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Diabetes insipidus (DI) literally means a large volume of urine (diabetes) that is tasteless (insipid). Central DI is characterized by a decreased release of antidiuretic hormone (ADH; vasopressin), resulting in polydipsia and polyuria. ADH deficiency may be a result of disorders or masses that affect the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, or the superior portion of the supraopticohypophyseal tract. Approximately 90% of the vasopressinergic neurons must be destroyed to cause symptomatic DI. Because the posterior pituitary gland stores but does not produce ADH, damage by intrasellar pituitary tumors usually does not cause DI. The most common causes of central DI are trauma (e.g., neurosurgery, closed-head trauma), primary or metastatic tumors, and infiltrative disorders. Central DI can be exacerbated by or first become apparent during pregnancy, during which ADH catabolism is increased by placental hyperproduction of the enzyme cysteine aminopeptidase (vasopressinase).

Persons with central DI typically have a sudden onset of polyuria and thirst for cold liquids. They usually wake multiple times through the night because of the need to urinate and drink fluids often ice cold water from the refrigerator. When seen in the outpatient clinic, these patients usually have a large thermos of ice water by their side. The degree of polyuria is dictated by the degree of ADH deficiency urine output may range from 3 L/day in mild partial DI to more than 10 to 15 L/day in severe DI. In patients with concurrent anterior pituitary failure, secondary adrenal insufficiency is associated with decreased glomerular filtration (associated with decreased blood pressure, cardiac output, and renal blood flow), leading to decreased urine output. Glucocorticoid deficiency also increases ADH release in patients with partial DI. These effects are reversed when glucocorticoid replacement is administered and DI is “unmasked,” resulting in the rapid onset of polyuria.

Plate 1-27

Neurosurgery in the sellar region (either by craniotomy or transsphenoidal routes) or blunt head trauma that affects the hypothalamus and posterior pituitary may result in DI. As many as 50% of patients experience transient central DI within 24 hours of pituitary surgery; it resolves over several days. With the minimally invasive endoscopic transnasal transsphenoidal approach to pituitary surgery, the rate of postoperative permanent DI is less than 5%; however, with transcranial operations and with larger tumors that have hypothalamic involvement (e.g., craniopharyngioma), up to 30% of patients develop permanent DI. Damage to the hypothalamus by neurosurgery or trauma often results in a triphasic response: (1) an initial polyuric phase related to decreased ADH release because of axon shock and lack of action potential propagation beginning within 24 hours of surgery and lasting approximately 5 days; (2) an antidiuretic phase (days 6–12), during which stored ADH is slowly released from the degenerating posterior pituitary, and hyponatremia may develop if excess fluids are administered; and (3) a permanent DI after the posterior pituitary ADH stores are depleted. In 10% to 25% of all patients who undergo pituitary surgery, only the second of these three phases is seen, and DI never develops because surgical trauma only damages some of the axons; this results in inappropriate ADH release, but the intact axons continue to function and prevent the onset of DI. However, this transient, inappropriate release of ADH can have serious consequences, with marked hyponatremia that peaks approximately 7 days after surgery and that may be associated with head-aches, nausea, emesis, and seizures. This sequence of events can be avoided by advising the patient to “drink for thirst only for the first 2 weeks” after a pituitary operation.

Primary (e.g., craniopharyngioma, germinoma) or metastatic (e.g., breast, lung, kidney, lymphoma, leukemia, colon, or melanoma) disease in the brain can involve the hypothalamic–pituitary region and lead to central DI. Polyuria and polydipsia may be the presenting symptoms of metastatic disease.

Patients with Langerhans cell histiocytosis are at high risk of developing central DI because of hypothalamic–pituitary infiltration. Additional infiltrative disorders that may cause central DI include sarcoidosis, Wegener granulomatosis, and autoimmune lymphocytic infundibulohypophysitis.

Familial central DI is an autosomal dominant disorder caused by mutations in the arginine vasopressin gene, AVP. The incorrectly folded and mutant AVP prohormone accumulates in the endoplasmic reticulum of the supraoptic and paraventricular nuclei and results in cell death. Thus, children with autosomal dominant disease progressively develop AVP deficiency, and symptoms usually do not appear until several months or years after birth. Indeed, the posterior pituitary bright spot on magnetic resonance imaging (see Plate 1-8) is present early and then slowly disappears with age and advancing damage to the vasopressinergic neurons.

Wolfram (DIDMOAD [diabetes insipidus, diabetes mellitus, optic atrophy, and deafness]) syndrome is characterized by central DI, diabetes mellitus, optic atrophy, and deafness. Diabetes mellitus typically occurs before central DI. This syndrome is usually inherited in an autosomal recessive manner with incomplete penetrance, although evidence suggests that there is another form of the disorder that may be caused by mutations in mitochondrial DNA.