Syndrome of Inappropriate Antidiuretic Hormone Secretion Associated With Congenital Hydrocephalus in a Dog

Introduction

In dogs, the syndrome of inappropriate antidiuretic hormone (i.e., vasopressin) secretion (SIADH) is a rare diagnosis. Cases are most commonly classified as idiopathic; however, the majority do not have advanced imaging of the central nervous system (CNS) or postmortem examinations performed to exclude other potential causes.^1–4 The current case report documents SIADH associated with severe hydrocephalus in a dog. The majority of neurological signs resolved following management of SIADH. This suggests that structural brain disease should be excluded before a diagnosis of idiopathic SIADH is made.

Case Report

A13-month-old, male bichon frise, weighing 4.1 kg, was presented for the investigation of intermittent seizures, ataxia, polyuria, and polydipsia of 6 months’ duration. Abnormal behavior, including inappropriate vocalization and loss of learned behavior, was also reported. Two partial seizures had occurred—one 6 months prior and the second 1 month prior to referral. Each episode was <5 minutes in duration and was characterized by lateral recumbency, excessive salivation, and trembling. Phenobarbital (15 mg per os [PO] twice daily) was prescribed by the referring veterinarian following the second episode. No further seizures occurred, but other clinical signs persisted. No vomiting or diarrhea was reported.

At presentation, clinical and neurological examinations revealed no significant abnormalities, with the exception of mild truncal ataxia and a dome-shaped skull. Routine clinicopathological testing showed that all hematological parameters were within reference ranges. A serum bio-chemical profile revealed mild hypoalbuminemia (2.8 g/dL; reference range 3.1 to 4.0 g/dL); decreased blood urea nitrogen concentration (8.1 mg/dL; reference range 10.1 to 24.0 mg/dL); mildly elevated alanine aminotransferase (25 μ/L; reference range 0 to 20 μ/L) and alkaline phosphatase (91 μ/L; reference range 0 to 50 μ/L) activities; severe hyponatremia (120 mEq/L; reference range 137 to 151 mEq/L); hypochloremia (90.7 mEq/L; reference range 99 to 110 mEq/L); and hypokalemia (3.13 mEq/L; reference range 3.7 to 5.8 mEq/L).

Causes of hyponatremia in dogs include hypoadrenocorticism; gastrointestinal disease; body cavity effusions; congestive heart failure; advanced renal disease; liver disease; psychogenic polydipsia; hypothyroidism; exercise-associated hyponatremia; diabetes mellitus; diuretic, mannitol, or hypotonic intravenous fluid administration; SIADH; the presence of unmeasured osmoles; and pseudohyponatremia associated with hyperlipidemia or hyperproteinemia. Diabetes mellitus, hyperlipidemia, hyperproteinemia, congestive heart failure, body cavity effusions, exercise-associated hyponatremia, and drug-related causes could be excluded by the history and routine clinical and clinicopathological findings. In addition, thoracic radiography and abdominal ultrasonography revealed no significant abnormalities other than mild cardiomegaly.

Calculated and direct serum osmolality were 255 and 233 mOsm/kg (reference range 290 to 315 mOsm/kg), respectively, excluding the presence of unmeasured osmoles. Adrenocorticotropic hormone (ACTH) stimulation testing revealed adequate cortisol and aldosterone responses following administration of intramuscular ACTH.^a This ruled out hypoadrenocorticism (pre- and post-ACTH cortisol and aldosterone concentrations of 284 and 513 nmol/L, and 111 and 1441 pmol/L, respectively). Total thyroxine (18.6 nmol/L; reference range 15 to 50 nmol/L) and canine thyroid stimulating hormone (<0.03 ng/mL; reference range <0.68 ng/mL) concentrations were within reference ranges.

Fecal parasitology was negative, and no history or clinical evidence of gastrointestinal disease was present. Pre-and postprandial serum bile acid (4.5 and 16.4 μmol/L, respectively; reference range 0 to 15 μmol/L) and blood ammonia concentrations (13.5 μmol/L; reference range 0 to 50 μmol/L) were within their respective reference intervals. Urine collected by cystocentesis yielded a specific gravity of 1.016 and an osmolality of 958 mOsm/kg, which was inappropriately high given the marked serum hypoosmolality. Urine bacteriological culture was negative, and fractional sodium clearance increased (1.23%; reference range 0% to 0.7%).

Phenobarbital concentrations (11 mg/L; therapeutic range 20 to 40 mg/L) were below the therapeutic range at presentation. Therapy was discontinued because of the suspected metabolic cause of neurological signs. Water restriction was not commenced, as test results were pending. Serum biochemical analysis was repeated 2 weeks after discontinuation of phenobarbital and revealed persistence of hyponatremia (119 mmol/L).

A diagnosis of SIADH was made, and water restriction was commenced. After 1 week, clinical signs had improved, and the sodium concentration (130.4 mmol/L) and calculated serum osmolality (281 mOsm/kg) had increased. Urine specific gravity had increased to 1.038. Magnetic resonance imaging performed at this time showed marked symmetrical dilatation of the lateral ventricles, with a thin rim of gray and white matter remaining [Figures 1, 2]. A wide communication was seen between the lateral ventricles, with absence of the septum pellucidum and corpus callosum. The gyri of the caudal forebrain were smoothed bilaterally. A diagnosis of congenital hydrocephalus was made.

Surgical management of hydrocephalus was declined by the owner. Water restriction was continued. When the dog was reexamined 4 months later, almost all clinical signs, other than mild behavioral abnormalities, had resolved. The serum sodium concentration, measured serum osmolality, and urine osmolality measured 132 mmol/L, 275 mOsm/kg, and 924 mOsm/kg, respectively, at that time.

Discussion

In healthy animals, plasma osmolality is maintained within a narrow range, largely by secretion of vasopressin in response to small increases in osmolality and activity of the thirst center.⁵ The SIADH is characterized by persistent vasopressin release, despite decreased plasma osmolality. This, combined with unrestricted water intake, results in excessive free water reabsorption in the distal tubule and collecting duct of the kidney, thereby expanding blood volume and diluting the plasma sodium concentration. Hyponatremia is worsened by continued renal sodium excretion secondary to this volume expansion. The resultant hypoosmolality is responsible for the majority of clinical signs, largely because of its effect on the CNS.

Although uncommon in humans with SIADH, polyuria and polydipsia have been reported in many naturally occurring and experimentally induced canine cases.^1,3,4,6,7 Several theories for the development of polyuria and polydipsia have been proposed. The thirst and vasopressin centers are adjacent in the hypothalamus, and both may be affected by a common structural lesion. Increased blood volume may cause pressure diuresis. Persistently elevated vasopressin concentrations may induce renal vasopressin type 2 receptor desensitization. Lastly, glomerular tubular balance may be affected, with resultant natriuresis and diuresis. However, the reason for the difference between human and canine SIADH remains unclear.

In humans, SIADH has been reported in association with malignant neoplasia (i.e., ectopic antidiuretic hormone production), pulmonary disorders, CNS diseases, bilateral head and neck dissections, acquired immunodeficiency syndrome, prolonged strenuous exercise, senile atrophy, and a variety of drugs.^5,8 Structural CNS disorders related to SIADH in humans include inflammatory and infectious diseases, neoplasia, cerebrovascular accidents, head trauma, and hydrocephalus.^5,8–11 Hereditary and idiopathic forms of the disease are also recognized.

In dogs, cases are most commonly classified as idiopathic; however, the majority do not have advanced CNS imaging or postmortem examinations performed to exclude other potential causes.^1–4 Individual cases of SIADH associated with presumptive dirofilariaris¹² or structural CNS disease (namely, granulomatous amebic meningoencephalitis¹³ and a meningeal sarcoma affecting the thalamic and dorsal hypothalamic regions⁶) have been described. Finally, SIADH has been experimentally induced in dogs by caval constriction and obstruction.^7,14,15

The diagnosis of SIADH in dogs is confirmed by exclusion of other causes of hyponatremia; demonstration of concurrent plasma hypoosmolality and inappropriately high urine osmolality; adequate renal and adrenal function; natriuresis despite hyponatremia; lack of clinical evidence of hypovolemia, ascites, or edema; and correction of hyponatremia with fluid restriction.¹⁶ All criteria were fulfilled in the current case.

Measurement of plasma vasopressin concentrations is not necessary to confirm the diagnosis. Plasma vasopressin concentrations are variable in human cases.⁵ In dogs, the vasopressin response to hypertonic saline infusion shows an inconsistent ability to differentiate between various clinical syndromes associated with polyuria and polydipsia.⁴ Furthermore, the pulsatile nature of vasopressin secretion can interfere with interpretation of the test. In healthy dogs, peak plasma concentrations during the hypertonic saline infusion test reach levels that could be interpreted as erratic bursts of vasopressin secretion.¹⁷

In the current case, extracranial causes of SIADH were excluded by a combination of clinical, clinicopathological, and diagnostic imaging findings. Thoracic radiography revealed mild cardiomegaly, but this likely reflected the intravascular volume expansion associated with SIADH. No evidence of pulmonary disease or neoplasia was seen; both are reported causes of SIADH in humans. Phenobarbital had been prescribed prior to referral, but it was discontinued following the identification of a potential metabolic cause of the neurological signs. Phenobarbital intoxication has been linked to SIADH in one human infant.¹⁸ However, such an association has not been described in other species. Serum concentrations of phenobarbital in the current case were below the therapeutic range, and hyponatremia persisted following discontinuation of the drug. Therefore, phenobarbital was excluded as a cause of SIADH.

Hydrocephalus is a recognized cause of SIADH in human medicine.^9–11 Vasopressin is synthesized within neurons of the supraoptic, paraventricular, and suprachiasmatic nuclei in the hypothalamus. Then vasopressin is transported to the posterior pituitary and stored in neurosecretory granules until released in response to appropriate stimuli. Vasopressin-secreting neurons receive excitatory input from osmoreceptive cells, thought to be located in the organum vasculosum of the lamina terminalis and in areas of the anterior hypothalamus near the anterior wall of the third ventricle. These osmoreceptive cells are also in brainstem cardiovascular regulatory centers and emetic centers.⁵ Because of the wide distribution of neurons affecting vasopressin secretion, a variety of CNS disorders have potential to cause SIADH, through excitatory or suppressive effects on stimulatory and inhibitory pathways, respectively. This highlights the importance of performing advanced imaging to exclude CNS disease before making a definitive diagnosis of idiopathic SIADH. Although a causal relationship between hydrocephalus and SIADH cannot be confirmed in the current case, the presence of both conditions concurrently and the reported association in human medicine make such a relationship likely. The majority of clinical signs were likely related to SIADH, given the marked improvement following water restriction and normalization of serum osmolality.

In human medicine, judicious administration of hypertonic saline is recommended in symptomatic hyponatremic patients with SIADH, with the aim of alleviating clinical signs rather than normalizing the serum sodium concentration. ⁸ Water restriction is preferred in asymptomatic cases.⁸ Sodium-containing fluids were not administered in the current case because of the lack of neurological signs at presentation.

Treatment of hydrocephalus by shunt surgery has improved the symptoms of SIADH in humans.^9,10 Surgery was declined by the owner in the current case. Vasopressin receptor antagonists have been used successfully in humans¹⁹ and a dog,² but they were unavailable for use in the current case. Objective evidence for the benefit of medical therapy of hydrocephalus in dogs is lacking, and the use of diuretic or glucocorticoid drugs could potentially have further disturbed water homeostasis.

Conclusion

The current case report documents the first case of SIADH associated with hydrocephalus in a dog. Structural brain disease should be excluded before a diagnosis of idiopathic SIADH is made.