• Traumatic or post-surgical
• Related to tumor invasion of posterior pituitary:
  • Extension from anterior pituitary/suprasella: optic glioma, rarely adenomas
  • Hypothalamic: germinoma, craniopharyngioma, meningioma
  • Lymphoma
  • Granulomas: histiocytosis X, sarcoidosis
  • Metastatic carcinoma
• Post-severe ischemic or hypoxic injury to the brain
• Familial (autosomal dominant)
• Congenital malformation of central nervous system
• Infection
  • Viral encephalitis
  • Meningitis
  • Tuberculosis
• Increased metabolic clearance of ADH (gestational diabetes insipidus)
• Drug- or toxin-related: snake venom, tetrodotoxin
• Autoimmune disorders
• Psychogenic: excessive water drinking
• Idiopathic: must observe for many years to exclude slow-growing tumors

• Familial or “nephrogenic” (X-linked dominant and autosomal recessive forms)
• Tumor-related
• Urinary tract obstruction, especially in utero
• Renal medullary cystic disease
• Electrolyte disturbances: hypokalemia, hypercalcemia (hypercalciuria)
• Drugs: usually reversible
  • Diuretics
  • Diphenylhydantoin
  • Reserpine
  • Cisplatin
  • Rifampin
  • Lithium: may become permanent
  • Demeclocycline
  • Ethanol
  • Chlorpromazine
  • Volatile anesthetics
  • Foscarnet
  • Amphotericin B
• Loss of the medullary concentrating gradient due to successive free water intake relative to solute intake

• ADH stimulates the formation of cyclic adenosine monophosphate (cAMP) in the renal collecting ducts, thereby increasing water permeability and increasing reabsorption of free water.
• Lack of ADH effect results in urinary loss of free water.
• Patients with an intact thirst mechanism drink copiously (polydipsia) to compensate for free water loss.
• If the thirst mechanism is not present or if access to free water is limited (e.g., infants or vomiting), severe dehydration can occur.

• Rare cases of autosomal dominant transmission of ADH deficiency
• Nephrogenic diabetes insipidus (DI) is usually familial (either autosomal recessive or X-linked dominant)

• Without treatment and without access to water:
  • Hypernatremia
  • Dehydration
  • Coma
• When overdosed with water:
  • Hyponatremia
  • Seizures
  • Cerebral edema

• Generally good but depends on the primary cause

• Psychogenic polydipsia
• Abnormal thirst mechanism (dipsogenic DI)
• Hypernatremic dehydration
• Diabetes mellitus
• Polyuric renal failure (e.g., renal tubulopathy)
• Hypercalcemia
• Adrenal insufficiency
• Cerebral salt wasting

Question: Is the child growing normally?
Significance: Abnormal growth can be a sign of DI.

Question: Does the patient wake up during the night to drink or void? If so, what does the patient prefer to drink?
Significance: True DI is associated with polyuria throughout the day and night. Enuresis may be the first sign in a child who previously acquired bladder control. Patients, including infants, prefer water over other liquids such as juice, soda, or milk

Question: How many hours can the patient go without drinking?
Significance: Patients with complete DI do not voluntarily stop drinking for more than 1 to 2 hours, unless the thirst mechanism is also abnormal.

Question: Volume of urine output in a day (not just frequency of urination)?
Significance: The daily volume of urine can be as high as 4 to 10 liters. Younger or dehydrated children with DI tend to make less urine daily than older or hydrated children with DI.

Question: Familial history of DI?
Significance: Nephrogenic DI will typically affect maternal uncles during infancy.

Question: Has the child had frequent episodes of dehydration requiring medical attention?
Significance: Families may disregard the polydyisia as normal behavior. Repeated episodes of severe dehydration can damage the brain.

Finding: Signs of dehydration
Significance: DI is typically associated with dry, pale skin and mucus membranes.

Finding: Complete neurological examination
Significance: Check for impaired visual fields which can be the first sign of brain tumor.

Test: Morning urinary osmolality with simultaneous serum sodium and serum osmolality.
Significance: If urine osmolality is at least two times higher than serum osmolality, patient does not have complete DI.

Test: Water-deprivation test
Significance: Though definitive, it requires admission to the hospital for controlled testing under the close supervision of a pediatric endocrinologist. Patient fails test if either:

Once patient fails the water deprivation test, a dose of aqueous vasopressin should be given followed by close monitoring of urinary osmolality to document responsiveness to ADH.

Test: Urinary specific gravity
Significance: Insufficient by itself and non-diagnostic during a water deprivation test.

Test: MRI of the head
Significance: To confirm the “bright spot” normally seen in the posterior pituitary and to search for tumors.

HOME TESTING

Test: 24-hour urine collection
Significance: To obtain accurate urinary volume while patient has free access to water.

Do not restrict water intake unless the patient is in the hospital under close surveillance!

• DDAVP: intranasal spray or oral tablets
• Aqueous vasopressin: subcutaneous
• Duration of action of DDAVP is variable from patient to patient. Titration and frequency of dosing should be made by the family under the supervision of an endocrinologist.
• Control of DI in infants is more difficult because these patients may increase fluid intake due to hunger or increase caloric intake due to thirst, thereby causing an imbalance between free water intake and output. Some infants can be treated with diluted formula—the volume and frequency of feedings will be increased, but intake of free water will better match urine output. Strict record keeping of intake/output and accurate daily weighing are usually necessary for infants or patients without an intact thirst mechanism.
• Nephrogenic DI has been treated with diuretics since these patients are resistant to DDAVP.

• Facial flushing
• Increase in blood pressure
• Headache
• Nasal congestion
• Hyponatremia: caused by water overdose (intoxication), not by overdose of drug. Taking a higher dose of DDAVP will generally extend the period of anti-diuresis but will not cause hyponatremia. Drinking too much water in the setting of anti-diuresis causes hyponatremia. Water intoxication most often occurs in anti-diuresed patients who also are on intravenous fluids, lack an intact thirst mechanism, or have psychogenic polydipsia.

• Patients with an intact thirst mechanism should drink only when thirsty.
• Patients without an intact thirst mechanism should drink only a carefully calculated fluid volume.

• Effects of DDAVP are immediate.
• Most cases of DI are lifelong. One exception is DI that occurs during the 7 to 10 days immediately after neurosurgery, since this post-surgical DI may resolve spontaneously within 1 to 2 weeks after surgery.

• Lethargy
• Somnolence
• Irritability
• Hyperpyrexia
• Any sign of dehydration
• Seizures

• Management of patients without an intact thirst mechanism and of newborns is difficult.
• Patients with psychogenic polydipsia may fail a water deprivation test because prolonged excessive water intake can wash out the renal medullary gradient required for concentrating the urine.
• Surreptitious water intake during water deprivation test.
• Idiopathic, acquired DI can be due to slowly growing brain tumors not visible on the initial MRI.

Q: In a patient with intact thirst mechanism and partial DI is the use of DDAVP necessary?
A: No, as long as the patient has constant access to free water.

Q: How does therapy of DI affect daily life? Is it easily integrated into normal activity and eating patterns?
A: DDAVP is used in a patient with intact thirst mechanism to facilitate the daily routine as well as to allow patients to sleep without the need to void frequently during the night.

Q: Is there a longer acting preparation or an implantable pump for dosing?
A: The longest-acting form of ADH is an injected medication and can have effects for 3 days, increasing the risks of hyponatremia. Home use of the nasal spray or tablets is, therefore, easier and safer than the use of injections.

Mootha SL, Barkovich AJ, Grumbach MM, et al. Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab 1997;82(5):1362–1367.

Kirchlechner V, Koller DY, Seidl R, Waldhuser F. Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride. Arch Dis Child 1999;80(6):548–552.

Leger J, Velasquez A, Garel C, Hassan M, Czernichow P. Thickened pituitary stalk on magnetic resonance imaging in children with central diabetes insipidus. J Clin Endocrinol Metab 1999;84(6):1954–1960.

Robertson GL. Diabetes insipidus. Endocrinol Metab Clin N Am 1995;24(3):549–572.

Siegel AJ, Baldessarini RJ, Klepser MB, McDonald JC. Primary and drug-induced disorders of water homeostasis in psychiatric patients: Principles of diagnosis and management. Harv Res Psychiatry 1998;6(4):190–200.