Clinical Signs

It is believed that dogs with medically controlled PDH eventually develop a tumor large enough to cause neurologic signs. However, the rate of tumor growth is variable. Slow enlargement likely explains the lifetime risk of developing neurologic signs being as low as 10% to 30% (Bertoy et al, 1996). Indirect assessment of tumor growth can be done clinically and radiologically. Fast-growing tumors are associated with rapid onset of clinical signs of PDH and development of neurologic signs after diagnosis of PDH. Vasogenic edema surrounding the tumor mass on cross-sectional imaging is common in dogs with rapidly expanding tumors.

Neurologic abnormalities in dogs with PDH may be specific to the central nervous system (CNS) (e.g., circling, seizures, blindness) or nonspecific (e.g., mental dullness, lethargy, poor appetite, aimless pacing). Neurologic signs have been associated with tumor size (height) relative to brain size and tumor growth rate but other factors such as hemorrhage and/or necrosis may play a role. Acute neurologic signs may be associated with small tumors that have a rapid growth rate and may not allow enough time for the surrounding brain tissue to compensate for the mass effect. On the other hand, slow-growing tumors may reach a large size before causing neurologic signs (Wood et al, 2007). Of dogs with neurologic signs caused by a large pituitary tumor, approximately 15% have the signs when PDH is diagnosed, 35% exhibit signs 30 to 120 days after medical treatment for PDH has been initiated, and 50% exhibit signs more than 6 months after medical treatment for PDH has been initiated.

The most common nonspecific neurologic abnormalities caused by a large pituitary tumor include listlessness, inappetence or anorexia, dull behavior, and aimless pacing. These signs usually develop slowly, are insidious, and are often recognized by owners without being obvious to veterinarians. They may initially be attributed to other causes, such as hyperadrenocorticism, hypoadrenocorticism, medical therapy toxicosis, or old age. Thus initial management should determine a cause for the clinical signs. A database (complete blood count, serum chemistry profile, urinalysis, thoracic radiography, and abdominal ultrasonography) may be warranted in an attempt to quickly identify any new or previously unsuspected problem. Dogs with hyperadrenocorticism may acquire diabetes mellitus with or without ketoacidosis, pancreatitis, infection, or a number of other conditions that could result in listlessness, dull behavior, or anorexia. If the database does not identify the cause for illness, an ACTH stimulation test should be completed to determine if medical therapy has caused hypocortisolism, and the dog should then be treated for several days with prednisone or prednisolone therapy at a dose of 0.1 to 1.0 mg/kg q12h. This approach should provide solid evidence against or in favor of a large pituitary mass causing the clinical signs. Dogs with hypocortisolism typically have plasma cortisol concentrations (pre- and post-ACTH administration) that are 1.5 µg/dl or lower (≤40 nmol/L), and they quickly improve with glucocorticoid therapy. If the database, ACTH stimulation test result, and glucocorticoid therapy neither explain nor resolve the clinical signs, a large pituitary mass should be considered.

Specific neurologic signs associated with brain compression by the tumor mass are not as common. Less than 50% of dogs with large pituitary tumors exhibit ataxia, head pressing, head tilt, circling, urinating or defecating in the home, seizures, a behavioral change, or cranial nerve deficits. If they develop, these signs usually have a rapid onset. Blindness is an uncommon complication. In a series of 70 dogs with PDH, 12 dogs (17%) were blind when diagnosed with the disease. Acute blindness was observed in 2 of these dogs as a direct result of optic chiasm compression. Chronic progressive blindness (1.5 years mean duration) in the other 10 dogs was a result of retinal damage due to vascular and metabolic alterations associated with PDH (Cabrera Blatter et al, 2012). Rare problems attributed to large tumors and hypothalamic compression/invasion include diabetes insipidus and thermoregulatory disturbances.

Endocrine Testing

Diagnosis of a large pituitary mass before development of neurologic signs has been challenging and requires a high index of suspicion. Endocrine testing as a means of differentiating pituitary microtumors from macrotumors in PDH dogs is not widely accepted. Inconsistencies between different studies reflect variable definition of large tumor and development of new endocrine testing assays. Of all diagnostic tests, plasma concentrations of ACTH and ACTH precursors have been shown to correlate with tumor size and even more with tumor size relative to brain size in dogs with PDH (Bosje et al, 2002; Granger et al, 2005). Furthermore, PDH dogs with neurologic signs have mean endogenous ACTH concentrations that are twice as high as PDH dogs without neurologic signs, although overlap exists between the groups (Wood et al, 2007). Measurement of pro-opiomelanocortin (POMC)/pro-ACTH may represent a promising means of determining whether imaging of the pituitary gland should be pursued before neurologic signs develop.