These observations opened up the entire field of neuroendocrinology.

As already stated, the usual cause f DI is a lack of vasopressin (antidiuretic

hormone, or ADH) as a result of a lesion of the neurohypophysis. This leads to a
reduction in its action in the kidney, where it normally promotes the absorption
of water. As a consequence there is diuresis of low-osmolar urin (polyuria).
Reduction in blood volume, and dringking of water (polydipsia) in an attempt to
maintain osmolality. A congenital abnormality of renal tubular epithelium or
destruction of the epithelium has similar effect nephrogenic DI. DI is also of
interest to the neurologist because of its association with lithium toxicity. Which
impairs renal tubular water absorption.
Among the established causes of acuquired DI. The most important are brain
tumors, infiltrative granulomatous diseases, head injury, and intracranial surgical
trauma (which has become less frequent with the transphenoidal approach to
pituitary tumors). In a series of 135 cases of persistent DI reported by Moses
and Streeten, 25 percent were idiopathic, 15 percent complicated primary brain
tumors, 24 percent were postoperative (most after hypophysectomy or surgery
for craniopharyngioma), 18 percent were due to 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-schullerchristian disease is a more frequent cause of DI in young patients. Of the primary
tumors, glioma, hamartom and craniopharyngioma, granular cell tumor
(choristoma), large chromophobe adenomas, and pinealoma are natable. The
primary tumors cam present with DI alone. Where as the granulomatous
infiltrating processes generaly exhibit other systemic manifestations befor
polydipsia and polyuria appear. Metastatic tumors originalingin the lung or breast
or leukemic infiltration may also cause GI, sometimes in conjunction with pituitari
disturbances and impairment of vision. The mild global hypothalamic disfunction
that often follows brain irradiation for glioma may occasionally include DI as a
feature. The most extreme cases hypothalamic destruction occur in brain death,
in which DI is a regular component, although it is not always evident at the time
brainstem reflexes are lost.
Pituitary tumors are infrequently associated with DI unless they become massive
and invade the stalk of the pituitary and the infundibulum. This anatomic
ralationship has been substantiated by surgical sections of the stalk for
metastatic carcinoma and for retinitis proliferans, which result in DI only if the
section is high enough to produce retrograde degeneration of supraoptic
neurons.
Among the idiopathic form of DI, there also exists a congenital type of
hypothalamic DI, of which a small number of familial case has been described.
The disorder is evident at an early age and persist throughout life, owing to a
developmental defect of the supraoptic and paraventricular nuclei and smallness
of the posterior lobe of the pituitary. This defect has been related in some case to
a point mutation in the vassopresin-neurophysin-glycopeptide gene. It may be
combined with other genetic disorders such as diabetes mellitus, optic atrophy,
deafness (wolfram syndrome), and friedreich ataxia.
Acquired Idiopathic DI may occur at any age, most often in childhood or early
aduld life and more often in males, and by definition has no apparent cause.
Other signs of hypothalamic or pituitary desease are lacking in 80 percent of
such patients, but steps must be taken to exclude other desease processes by

repeating the endocrine and radiologic studies periodically. In some case of

idiopathic DI, there are serum antibodies that react with the supraoptic neurons,
raising the question of an autoimmune disoder. In a few such intances,
postmortem examination has disclosed a decreased number of neurons in the
supraoptic and paraventricular nuclei. Also, anorexia nervosa is often associated
with mild DI.
Finali, it should be mentioned that certain drugs used in neurologic practice-for
example, carbamazepine-may be the cause of reversible DI (excessive secretion
of ADH is more common on relation to this drug), and as mentioned, lithium
regularly cases DI, even at times at the upper range of its therapeutic serum
concentration.
In all these conditions, the severity and permanence of the DI are determined by
the nature of the lesion. In cases of acute onse, three phases have been
delineated: first, a severe DI lasting days; then, as the neurohypophysis
degenerates, a reduction in severity of DI due to release of stored ADH; and
finally a persisten pattern, usualy lifelong. The neurohypophysial axons can
regenerate, alowing for some degree of recovery even after years.
Diagnosis of DI This is always suggestes by the passage of large quantities of
dilute urine accompanied by polydipsia and polyuria lasting throughout the night.
The last two signs are, of course, obscured in an unresponsive patient, in which
case careful measurement of fluid output and input are needed to expose the
disorder. 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.
A low urine osmolality and specific gravity are found in DI, in conjunction high
serum osmlality and sodium values. Osmotic dehydration as a cause of the
polydipsia-polyuria syndrome, such as occurs with the glycosuria of diabetes
mellitus, must, of course. Be excluded. A period of 6 to 8 h of dehydration
increases urinary osmolality in a person with normal kidneys and
neurohypophysis; it is this change in urine concentration that is most useful in
the differential diagnosis of polyuria, particularly in distinguishing compulsive
water drinkers from those with DI; in the latter group, urinary volume and serum
electrolytes normalize with dehydration. Proof that the patient has a central
cause of DI and not nephrogenic unresponsiveness to vasopressin is obtained by
injecting 5 U of vasopressin (pitressin) subcutaneusly; this will diminish urine
output and increase osmolality when there is a central cause of DI. Diagnosis is
aided by the radioimmunoassay for plasma ADH; ADH is usually reduced to less
than 1.0 pg/mL in patient with central DI (normal, 1.4 to 2.7 pg/mL).
Treatment of DI Vasopressin tannate in oil, sythetic vasopressin nasal spray,
and a long-acting analogue of aginine vasopressin (desmopressin, DDAVP)
administered by nasal insufflation (10 to 20 mg or 0.1 to 0.2 mL) are use to
control chronic DI. The nasal form is generally preferred because of its long
antidiuretc action an few side effects. In unconscious patients, aqueous
vasopressin 5 to 10 U given subcutaneously, in effective for 12 to 24 h. These
drugs must be given repeatedly, guided by urine output and osmolality (we have
given these drugs intravenously in critical situation). The brief duration of action
of the medicaton is advantageous in postoperative states and after head injury,
for it allows the recognition of recovery of neurohypophyseal function an the
avoidance of water intoxication. If a longer duration of treatment in anticipated,

one uses vasopressin tannate in oil (2.5 U), the action of which persist for 24 to
72 h. In the unconcious 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 fluid to the
urinary volume and by evaluating serum and urine osmolalities every 8 to 12 h.
For patient with partial preservation of ADH function, chlorpropamide, clofibrate,
or carbamazepine can be used stimulate release of hormone.
Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Secretion As
mentioned, blood volume and osmolality are normally maintained within narrow
limits by the secretion of ADH and the thirst mechanism. A reduction in
osmolality oe 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 its reaches 287 mmol/kg (osmotic threshold). At this point, plasma ADH
level are 2 pg/mL an increase rapidy as the osmolality rises. The response of ADH
secretion to hyperosmolality is not the same for all plasma solutes; in contras to
hypernatremia, for example, hyperosmolality induced by elevations in urea
nitrogen or endogenous glocose produce minimal or no elevation in ADH.
Derangement of this delicately regulated mechanism, taking the form of
dilutional hyponatremia and water retention without edema, is observed under a
variety of clinical circumstances in which the plasma ADH is above normal or in
appropriate normal despite plasma hypo-omolality. The term inappropriate
secretion of antidiuretic hormon (SIADH) was applied to this syndrome by
schwartz and bartter because of its similarity to that produce in animals by the
chronic administration of ADH. The same syndrome can arise from ectopic
production of the hormone by tumor issue. In such cases, the thirst mechanism is
not inhibited by decreased osmolality, and contiuned drinking further increases
blood volume and reduces its solute concentration; ADH levels are found be
persistenly elevated. The physiologic hallmarks of this condition are a
concentrated urine, usually with an asmolality above 300 mosm/L, and low
serum osmolality and sodium concentrations. Because of the dilutional effect,
urea nitrogen and uric acid are reduce in the blood and serve as markes of
excessive total body water. Tissue edema is not seen because sodium excreation
in the uine is maintaned by suppression of the renin-angiotensin system and by
an increase in atrial natriuretic peptide secretion (see below).
SIADH is observed frequently with a variety of cerebral lesions (infarct,
tumor, hemorrhage, meningitis, encephalitis) that do not involve the
hypothalamus directly and with many types of local hypothalamic disease
(trauma, surgery, vascular lesions). In most cases it tends be transient feature of
underlying illness. The acute dysautonomia of Guillain-Barre syndrome is a
common cause of SIADH, and hyponatremia is particularly likely to occur in such
patients being ventilated mechanically. The increased thoracic pressure induced
by positive-pressure ventilation promotes SIADH in susceptible patients. Acute
porphyric episodes have the same effect. Neoplasms, particularly oat-cell tumors
and sometimes inflammatory lesions of the lung, may elaborate an ADH-like
substance, and certain drugs-such as carbamazepine, chlorpromazine,
chlorothiazide, chlorothiazide, chlorpropamide, clofobrate, nonsteroidal
antiinflammatory agents, and vincristine-also stimulate ADH release and may
lead to hyponatremia. In some cases, no cause or associated desease in
apparent.

A fall in serum sodium to 125 meq/L usually no apparent clinical effects,

although signs of an associated neurologic desease, 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
generakized seizures. There may be asterixis. As is characteristc of most
metabolic encephalopathies, the more rapid the deline of the serum sodium, the
more likely there will be accompanying neurologic symtoms.
Treatment of SIADH the rapid restitutionof serum sodium to normal or aove
normal levels carries a risk of producing central pontine myelinolysis (see page
973), our usual procedur in patients with serum sodium concentrations of 117 to
125 meq/L is too slowly correct the sodium concentration by restrictng water to
400 to 800 ml/day and to verify