Diabetes insipidus and neurological disorders

1. DR. SUMIT KAMBLE
SR NEUROLOGY
GMC. KOTA

2.  Decreased secretion or action of AVP
 Syndrome characterized by the production of abnormally
large volumes of dilute urine.
 24-hour urine volume is >50 mL/kg body weight, and
osmolarity is <300 mosmol/L.

3. ETIOLOGY
 1. Neurohypophyseal DI , pituitary DI , or central DI -
usually results from agenesis or irreversible destruction of
the neurohypophysis .
 2. Gestational DI- deficiency of plasma AVP result from
increased metabolism by an N-terminal aminopeptidase
produced by placenta.
 3. Primary polydipsia- Secondary deficiencies of AVP
result from inhibition of secretion by excessive intake of
fluids.
 4. Nephrogenic DI - Primary deficiencies in the
antidiuretic action of AVP

4. Primary polydipsia
 1. Dipsogenic DI- inappropriate thirst caused by a
reduction in the set of the osmoregulatory mechanism.
Occurs in association with multifocal diseases of the brain
such as neurosarcoid, tuberculous meningitis, and multiple
sclerosis but is often idiopathic.
 2. Psychogenic polydipsia - is not associated with thirst,
and polydipsia seems to be a feature of psychosis or
obsessive compulsive disorder.
 3. Iatrogenic polydipsia - results from recommendations
to increase fluid intake for its presumed health benefits.

5. Central diabetes insipidus (DI)
 Most common
 Characterized by decreased release of antidiuretic
hormone, resulting in variable degree of polyuria.
 Lack of ADH can be caused by disorders that act at one or
more of the sites involved in ADH secretion: hypothalamic
osmoreceptors; supraoptic or paraventricular nuclei; or
superior portion of the supraoptico hypophyseal tract .

6. CLINICAL MANIFESTATIONS
 Polyuria, nocturia, polydipsia.
 Neurologic symptoms related to the underlying neurologic
disease.
 May develop decreased bone mineral density at the lumbar
spine and femoral neck.
 Serum sodium concentration in untreated central DI is
often in the high normal range
 Any form of CDI can be exacerbated or first become
apparent during pregnancy, since catabolism of
antidiuretic hormone is increased by vasopressinases
released from the placenta

7. Causes of central diabetes insipidus
1. Acquired
 Head trauma (closed and
penetrating) including pituitary
surgery
 Neoplasms
a) Primary
- Craniopharyngioma
-Pituitary adenoma (suprasellar)
-Dysgerminoma
- Meningioma
b) Metastatic (lung, breast)
C) Hematologic (lymphoma,
leukemia
 Granulomas
-Sarcoidosis
-Histiocytosis
-Xanthoma disseminatum
 Infectious
-Chronic meningitis
-Viral encephalitis
-Toxoplasmosis
 Chemical toxins
-Tetrodotoxin
-Snake venom

8.  Inflammatory
-Lymphocytic
infundibuloneurohypophysitis
-Granulomatosis with polyangiitis
(Wegener’s)
-Lupus erythematosus
-Scleroderma
 Vascular
-Sheehan’s syndrome
-Aneurysm (internal carotid)
-Aortocoronary bypass
-Hypoxic encephalopathy
 Pregnancy (vasopressinase)
 Idiopathic
2. Congenital malformations
 Septo-optic dysplasia
 Midline craniofacial defects
 Holoprosencephaly
 Hypogenesis, ectopia of
pituitary
3. Genetic
 Autosomal dominant (AVP-
neurophysin gene)
 Autosomal recessive (AVP-
neurophysin gene)
 Autosomal recessive-Wolfram-
(4p – WFS 1 gene)
 X-linked recessive (Xq28)
 Deletion chromosome 7q

10. CAUSES
1. Idiopathic CDI —
 Approximately 30-50% of CDI are idiopathic.
 Associated with destruction of the hormone-secreting cells
in the hypothalamic nuclei.
 Autoimmune process is involved in many.
 Presence of cytoplasmic antibodies directed against
vasopressin cells (Ab-positive)

11.  Characterized by lymphocytic inflammation of the
pituitary stalk and posterior pituitary that resolves after
destruction of the target neurons.
 MRI early in the course often reveals thickening or
enlargement of these structures.
 Associated with age less than 30 years, and history of
autoimmune disease.

12. 2. Familial and congenital disease
a. Familial CDI
b. Wolfram syndrome
c. Congenital diseases such as congenital hypopituitarism
and septo-optic dysplasia.
Familial CDI — familial neurohypophyseal diabetes
insipidus or FNDI
 Autosomal dominant disease caused by mutations in the
gene encoding antidiuretic hormone.

13. Wolfram syndrome —
 Wolfram or DIDMOAD syndrome is characterized by CDI,
diabetes mellitus, optic atrophy, and deafness;
 Inherited as an autosomal recessive trait with incomplete
penetrance.
 Caused by two different genes: WFS1 and ZCD2
Congenital hypopituitarism —
 CDI has been described in patients with congenital
hypopituitarism with or without ectopia of the posterior
pituitary lobe.
 May be associated with isolated growth hormone
deficiency or multiple anterior pituitary hormone
deficiencies.

14. Septo-optic dysplasia —
 CDI can be seen in a number of congenital cerebral midline
abnormalities.
 Septo-optic dysplasia (SOD) has been associated with
defects in both anterior and posterior pituitary function
 Most cases of SOD are sporadic, but familial cases have
been described in association with mutations in genes for
developmental transcription factors (such as HESX1)

15. 3. Neurosurgery or trauma —
 CDI can be induced by neurosurgery (usually
transsphenoidal) or trauma to the hypothalamus and
posterior pituitary.
 Incidence of CDI varies with extent of injury, ranging from
10-20% after transsphenoidal removal of an adenoma
limited to the sella to as high as 60-80% after removal of
very large tumors.
 Serum sodium higher than 145 meq/L within the first five
days postoperatively had a high predictive value for
permanent DI development

16.  Severe damage to the hypothalamus or tract results in
typical triphasic response .
 Initial polyuric phase (24 hours - 4 to 5 days) reflects
inhibition of ADH release due to hypothalamic
dysfunction.
 Antidiuretic phase (Days 6 to 11 ) stored hormone is
slowly released from the degenerating posterior pituitary.
During this stage, excessive water intake can lead to
hyponatremia because of a transient syndrome of
inappropriate ADH secretion .
 Permanent DI - ensue after the posterior pituitary stores
are depleted.

17.  Despite relatively high frequency of CDI in patients
undergoing neurosurgery, most cases of polyuria in this
setting are not due to CDI .
 More common causes are excretion of excess fluid
administered during surgery and/or osmotic diuresis
induced by mannitol or glucocorticoids (which cause
hyperglycemia and glucosuria) given in an attempt to
reduce cerebral edema.
 Differentiated from CDI by measuring the urine
osmolality and the response to water restriction and
administration of ADH

18. 4. Cancer —
 Primary or secondary (most often due to lung cancer,
leukemia, or lymphoma) tumors in the brain can involve
the hypothalamic-pituitary region and lead to CDI .
 In some patients with metastatic disease, polyuria is
presenting symptom

19. 5. Hypoxic encephalopathy —
 Hypoxic encephalopathy or severe ischemia (as with
cardiopulmonary arrest or shock) can lead to diminished
ADH release.
 Appearance of DI in these patients is consistent with
occasional pathologic findings of scarring and atrophy in
the supraoptic nuclei and posterior pituitary gland.

20. 6. Infiltrative disorders —
 Patients with Langerhans cell histiocytosis are at
particularly high risk for CDI
 Sarcoidosis, Granulomatosis with polyangiitis and
Autoimmune lymphocytic hypophysitis

21. 7. Post-supraventricular tachycardia —
 Transient polyuria is occasionally seen after correction of a
supraventricular tachycardia
 Both a water diuresis and a natriuresis may be seen, due
respectively due to decreased secretion of ADH and to
increased release of atrial natriuretic peptide

22. 8. Anorexia nervosa —
 ADH release is often subnormal in patients with anorexia
nervosa, presumably due to the cerebral dysfunction

23. Diagnosis of polyuria and diabetes
insipidus
 Polyuria has generally been defined as a urine output
exceeding 3 L/day in adults and 2 L/m2 in children.
1. Onset of polyuria-
 Hereditary nephrogenic DI- during first week of life.
 Familial central DI - may present after the first year of life.
 In adults- onset is usually abrupt in central DI, and almost
always gradual in acquired nephrogenic DI or primary
polydipsia.

24.  New onset of nocturia in the absence of other causes of
nocturia (eg, prostatic enlargement in men over 50 years of
age or urinary tract infection in children) is often a first
clue to DI.
2. Family history
Familial forms of both central and nephrogenic DI.
3. Measurement of urine output
 Obtain timed urine collection to confirm the presence of
polyuria

25. 4. Plasma sodium and urine osmolality-
 Low plasma sodium concentration with a low urine
osmolality - primary polydipsia.
 High-normal plasma sodium concentration points toward
DI, particularly if urine osmolality is less than the plasma
osmolality.
 Normal plasma sodium concentration is not helpful in
diagnosis but, if associated with a urine osmolality more
than 600 mosmol/kg, excludes a diagnosis of DI.

26. 5. Water deprivation test
 Baseline
 Weight
 Plasma and urine osmolality
 Serum electrolytes
 Deprive of water
 Under constant supervision
 Monitor hourly serum/urine osmolality, urine output and
weight.
 Primary polydipsia - If urine concentrates and serum
osmolality remains low.

27.  If fluid deprivation does not result in urine concentration
(osmolarity >300 mosmol/L, specific gravity >1.010) before
body weight decreases by 5% or plasma osmolarity/sodium
rise above the upper limit of normal, patient has severe
pituitary or severe nephrogenic DI.
 These disorders usually can be distinguished by
administering desmopressin (0.03 μg/kg SC or IV) and
repeating the measurement of urine osmolarity 1–2 hours
later.
 An increase of >50% indicates severe pituitary DI, whereas
a smaller or absent response is strongly suggestive of
nephrogenic DI.

28. 6. Plasma and urine ADH measurement —
 Plasma or urine samples collected at baseline and
following water deprivation should be sent for
measurement of ADH :
 If there is an increase in plasma or urine ADH in response
to the rising plasma osmolality, central DI is excluded.
 If there is an appropriate elevation in urine osmolality as
ADH secretion is increased, nephrogenic DI is excluded.

29. MRI of Pituitary and Hypothalamus
 In most healthy adults and children, posterior
pituitary emits a hyperintense signal in T1-weighted
midsagittal images.
 This “bright spot” is almost always present in patients
with primary polydipsia but is invariably absent or
abnormally small in patients with pituitary DI.
 It is usually also small or absent in nephrogenic DI
presumably because of high secretion and turnover of
AVP.

32. Treatment of central diabetes insipidus
 Desmopressin , which is an ADH analog and is preferred
drug in almost all patients.
 Other drugs -chlorpropamide, carbamazepine , thiazide
diuretics, and non steroidal antiinflammatory drugs.
 A low solute (mostly low sodium, low protein) diet.
 Initial aim of therapy is to reduce nocturia.
 Once this is achieved, aims for partial control of the
diuresis during the day.

33. DESMOPRESSIN
 Desmopressin (DDAVP) is synthetic analogue of AVP
 Acts selectively at V 2 receptors to increase urine
concentration and decrease urine flow in a dose-dependent
manner
 More resistant to degradation than is AVP and has a three-
to fourfold longer duration of action.
 Preparations- can be given by IV or SC injection, nasal
inhalation, or oral tablet.
 Doses - 1–2 g qd or bid by injection, 10–20 g bid or tid by
nasal spray, or 100–400 g bid or tid orally.

34.  Onset of action is rapid, ranging from as little as 15 minutes
after injection to 60 minutes after oral administration.
 Safe during pregnancy for both the mother and the fetus

35. Thiazide diuretics, Chlorpropamide, carbamazepine ,
clofibrate, and nonsteroidal antiinflammatory drugs
 Increase ADH release or enhance ADH effect on the kidney
 Associated with more side effects than desmopressin and
are generally less effective.
 Lower urine output by 25 to 60%

37. REFERENCES-
 Uptodate.com
 Harrisons principles of internal Medicine. 19th edition
 Maghnie M, Cosi G, Genovese E, et al. Central diabetes
insipidus in children and young adults. N Engl J Med 2000;
343:998.