Seizures and Bilateral Adrenal Enlargement in an Older Boxer: Insulinoma, Cushing's Disease, or Something Else?

I'm looking for some advice for Alex, a 10-year old M/N Boxer who has been a long-term patient of mine. Alex's serious medical problems started a year ago, when he had his first seizure event. Blood work following this seizure was unremarkable aside from a mild elevation in the serum alkaline phosphate activity (219 IU/L; reference range, 5-131 IU/L). Alex's owner began keeping a seizure log, and Alex had further neurological issues until 7 months ago when he suffered another tonic-clonic seizure event, which lasted approximately 3 minutes.

Following this second seizure, Alex was examined by a neurologist, who found no abnormalities on his examination. Routine blood work again showed a mild elevation in the serum alkaline phosphate with all other serum chemistry values being normal. Due to Alex's age and breed, one obvious rule-out was a brain tumor or other intracranial disease, so an MRI was performed. Fortunately, the results of Alex's MRI was normal, with no brain or pituitary masses found.

Alex did well until about 4 months ago, when he had a severe seizure lasting about 5 minutes. A week later, Alex had multiple episodes of severe weakness and disorientation. His physical examination the following day was normal, but blood work revealed a further increase in the serum alkaline phosphate activity (382 IU/L), as well as a slightly low blood glucose concentration (58 mg/dl). Alex had not eaten since the night before, but in light of his clinical signs over the past few days, we sent out a serum insulin:glucose panel, which came back as follows:

• Glucose: 61 mg/dl (reference range, 70-140 mg/dl)
• Insulin: 32.2 µU/ml (reference range, 520 µU/ml)

In light of these findings, we referred Alex for an abdominal ultrasound looking for an insulinoma. No pancreatic nodules were seen. However, bilateral adrenal enlargement was noted, and the radiologist recommended a workup for Cushing's disease. Needless to say, Alex's owners were upset and frustrated with the results and recommendations, although they were told beforehand that there was a fair chance that an insulinoma would not be visible on an ultrasound examination (even if a pancreatic islet cell tumor was there).

Despite the lack of clinical signs consistent with Cushing's disease, we performed both an ACTH stimulation test as well as a low-dose dexamethasone suppression test, both of which came back completely normal. However, at the time of this same visit, Alex's blood glucose again read low (58 mg/dl) on our glucometer so we repeated a insulin:glucose panel. The serum results again came back in the borderline range for insulinoma:

• Glucose: 64 mg/dl (reference range, 70-140 mg/dl)
• Insulin: 29.2 µU/ml (reference range, 5-20 µU/ml)

By now, I'm sure that you're thanking every deity you've ever heard of that you have reached the bottom of this case history! My question is this—do we have enough evidence to make a diagnosis of insulinoma in this dog and initiate therapy? I know most specialists require a lower blood glucose (i.e., below 60 mg/dl) before they begin to interpret glucose:insulin ratios. However, in Alex, he has had a number of slightly low glucose values with slightly high insulin readings; in light of his clinical signs, insulinoma still remains my primary differential.

As I was writing this post, I just got a call from the owner — Alex had another episode of severe weakness this morning that seemed to respond to Karo syrup applied to his gums.  As you can see, we've been through the ringer with this dog and are just hoping to get the owners some answers at this point so they can sleep a little more soundly.

Thanks very much in advance for your help and very sorry for the length of this post!

My Response:

In the face of hypoglycemia, the serum insulin level should be low, so this dog's high-normal to slightly high insulin value is inappropriate given the low blood glucose values (1-4). Many dogs suffering from insulinoma can be difficult to diagnose, since many have borderline glucose and insulin values similar to what you are describing in this dog.

Could this dog have Cushing's disease?
Hyperadrenocorticism (Cushing's disease) is a clinical diagnosis and is based primarily on the finding of compatible signs (e.g., polydipsia, polyphagia hepatomegaly, hair loss, pot-belly). In a dog suspected of suffering from Cushing's syndrome, we confirm the diagnosis by using one or more of the adrenal function tests (e.g, ACTH stimulation or low-dose dexamethasone suppression tests) (5-7).

One should never make a diagnosis of hyperadrenocorticism based on the finding of large adrenal gland size alone. Remember that the stress of any nonadrenal illness commonly leads to an overactive hypothalmic-pituitary-adrenal axis. Therefore, any dog with chronic stress or illness can develop bilateral adrenocortical hyperplasia as a physiological response. I know that some radiologists like to diagnose Cushing's disease based on adrenal gland size, but this just cannot be done using this criteria alone (5,6). Dogs with Cushing's disease certainly tend to have larger adrenal glands, but large adrenal glands alone are not diagnostic for this disease.

The way I see it, it's highly unlikely that this dog has Cushing's disease. First of all, this dog doesn't have any of the classical signs associated with glucocorticoid excess (5-7). The slightly high serum alkaline phosphatase could be secondary to Cushing's disease, of course, but there is a long list of reasons what that enzyme could be high, including primary liver or bone disease, neoplasia, and other endocrine disease (8).  The history of seizures could go along with a macrotumor of the pituitary gland, but your MRI excluded a CNS or pituitary mass as the cause of the seizures. So the obvious question is this— if this dog has Cushing's disease, how do we explain the seizures and low blood glucose values, which have NOTHING to do with Cushing's syndrome! If anything, the glucocorticoid excess associated with Cushing's can lead to mild to moderate hyperglycemia, with overt diabetes developing in 5-10% of Cushing's dogs (5,6).

So let's not get sidetracked. Let's get back to why this dog has periodic weakness and seizures. Working up and treating Alex for Cushing's syndrome, even if he does have that disease, will not help the dog's main clinical problems.

Confirming or excluding insulinoma as the cause of hypoglycemia
Insulinoma is more likely in this dog, but your blood glucose values have not been very low and your insulin levels are just above reference range limits. It would be great to collect samples during a seizure episode but that's not always possible.

This is what I would recommend: I'd fast the dog overnight at home and have the owners drop the dog off at your clinic in the morning. Then collect samples for glucose and insulin every 1-2 hours throughout the day, stopping when the blood glucose falls to below 45 mg/dl, or when the dog has signs of hypoglycemia. Then submit the sample or samples that have a low glucose for insulin determination.

Ideally, we would see clinical signs of hypoglycemia, document significant hypoglycemia (less than 55
and the lower the better) together with significant hyperinsulinemia, and then give glucose (or feed) and see the signs resolve.

If you are monitoring him and you get a blood glucose of 55 mg/dl on your in-house machine, I'd go another hour (if not symptomatic) and get another sample. If that one isn't lower, I'd continue to sample through the day but monitor closely. You don't want to do this again if possible.

If the dog isn't becoming hypoglycemic by the middle of the day, it's sometimes helpful to take the dog for a brisk walk of 5 to 10 minutes and then check a blood glucose (and insulin) concentration. This exercise can help induce hypoglycemia and hyperinsulinemia in some dogs and therefore, increasing the diagnostic yield of this prolonged fast.

Follow-up Testing and Response to Treatment on Alex:

We performed fasted "glucose curve" in our hospital as you suggested. Alex's serum glucose concentration continued to decrease throughout the day, bottoming out at 42 mg/dl (glucometer reading) after a short afternoon walk. He had minimal clinical signs but did start hypersalivating, so we stopped the test at that point. We collected blood samples for serum insulin and glucose to send out to our lab, and fed the dog. Alex ate well and the hypersalivating resolved almost immediately thereafter.

The serum results came back as follows:

• Glucose: 39 mg/dl (reference range, 70 - 140 mg/dl)
• Insulin: 52 µU/ml (reference range, 5 - 20 µU/ml)

Based on these results — severe symptomatic hypoglycemia that responding to feeding together with overt hyperinsulinemia, we made a diagnosis of insulinoma.

I am happy to report that Alex has been doing well on treatment with prednisone and an adjusted feeding schedule (many smaller meals throughout the day). To this point our spot checks in the hospital have been very normal, and the seizure episodes have resolved.

We know that we are only controlling signs of hypoglycemia in this dog and growth and metastasis of Alex's insulinoma is likely within the next few months, Due to his age, the owners have declined exploratory surgery for now and just want to control the hypoglycemia medially at this time.  

References:

1. Goutal CM, Brugmann BL, Ryan KA. Insulinoma in dogs: a review. J Am Anim Hosp Assoc 2012;48:151-163. 
2. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
3. Mehlhaff CJ, Peterson ME, Patnaik AK, et al. Insulin producing islet cell neoplasms:  Surgical considerations and general management in 35 dogs. J Am Anim Hosp Assoc 1985;21:607-612. 
4. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
5. Peterson ME. Diagnosis of hyperadrenocorticism in dogs. Clin Tech Small Anim Pract 2007;22:2-11. 
6. Melián CM, Pérez-Alenza D, Peterson ME. Hyperadrenocorticism in dogs In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
7. Kooistra HS, Galac S. Recent advances in the diagnosis of Cushing's syndrome in dogs. Vet Clin North Am Small Anim Pract 2010;40:259-267. 
8. Fernandez NJ, Kidney BA. Alkaline phosphatase: beyond the liver. Vet Clin Pathol 2007;36:223-233. 

My Other Blog Posts that Discuss Insulinoma and Hypoglycemia:

• http://endocrinevet.blogspot.com/search/label/Hypoglycemia