the clinical and morphologic data must be expressed in units that are comparable. Early in life, very precise age periods are difficult to ascertain because of the difficulty in fixing the time of conception. The average human gestational period is 40 weeks (280 days), but birth may occur with survival as early as about 24 or as late as 49 weeks (a time span of almost 5 months), and the extent of nervous system development varies accordingly.


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Neurology_Adams. After birth, any given item of behavior or structural differentiation must always have two reference points: (1) to a particular item of behavior that has already been achieved, and (2) to units of chronologic time or duration of life of the organism. The chronologic or biologic scale assumes special significance in early prenatal life. During that period development proceeds at such a rapid pace that small units of time weigh heavily and the organism appears to change literally day by day. In infancy, the tempo of development slows somewhat but is still very rapid in comparison with later childhood. The neurologist will find it advantageous to organize knowledge of normal development and disease around the timetables for human growth and development listed in Tables 27-1 and 27-2. In addition, the last several decades have brought major advances in the understanding of the genetic and molecular control of neural development. That topic is considered in Chap. 37.


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Neurology_Adams. Neuroanatomic Bases of Normal Development A large body of knowledge has accumulated concerning the functional and structural status of the nervous system during each successive period of life. This information is reviewed briefly in the following paragraphs and is summarized in Table 27-2. It must be kept in mind that development of the nervous system does not proceed stepwise, from one period to the next, but is continuous from conception to maturity. The sequences of development are much the same in all infants, although the rate may vary slightly. Any given behavioral function, in order to be expressed, must await the development of its neural substrate. Furthermore, at any given moment in development, several measurable functions appear in parallel, and it is often a dissociation between them that acquires clinical significance.


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Neurology_Adams. What we know of the nervous system in the germinal and embryonal periods has been derived from the anatomical study of fetuses. Neuroblastic differentiation, migration, and neuronal multiplication are already well under way in the first 3 weeks of embryonic life. The control of each of these phases (and, later, of connectivity of neurons) is determined by the genome of the organism. Primitive cells destined to become neurons originate in, or close to, the neuroepithelium of the neural tube. These cells proliferate at an astonishingly rapid rate (250,000 per minute, according to Cowan) for a circumscribed period (several days to weeks). They become transformed into bipolar neuroblasts, which migrate in a series of waves toward the marginal layer of what is to become the cortex of the cerebral hemispheres. The first glial cells also appear very early and provide the scaffolding along which the neuroblasts move. Each step in the differentiation and migration of the neuroblasts proceeds


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Neurology_Adams. hemispheres. The first glial cells also appear very early and provide the scaffolding along which the neuroblasts move. Each step in the differentiation and migration of the neuroblasts proceeds in an orderly fashion, and one stage progresses to the next with remarkable precision. The process of neuronal migration is largely completed by the end of the fifth fetal month but continues at a much slower rate up to 40 weeks of gestation, according to the classic studies of Conel and of Rabinowicz. Because the migration of most neurons involves postmitotic cells, the cerebral cortex by this time has presumably acquired its full complement of nerve cells, numbered in the many billions. This concept was, however, revised with the discovery that active stem cells in the adult brain generate neurons in the hippocampal formation and in the subventricular matrix zones, giving rise most evidently to olfactory neurons in the adult brain but possibly also to other nerve cells (see the reviews by


Neurology_Adams

Neurology_Adams. in the hippocampal formation and in the subventricular matrix zones, giving rise most evidently to olfactory neurons in the adult brain but possibly also to other nerve cells (see the reviews by Alvarez-Buylla and Garcia-Verdugo, Kempermann, and also Bond and colleagues).


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Neurology_Adams. Despite the almost universal acceptance of the presence of neurogenesis in the human brain, the methodology that demonstrates it is complex (see review by Kuhn and colleagues) and has been questioned by authoritative individuals such as Rakic, whose perspective should be consulted for a complete portrait of the subject. Actually, we have little idea of the number of nerve cells in the cerebral and cerebellar cortices at different ages. Many more are formed than survive, as programmed cell death (apoptosis) constitutes an important component of development.


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Neurology_Adams. Within a few months of mid-fetal life, the cerebrum, which begins as a small bihemispheric organ with hardly a trace of surface indentation, evolves into a deeply sulcated structure. Every step in the folding of the surface to form fissures and sulci follows a temporal pattern of such precision as to permit a reasonably accurate estimation of fetal age by this criterion alone. The major sylvian, rolandic, and calcarine fissures take on the adult configuration during the fifth month of fetal life, the secondary sulci in the sixth and seventh months, and the tertiary sulci, which vary slightly in location from one individual to another, in the eighth and ninth months (see Fig. 27-1 and Table 27-2).


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Neurology_Adams. Concomitantly, subtle changes in neuronal organization are occurring in the cerebral cortex and central ganglionic masses. Involved here are the processes of synaptogenesis and axonal pathfinding. Neurons become more widely separated as differentiation proceeds, owing to an increase in the size and complexity of dendrites and axons and enlargement of synaptic surfaces (Fig. 27-2). The cytoarchitectural patterns that demarcate one part of the cerebral cortex from another (as described in Chap. 21) are already in evidence by the 30th week of fetal life and become definitive at 40 weeks and in succeeding months. As the maturational process of cortical neurons proceeds, the patterns of neuronal organization in different regions of the brain (motor, premotor, sensory, and striate cortices, Broca and Wernicke areas) continue to change.


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Neurology_Adams. Myelination provides another parallel index of development and maturation of the nervous system and is apparently related to the functional activity of the fiber systems. The timing and precision of these connecting pathways are no less precise and time locked than is neuronal development (see Flechsig myelinogenic cycle as shown in Fig. 27-3). The acquisition of myelin sheaths by the spinal nerves and roots by the 10th week of fetal life is associated with the beginning of reflex motor activities. Segmental and intersegmental fiber systems in the spinal cord myelinate soon afterward, followed by ascending and descending fibers to and from the brainstem (reticulospinal, vestibulospinal). The acoustic and labyrinthine systems stand out with singular clarity in myelin-stained preparations by the 28th to 30th weeks, and the spinocerebellar and dentatorubral systems by the 37th week.


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Neurology_Adams. After birth, the brain continues to grow dramatically. From an average weight of 375 to 400 g at birth (40 weeks), it reaches about 1,000 g by the end of the first postnatal year. Glial cells (oligodendrocytes and astrocytes) derived from the matrix zones continue to divide and multiply during the first 6 months of postnatal life. The visual system begins to myelinate about the 40th gestational week; its myelination cycle proceeds rapidly, being nearly complete a few months after birth. The corticospinal tracts are not fully myelinated until halfway through the second postnatal year. Most of the principal tracts are myelinated by the end of this period. In the cerebrum, the first myelin is seen at 40 weeks in the posterior frontal and parietal lobes, and the occipital lobes (geniculocalcarine tracts) myelinate soon thereafter. Myelination of the anterior frontal and temporal lobes occurs later, during the first year of postnatal life. By the end of the second year, myelination of the


Neurology_Adams

Neurology_Adams. tracts) myelinate soon thereafter. Myelination of the anterior frontal and temporal lobes occurs later, during the first year of postnatal life. By the end of the second year, myelination of the cerebrum is largely complete (Fig. 27-3). These steps in myelination can be followed by MRI, where increasing myelination results in progressive T1 hyperintensity and T2 hypointensity of white matter. Despite these careful anatomic observations, their correlation with developmental clinical and electroencephalographic data has not been precise.


Neurology_Adams

Neurology_Adams. Childhood, Puberty, and Adolescence Growth of the brain continues, at a much slower rate than before, until 12 to 15 years, when the average adult weight of 1,230 to 1,275 g in females and 1,350 to 1,410 g in males is attained. Myelination also continues slowly during this period. Yakovlev and Lecours, who reexamined Flechsig’s classic findings on the ontogeny of myelination (the term Flechsig myelinogenic cycle is still used), traced the progressive myelination of the middle cerebellar peduncle, acoustic radiation, and bundle of


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Neurology_Adams. Vicq d’Azyr (mammillothalamic tract) beyond the third postnatal year; the nonspecific thalamic radiations continued to myelinate beyond the 7th year and fibers of the reticular formation, great cerebral commissures, and intracortical association neurons to at least the 10th year and beyond (Fig. 27-3). These investigators noted that there was an increasing complexity of fiber systems through late childhood and adolescence, and perhaps even into middle adult life. Similarly, in the extensive studies of Conel and Rabinowicz, depicting the cortical architecture at each year from mid-fetal life to the 20th year, the dendritic arborizations and cortical interneuronal connections were observed to increase progressively in complexity; the “packing density” of neurons, that is, the number of neurons in any given volume of tissue increases through the age of approximately 15 months and then decreases (Fig. 27-2).


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Neurology_Adams. Interesting questions are whether neurons begin to function only when their axons have acquired a myelin sheath; whether myelination is under the control of the cell body, the axon, or both; and whether the usual myelin stains yield sufficient information as to the time of onset and degree of the myelination process. At best these correlations can be only approximate. It seems likely that systems of neurons begin to function before the first appearance of myelin, at least insofar as shown in conventional myelin stains. These correlations will undoubtedly be restudied using more delicate measures of function and finer staining techniques, as well as the techniques of quantitative biochemistry, phase and electron microscopy, and the emerging techniques of connectivity and network imaging. Neural Development in the Fetus


Neurology_Adams

Neurology_Adams. The human fetus is capable of a complex series of reflex activities, some of which appear as early as 5 weeks of postconceptional age. Cutaneous and proprioceptive stimuli evoke slow, generalized, patterned movements of the head, trunk, and extremities. More discrete movements appear to differentiate from these generalized activities. Reflexes subserving blinking, sucking, grasping, and visceral functions, as well as tendon and plantar reflexes, are all elicitable in late fetal life. They seem to develop along with the myelination of peripheral nerves, spinal roots, spinal cord, and brainstem. By the 24th week of gestation, the neural apparatus is functioning sufficiently well to give the fetus some chance of survival should birth occur at this time. However, most infants fail to survive birth at this age, usually owing to an inadequacy of pulmonary function. Thereafter, the basic neural equipment matures so rapidly that, by the 30th week, postnatal viability is relatively common. It


Neurology_Adams

Neurology_Adams. birth at this age, usually owing to an inadequacy of pulmonary function. Thereafter, the basic neural equipment matures so rapidly that, by the 30th week, postnatal viability is relatively common. It seems that nature prepares the fetus for the contingency of premature birth by hastening the establishment of vital functions necessary for extrauterine existence.


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Neurology_Adams. It is in the last trimester of pregnancy that a complete timetable of fetal movements, posture, and reflexes would be of the greatest value, for mainly during this period does the need for a full clinical evaluation arise. That there are recognizable differences between infants born in the sixth, seventh, eighth, and ninth months of fetal life has been documented by Saint-Anne Dargassies, who applied the neurologic tests earlier devised by André-Thomas and herself. Her observations document prevailing postures; control and attitude of head, neck, and limbs; muscle tonus; and grasp and sucking reflexes. These findings are of interest and may well be a means of determining exact age, but many more observations are needed with follow-up data on later development before they can be fully accepted. Part of the difficulty here is the variability of the premature infant’s neurologic functions, which may change literally from hour to hour. Even at term there may be variability in neurologic


Neurology_Adams

Neurology_Adams. Part of the difficulty here is the variability of the premature infant’s neurologic functions, which may change literally from hour to hour. Even at term there may be variability in neurologic functions from one day to the next. This variability reflects in part the effects of parturition and the effects of medications given to the mother, as well as the inaccurate dating of conception and rapid developmental changes in the brain.


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Neurology_Adams. Development During the Neonatal Period, Infancy, and Early Childhood


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Neurology_Adams. At term, effective sucking, rooting, and grasping reactions are present. The infant is able to swallow and cry, and the startle reaction (e.g., Moro reflex, as described in the following text) can be evoked by loud sound and sudden extension of the neck. Support and steppage movements can be demonstrated by placing the infant on its feet, and incurvation of the trunk by stroking one side of the back. Also present at birth is the placing reaction, wherein the foot or hand, brought passively into contact with the edge of a table, is lifted automatically and placed on the flat surface. These neonatal automatisms depend essentially on the functioning of the spinal cord, brainstem, and possibly diencephalon and pallidum. The Apgar score, a universally used but somewhat imprecise index of the well-being of the newly born infant, is in reality a numerical rating of the adequacy of brainstem-spinal mechanisms (breathing, pulse, color of skin, tone, and responsivity) (Table 27-3).


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Neurology_Adams. Studies of local cerebral glucose metabolism by positron emission tomography (PET) have provided interesting information about the functional maturation of the brain. There are remarkable differences between the newborn and the mature individual. Neonatal values, adjusted for brain weight, are only one-third those of the adult; except for the primary sensorimotor cortex, they are confined to brainstem, cerebellum, and thalamus. During infancy, there is a progressive evolution in the pattern of glucose metabolism in the parietal, temporal, striate, dorsolateral occipital, and frontal cortices, in this order. Only by the end of the first year do the glucose metabolic patterns qualitatively resemble those of the normal young adult (Chugani).


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Neurology_Adams. Behavior during infancy and early childhood is also the subject of a substantial literature, contributed more by psychologists than neurologists. In particular they have explored sensorimotor performance in the first year and language and social development in early childhood. In the first 6 years of life, the infant and young child traverse far more ground developmentally than they ever will again in a similar period. From the newborn state, when the infant demonstrates a few primitive feeding and postural reflexes, there are acquired, within a few months, smiling and head and hand–eye control; by 6 months, the ability to sit; by 10 months, the strength to stand; by 12 months, the muscle coordination required to walk; by 2 years, the ability to run; and by 6 years, mastery of the rudiments of a game of baseball or a musical skill. On the perceptual side, the neonate progresses, in less than 3 months, from a state in which ocular control is tentative and tonic deviation of the eyes


Neurology_Adams

Neurology_Adams. of a game of baseball or a musical skill. On the perceptual side, the neonate progresses, in less than 3 months, from a state in which ocular control is tentative and tonic deviation of the eyes occurs only in response to labyrinthine stimulation to one in which he is able to fixate on and follow an object. (This last corresponds to the development of the macula.) Later, the child is able to make fine discriminations of color, form, and size. Gesell has provided a graphic summation of the variety and developmental sweep of a child’s behavior. He writes


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Neurology_Adams. At birth the child reflexly grasps the examiner’s finger, with eyes crudely wandering or vacantly transfixed . . . and by the sixth year the child adaptively scans the perimeter of a square or triangle, reproducing each form with directed crayon. The birth cry, scant in modulation and social meaning, marks the low level of language, which in two years passes from babbling to word formation that soon is integrated into sentence structure, and in six years to elaborated syntactic speech with questions and even primitive ideas of causality. In personality makeup … the school beginner is already so highly organized, both socially and biologically, that he foreshadows the sort of individual he will be in later years.


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Neurology_Adams. The early studies of Gesell and of others represent attempts to establish age-linked standards of behavioral development, but the difficulties of using such rating scales are considerable. The components of behavior that have been chosen as a frame of reference for neurological development are not likely to be of uniform physiologic value or of comparable complexity, and they have seldom been standardized on large populations drawn from different cultures. Also, the examinations at specified ages are cross-sectional assessments, which give a limited idea of the dynamics of behavioral development. As already stated, temporal patterns of behavior reveal an extraordinary degree of variation in their emergence, increment, and decrement, as well as marked variation from one individual to another.


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Neurology_Adams. Indeed, the predictive value of developmental assessment has been the subject of a lively dispute. Gesell took the position that careful observation of a large number of infants, with accurate recording of the age at which various skills are acquired, permits the establishment of norms or averages. From such a framework one can determine the level of developmental attainment, expressed as the development quotient (DQ = developmental age/chronologic age), and thus ascertain whether any given child has superior, average, or inferior performance. Furthermore, after examining 10,000 infants over a period of 40 years, Gesell concluded that “attained growth is an indicator of past growth processes and a foreteller of growth yet to be achieved.” In other words, the DQ predicts potential attainment.


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Neurology_Adams. The other position—taken by Anderson and others—is that developmental attainments are of no real value in predicting the level of intelligence but are measures of completely different functions. Illingworth and most clinicians, including the authors, have taken an intermediate position, that the developmental scale in early life is a useful source of information, but it must be combined with a full clinical assessment. When this is done, the clinician has a reasonably certain means of detecting delays in cognitive development and other forms of neurologic impairment.


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Neurology_Adams. The trajectory of rapid growth and maturation continues in late childhood and adolescence, although at a slower pace than before. Motor skills attain their maximal precision in the performances of athletes, artists, and musicians, whose peak development is at maturity (age 18 to 21 years). Intelligence and the capacity for reflective thought and the manipulation of mathematical symbols become possible for most individuals only in adolescence and later. Emotional control, precarious in the school age and all through adolescence, stabilizes in adulthood. We tend to think of all these phenomena as being achieved through the stresses of human relations, which are conditioned and habituated by the powerful influences of social approval. In this extensive and pervasive interaction between the individual and the environment, which is the preoccupation of the child psychiatrist, it is well to remember that the processes of extrinsic and intrinsic organization can be separated only for the


Neurology_Adams

Neurology_Adams. individual and the environment, which is the preoccupation of the child psychiatrist, it is well to remember that the processes of extrinsic and intrinsic organization can be separated only for the purpose of analytic discussion. There is always interdependence between them.


Neurology_Adams

Neurology_Adams. As indicated earlier and in Table 27-4, the wide variety and seemingly random movements displayed by the healthy neonate are from birth, and certainly within days, firmly organized into reflexive-instinctual patterns called automatisms. The most testable of the automatisms are blinking in response to light, tonic deviation of the eyes in response to labyrinthine stimulation (turning of the head), prehensile and sucking movements of the lips in response to labial contact, swallowing, avoidance movements of the head and neck, startle reaction (Moro response, see further on) in response to loud noise or dropping of the head into an extended position, grasp reflexes, and support, stepping, and placing movements. This repertoire of movements, as mentioned earlier, depends on reflexes organized mainly at the spinal and brainstem levels. Only the placing reactions, ocular fixation, and following movements (the latter are established by the third month) are thought to depend on emerging


Neurology_Adams

Neurology_Adams. mainly at the spinal and brainstem levels. Only the placing reactions, ocular fixation, and following movements (the latter are established by the third month) are thought to depend on emerging cortical connections, but even this is debatable. In the neonatal period, when little of the cerebrum has begun to function, extensive cerebral lesions may cause little derangement of motor function and may pass unnoticed unless special methods of examination—sensory evoked potentials, electroencephalography (EEG), CT, and MRI—are used. Of clinically testable neurologic phenomena in the neonatal period, disturbances of ocular movement, seizures, tremulousness of the arms, impaired arousal reactions and muscular tone, all of which relate essentially to upper brainstem and diencephalic mechanisms, provide the most reliable clues to the presence of neurologic disease. Prechtl and Beintema have affirmed the importance of disturbances of these neurologic functions at this early age as predictors of


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Neurology_Adams. the most reliable clues to the presence of neurologic disease. Prechtl and Beintema have affirmed the importance of disturbances of these neurologic functions at this early age as predictors of delayed development.