Thank you very much, Bruce. Good evening, everyone. Welcome to this presentation on difficult cases of Cushing's disease.

And, I, I think we, we'll start, with a plan, some considerations, we need to think about before we start. Then, we'll talk a little bit about difficult cases in terms of unusual clinical signs. Then talk about Difficult cases that may have perfectly normal clinical signs, but the test results don't match the appearance.

Difficult cases with adrenal tumours, difficult cases with pituitary macroadenomas, and finally some difficult cases and considerations when we have concurrent conditions and hopefully then they'll be some time for questions. I think the first question I always ask myself when I see a case of Cushing's disease is, is it really important? Just today we were presented with a dog that has an adrenal tumour invading the caudal vena cava, but its main sign is of pancreatitis, and, and it's, it's very easy to get swept away with this adrenal tumour, whereas actually the pancreatitis is, is the thing that's going to cause this dog the most problems right here and now.

It's very easy to come away from one of these talks, thinking that Cushing's is all important. And I always invite you to consider this scenario of tomorrow morning, you're in your clinics and an 8 year old dog comes in for routine vaccination. You see the mild alopletia, you ask about the PUPD and to cut a long story short, you diagnose Cushing's disease and treat it with adrenal suppressive drugs, and the result of all this treatment is an acute Addisonian crisis and death.

And then the owner comes in and says, but I only came in for the vaccination. My dog wasn't ill before. I think it's hugely important that before we go down this pathway, we establish the clinical signs that we're trying to treat.

There are cases of Cushing's disease out there that do not have significant clinical signs, and if they are clinical signs are insignificant, it's probably better to wait and see. So before we diagnose or treat Cushing's, we need to be sure of the diagnosis. The treatments that we're offering for these conditions are not entirely safe.

Some are safer than others, but it is often safer to wait if you're not sure. I think before we even start diagnosing or treating these conditions, we need to counsel the owner. The costs of diagnosis may not be cheap.

The costs of treatment may not be cheap. We need to talk about the benefits of it, but also to acknowledge in the same, sentence, the risks, those risks, include a failure of treatment, of course, adverse reactions to the treatment. And most importantly, the unmasking of disease.

Another case I have at the moment, every time we try and treat it, we try a stain, it develops diarrhoea. The dog has, it seems, an inflammatory bowel disease that is being controlled by the Cushing's. We treat the Cushing's, the inflammatory bowel disease, so you have to choose what's on your carpet, the PUPD or the diarrhoea.

The owner chooses the PUPD. In all these cases, it is always worthwhile considering monitoring rather than treatment that enables the owners to really appreciate how bad the dog is and how much it's really affected and you, and gives them greater confidence to the decision to treat or alternatively not to treat. So before we start, we need to think of those considerations.

Sometimes we're presented with cases with unusual clinical signs, and these are a range of signs that may or may not be caused by Cushing's disease. And my question to you for the poll question is which of these signs can be caused by Cushing's disease? You can choose up to 4.

Right, folks, the poll is launched. You know how it goes. Just read through it, select the ones that you feel are correct or the one, and click on that.

The answers or the, the figures coming through are completely anonymous, so we don't know who has voted what. So don't be shy. Let's, get involved and give us your opinion.

Come on guys. We're at a minute now and only half of you have voted. It's a takes a while to do this question, Bruce, because actually everyone's got to read and think it is one of those ones you really do have to read and think.

Could this be caused by? Is it any connection at all, or is there none? It's, I've done this question a few times for a few audiences and, and it always makes people stop and think and I think that's the, the purpose of the question is to make people stop and think, could this be, could it be?

Yeah, always a good, a good, outcome I think. So we'll be a little more patient and instead of the usual 1 minute to answer, we'll push it a bit up to 2 minutes, I think. About 10 seconds left, folks.

Right, I, I'm going to end the poll now and show those answers to us. Here we go. Can you see that?

I can see that. And if you can just leave those answers up there, we, we can, just quickly run through them. First of all, the, the market leader in, in odd signs for Cushing's excess bruising.

Yes, absolutely. Cushing's causes a, a failure of the elastic recoil of blood vessels, and excess bruising is, is quite common. Next up, jaundice.

Now I, I, I'm, I'm surprised to see people answering this. I, I cannot actually think of a way that this could, except possibly. Some people might link Cushing's disease with biliary mucous cells, and they may present as as jaundice.

But despite the really severe increase sometimes in liver enzymes, jaundice itself is, is actually not reported as a complication of, of Cushing's disease. So, so, I, I would, I would say possibly not. Bradycardia, not, not so either, actually.

that, that, that's something we associate with Addison's disease, and, and I'm not aware of any pathogenetic mechanisms which would lead to, bradycardia. However, acute respiratory distress, absolutely, pulmonary thromboembolism. Rare though it is, presents as acute respiratory distress, and over the years I've seen a number of dogs with signs of Cushing's that have rocked up in some considerable respiratory distress, panting and struggling to breathe with, with arterioven arterial alveolar mismatch in their, in their oxygenation.

Weight loss, weight loss is an interesting one actually. There are some people who argue that that, that can happen. The catabolic effects of the, the steroids can happen.

I, I've never seen one myself, but, but I, I believe it. Seizures, I guess that's because of the pituitary tumour, but again, I have to say, not so much actually. Pituitary tumours being at the base of the brain do not really impinge on the cortical function.

Which is, which is what is required to generate seizures, so, so possibly not. Whereas loss of surface or sensation by some peculiarity and I've got a slide on this later on, loss of facial sensation has been seen with some cases of Cushing's. Lastly, the one that actually is, is probably the most common of those is, oxalate urothiasis.

Many, many, many dogs, with Cushing's disease, have got, got oxalate crystals in their urine and, and may develop, in fact, calcium oxalate urus. Steroids increase calcium excretion, and that increased calcium excretion helps that formation of calcium oxalate urotiasis. So, so there's, there's quite a, a, a, a number, a number of signs there that do have some link to Cushing's.

And, well, we'll just run through, through these in a bit more detail because these are the difficult cases to, to spot and to be, to be aware of. So obviously, most, most dogs with Cushing's have all the signs you'd expect PUPD dematronical changes, pot-bellied, polyphagia, lethargy, panting, and obesity, and we, we know that. However, despite what they show in the textbooks, quite a lot of dogs I see with Cushing's do not have dermatological change or not significant dermatological change.

The trouble is that when you're writing a textbook chapter and I've been guilty of this myself over the years. It's very difficult to show good pictures of Cushing's without showing dermatological change. So as a result, we tend to get this idea printed on our brains that dermatological change is very, very common in Cushing's.

In fact, only about 30 to 50% of dogs have dermatological change that owners will notice, and, and it sometimes requires a bit of questioning from our part, and it's very breed dependent about how much change you, you see. So I think it's important to remember that some of those classic, classic photographs that you see of Cushing's disease, are, are perhaps a little unrepresentative, nowadays. Hemostatic abnormalities, we mentioned in our little survey.

This is an example that that bichon frise that I showed you in the black and white photograph. That's a colour photograph of the neck of this dog, having had a singular jugular blood sample, done for, for, for sampling purposes. And you can see the bruising, that bruising, I can tell you is stranded all the way down into the thoracic inlet and into the area between the two axillae.

That's a fairly substantial amount of, bleeding, for, for a little, little dog, and it was done from a singular jugular blood sample, that, that, that dog had Cushing's. Reproductive problems, so poor, poor, reproductive function from both males and females. So you often will see, very soft and, and small, testicles, and, pendulous prep uses in the males and in females, you will see a loss of normal cycling.

Neurological signs will come on to diabetes mellitus, of course, can be a complication, and pancreatitis and, and there's. Some debate about how much cause, cause, Cushing's does represent a pancreatitis, but we know from, a couple of studies that that dogs with pancreatitis seem to be overrepresented in the dogs with Cushing's and, and vice versa. the only thing I, I, I would just say on that is that, just be aware that when you look at, dogs with Cushing's but who do not have, do not have pancreatitis, the number of abnormal.

Snap PL test, snap PLI tests is really rather high. The steroids induce PLI in the same way that they induce, Alcross and, and ALT, and, and it also, that also applies to, to, to, to some of the other enzymes as well. So just be aware that dogs can with Cushing's cannot be diagnosed with pancreatitis just on the basis of a snap PL.

You need other evidence as well. One particular clinical sign that, that, interests me is, is the myotonia, pseudomyotonia of, of Cushing's disease is a recognised complication. It's seen particularly in, in poodles, but also we see it in other breeds as well.

And this is, this is, a case of, pseudomyotonia or myotonia in a cushingoid dog. And you can see here the very stiff hind limb gait. These dogs get.

Now, now this, this dog, even if you treat its Cushing's, may well struggle to walk normally for the rest of its life. And you, this can be quite debilitating for, for the dog. It can make normal exercise impossible, and in the most severe cases can lead to collapse.

So that's another example of a presentation for Cushing's disease. This was actually to the neurology service and they, and they filmed this, not knowing this dog had, had. Cushing's, although they were suspicious, and these things can, can, can confuse us quite a bit, quite a bit depending on their presentation.

Just watch it walk again, that, that very stiff hindling game. And this to me, this is, this is a, a classic example where you really do have to get good control of the cushings quickly, if you're going to get this dog, functional again. We may see neurological signs due to that expanding pituitary tumour, but seizures are rare, and we'll come back to, to, to that when we talk about the pituitary macroadenomas.

The other thing that we can see, and this is the eye of a dog with Cushing's disease being having a swab placed very close to it, and touching the able to touch the cornea, is, is the, loss of facial, facial sensation, which may be unilateral, and, but may Occur on the other side a few weeks later. We don't know why this happens. It seems to happen often around the time we're starting treatment.

So is it that the action of treatment that's causing it or, or, or, or is it the condition itself? The condition seems to resolve by Self over weeks, months, but during that time, we have to keep the eye lubricated and check for foreign bodies and so forth. But you see these, these mono neuropathies and, and no one knows the pathogenesis of it, but it is another sign of, of Cushing's disease.

All of these things that I've shown you. Always have usual clinical signs as well. And I think it's a recognition that these other things may occur and be, not be evidence of a second condition, but rather just evidence of the primary condition.

Then it's important. And if you see these cases and they don't have evidence of Cushing's on clinical examination, then it's probably not Cushing's. It's probably another cause of this.

So if you see a little Westie walking like that, and it has no evidence of Cushing's, then it probably. It isn't that. But if there is these sorts of signs and you do have evidence of Cushing's, then you can relate them.

And it's worthwhile if you, if you get a dog with Cushing's contacting an endocrinologist, if you come across a weird sign, just in case it's actually to do with that. What that does mean, however, is that when you start looking at these dogs with these weird, slightly weird signs, you need to be slightly more stringent on your testing in terms of the threshold that you will accept for positive results because clearly it's not typical. So that group of difficult cases that we encounter are not the presentations, but actually the diagnosis diagnosis and particularly where we have signs of PUPD, alopeci lethargy, and biochemical changes, all of which may be caused by something else, of course, but, the clinical signs, the, sorry, the diagnostic tests have not given us the result we expect.

And the only thing I would say is that obviously the more clinical signs you have of Cushing's, the more chance it actually is of Cushing's. It sounds obvious, but therefore, the less stringent you need to be on your endocrine test. We, we, we as a profession tend to take the report from the referral laboratory, when, when it says, you know, the cutoff of the diagnosis of Cushing's is X.

We assume that we have to have X + 1 and we diagnose Cushing's, and X minus 1, we do not. And that is In a particularly good way of looking at it, it's better to look at varying your thresholds according to how many clinical signs. And that comes with experience, being able to know how much you can lower your threshold because there's a lot of clinical signs or increase your threshold because there's very few or some very odd clinical signs.

ACTH stimulation tests are a good example of this. If you send off a test to a laboratory, then they will tell you that the normal goes up to about 450 post ACTH cortisols in nanomoles per litre, and Cushing's disease is diagnosed over 550. That leaves apparently good clear blue water between those two things.

Everything should be very simple. However, of course, that's not, not, not true. That value of 550 or 600 is merely an average cutoff value, and there will be some cases that you'll be able to diagnose confidently with a slightly lower post ACTH cortisol.

And equally, there are some dogs which have other concurrent clinical conditions, for example, diabetic ketoacidosis. Who do not have Cushing's but whose post ACTH cortisol might be higher than that cut off of 400. So interpretation of these stimulation tests is really in the hands of the vet who's got the dog, and, and the laboratories can provide some guide, but we need to be able to say, OK, in this particular case, because there is so much going on, we can be a bit more firm, on our diagnosis and therefore we do not need as much evidence from that ACTH stimulation test.

And equally, if there's the, the case is very, very mild and, and you're not sure, then you probably need to set your threshold for that diagnosis, a little bit higher. and that's just to remind us that if you get a flatline ACTH stimulation test, and lots of clinical signs, then the dog is probably getting steroids from somewhere. This, this graph here, is, is essentially the same as what you've just seen.

It's a study by the Swiss led by Claudia Rosn and Nadia Sibiuel, and they took a group of dogs with pituitary dependent disease, dogs with other diseases and healthy dogs, and you can see here the sort of, distribution that you get with clearly, some, of these, Right, let me just draw it on here. Some of these cases having a Sorry to options. So here some of these cases here.

In the post ACTH sample of the dogs with other diseases, they are actually above. There's a couple there, and equally well, some here that are really trending down, and the ability to distinguish these dogs here depends more on your clinical exam than anything else. So immediately you think, well, OK then, so non ACH, why not low dose texts, and we know that if we suppress the cortisol production, that these dogs are probably normal, but if the suppression can be broken or never is suppressed, then they have Cushing's, and we usually take a cutoff here of about 14 animals per litre to distinguish those two.

Is this reliable? Well, I, I, I, I think that in the, in the nice sense, it probably is, but in some cases, it's not that easy. So here's, here's a, here's a test for, for you, and, and there isn't the right answer here, I would hasten to add, that, when you are faced with a dog whose post ACTH cortisol, sorry, whose postexam methasone cortisol is 35, but whose predex and 3 are post X are 195.

195. What's your interpretation of that? Is, is that adrenal, pituitary, Cushing's, but you don't know what sort, not Cushing's.

The DEX has not been given or is uninterpretable, and would you reject that result? I'd be interested in how you, how you see this. Right, there we go, folks.

The poll is live. Click away and it is a bit of a tricky question. Maybe not as complex as the first one, Ian, but still a tricky question.

Yes. Judging by the voting numbers, I think you have got about the same response so far as what we had last time. Yeah.

It takes a, it takes a while. This, this, by the way, is, is what's known as the inverse, inverse dexamethasone, inverse response to the dexamethasone suppression test and has been the focus of some, controversy. So, I, I, this is a controversial result.

Excellent. Right, 10 seconds to go, folks. Right, let's end that poll and share those results with you.

Right, OK then, great. Oh yeah, so this shows, that as you can see, everyone's dis and everyone's sort of going, I don't know, and we've got things, and I, I think the person who, who put decks not given. Actually, you are, you are just as right as everyone else, that.

But if dexa dexamethasone had not been given to this patient, do not presuppose that it's, it's cortisol would remain constant throughout the day. Our cortisol varies during the day quite easily that much, and it'd be quite possible, quite possible that this animal had never had dexamethasone injected. it, it, it certainly is a possibility.

Could it be adrenal? Possibly. Could it be pituitary?

Possibly. Could it be Cushing's? Well, possibly, but the problem with, with, with, with all those top three answers is that post, 8-hour dexamethaone or the 8-hour dexamethasone is below that threshold.

so do we say, oh, well, that's not Cushing's end, but it's not suppressed at 3 hours either. And that, that means that this, this is unsuppressible cortisol production. And that's, that's pushing more towards Cushing.

So we've got contradiction here. So the two people who put uninterpretable and reject results, you're brave, but that's where I'm going with this one. It, it is, it is hard to turn around to a client having done, 8 hours of testing.

And probably, quite a bit of money to turn around and say this did not work. But, but that, that is, that is certainly, a, a, a very, how should I say, a, a strong, strong, line to take, but it's probably the safest is to say that this is not, not known. If we, if we go on.

And look at this, this inverse pattern. This is, this is essentially what happened in this case is, is that it did not suppress and then it did suppress. And it's been some controversy, but, in order to resolve this, the group from Dublin have looked hard at their low dose dexamethasone suppression tests.

And they, they managed to find 135 cases where they had not only the results, but also they had, investigated these cases to the limit of their capability of these cases being investigated in a referral setting. So we can be pretty confident about, the outcome. And of the 123 cases, they had 59 that did they decide turn out to be Cushing's and 64, that did not.

And if you take the inverse pattern, then that would fall into that bottom category there where you can see that they had 5 cases, 5 cases that had the inverse pattern. 2 of which turned out to have Cushing's and 3 of which turned out not to have Cushing's down here. And, and that shows you that these tests aren't, aren't, aren't that, always that diagnostic.

They don't give you the neat, nice pattern. And if you look at the samples where there was only partial suppression or there was an escape pattern, then it becomes, clear that it is difficult to, use these tests brilliantly. Indeed.

Their final conclusion was that in dogs that had Cushing's, 16% of the dogs that had Cushing's had a low dose dexamethasone test. It was either wrong, i.e., said the dog did not have Cushing's, or was hard to interpret, uninterpretable.

And that's probably higher than most people expected. One of the figures that's often going that is that the dexamethasone suppression tests are 95% sensitive and, and therefore you don't miss a case. Well, actually they would argue from this data that figure should be revised downwards quite a bit.

More worryingly, 33% of the non-adrenal illnesses gave results that were wrong, i.e., gave the result that suggested this dog had Cushing's disease, or it was hard to interpret and therefore would have to be rejected.

And that's a really high figure. So doing this test in a group of dogs which you are not sure has Cushing's in the first place, actually 1 in 3 is going to give you a false positive result. And then, and then I think.

this paper bears a lot of looking, particularly if you get an abnormal low dose depression test, which doesn't fit a nice pattern, then actually, saying this is uninterpretable is probably the right way forward until we know more. This brings us on to the concept of atypical Cushing's disease, and by atypical Cushing's disease, I mean dogs like this Pomeranian that have typical clinical signs aloplecia, potbelly, PUPD polyphagic. But in this dog, ACTH stem and low dose X were both unequivocally negative.

And they respond to trial. So there's something going on in these dogs, which we're not quite sure about. We believe from this research done in 2015 that looked at dogs first here on that higher line that have typical Cushing's against dogs that have not got Cushing's down here, that the atypical dogs that have these abnormal ACTH stems and low dose DX suppression tests.

Have increased cortisol over a 24 hour period, but in fact, have a slightly lower level than we've seen in typical Cushing eye dogs. And it's rather their response to this slightly high level that's abnormal rather than anything else. And the question Is that then given that we don't want to do 24 hour cortisol curves in these dogs, and even if we did, there's significant overlap between those two groups, to make any, any, good recommendations on, on, on interpretation.

How do we demonstrate that there is, abnormalities of steroid in these dogs without, having abnormalities of the cortisol to fall back on. The most obvious way about doing this is, is to go immediately for the, for the urine corticoid creatinine ratio, reported to be a very sensitive test, in some people's hands. In others, not so much.

And, and one of the reasons why this, this assays, had problems is that there are different antibodies used. For these tests. So the test that you get in one laboratory is not the same as the test you get in a another laboratory.

And that's because the antibody binds to different parts of the cortisol molecule. Antibody in here as you see binds one way, antibody B binds in another way. And that means that this test will perform differently.

In different clinical situations, because in the first case, it's measuring cortisol in the urine, and the second, it's measuring cortisol and its metabolites. So we see in urine sent off to different laboratories around Europe, very different results being produced for the urine, corticoid, creatinine ratios. So which one can you trust is, is a question of, of some debate.

The other test that's often mooted as an alternative is 17 hydroxyprogesterone. This is one of the cortisol precursors, and we know that it's increased in dogs with Cushing's disease, proper Cushing's disease. We know that it's less increased but still will be stimulated by ACTH in normal dogs.

And the problem really is, is what happens when you start doing this in dogs with other illnesses. This, this, this paper here from 2002, was the first sort of demonstration that you could use the 17 hydroxyprogesterones to diagnose Cushing's in dogs that had typical signs of Cushing's but were ACTHM and low dose de negative. People spend a lot of time looking at this, this, this paper here, from, 2003.

Suggested that they could see a difference between dogs with Cushing's and normal disease, but that there were another group that had increased values of 17 hydroxy progesterone, despite having no evidence of Cushing's, and the overlap was sufficiently bad that it was thought not to be worth doing by those authors. However, when you look at those dogs with other diseases, what you see is that the things that they were diagnosing like diabetes and hepatic disease, urinary tract disease and cancer. These should have been picked up during the routine physical, the routine blood tests, X-rays, and ultrasounds, and that actually the ability to distinguish between these two groups would depend more on the physical exam and the other tests that have been done that would be dependent on any one test.

So, so the, the, the moral of the story is really is to spend a lot of time looking for the other diseases. And if you can't find them, and your question is, is it normal or Cushing's, then the 17 hydroxyprogesterone probably can help. So sometimes I see cases where people have jumped to the diagnosis of Cushing's quite quickly and not done any or very little clinical pathology.

And, and I think it's important that this is done because it avoids the the problem of other things like diabetes and urinary tract infections and liver diseases and so forth, causing confusion, in our interpretation. These are at least as important. As any confirmatory endocrine tests.

And the same goes for radiography, and our abdominal ultrasonography. It is important that we have a look in the abdomen. And, and sometimes we, we will see a dog that has very minimal changes on radiography with Cushing's.

But sometimes we may see more. And, and here you can see these calcium oxalate crystals, these cars oxalate ur this, sorry. That we were talking about not only here in the bladder, but also the way all the way down the urethra.

Why is this dog still able to urinate past all these stones? Because the urethra is not swollen because the dog is on steroids and the steroids are coming from this calcified adrenal mass here, just below the lumbar vertebrae there. So, it may be tempting not to take radiographs.

It may be tempting not to, to do these things, but it is useful to do them. And I think it's important that when we're dealing with difficult cases of Cushing's, that we actually go back to those bases and make sure that we've done the routine clinical pathology. Abdominal ultrasound or abdominal radiography or both, thoracic radiography, is, is, is important as well to rule out those into current conditions that may be complicating or confusing our diagnosis.

So, when we have cases that don't have typical results, we first of all must reconsider our differentials and increase the use of clinical pathology and, and, and diagnostic imaging. But equally at the same time, we can apply perhaps less stringent thresholds for standard tests if we have a lot of clinical signs, and we are really very sure. So if we have lots of radiography, grey clinical pathology, lots of good clinical exams, and so forth, then our thresholds can be lower.

And, and actually one of the more recent papers has shown that 17 hydroxy. Progesterone is probably no more good than simply lowering our threshold at which we diagnose using a standard ACTH stimulation test. So taking our threshold down from 550 to maybe 450 or even 400 in some cases is perfectly justified if we have lots of compatible clinical signs.

So we talked, talked there about, the, the difficulty of, of those test results. What about, when we find out that the dog does have Cushing's, what about those unusual ones that have, adrenal tumours? Does it matter to make this distinction?

Well, I think it does prognostically. We, we know that dogs with adrenal tumours do not survive as long, and also that when they start to go downhill, they will go downhill quite quickly. So if we know that the dog has an adrenal tumour, when it starts to deteriorate, we can, we can, anticipate, the prognosis, fairly quickly then.

And it also matters that, that, that although these, these figures are for trying stain and might, but of course, the best treatment for a, an adrenal tumour is surgical removal and the survival from that. Go something like this. So it's important that if we can, we try to identify those surgical cases.

For that reason, I think it's important that we do try to establish the cause when we have a dog with Cushing's using specific endocrine tests such as the standalone endogenous ACTHRA. We're no longer doing high dose dexamethasone suppression tests anymore. They, they have, they have, largely been superseded now.

And, doing, diagnostic imaging if we've not already done it, such as adrenal ultrasound, CT and MRI. In practise, the easiest way to tell the difference is to use the ACTH assay. It's something that everybody can do.

You can simply need to be able to take an EDTA blood sample, spin it down straight away, separate off the EDTA plasma, put the EDA plasma in a serum tube, put the serum tube in the freezer. And then from the lab to send you one of these cool transporter containers for the, for the onward shipping of this and keep it frozen because it needs to arrive at the lab in a frozen state. It isn't difficult to do.

It's a bit of a faff, but there's nothing technically difficult about it. And if we have an ACTH level that is above 20, then we can say it's probably pituitary dependent or almost certain pituitary. If it's low, then it's adrenal dependent or It's melted in the post, which is why it's important that we know that it's been taken properly.

following on from that, the next, next option really is to do adrenal ultrasound. this is an example of an adrenal tumour here, which we can see, clearly arising from the pole of, of one of the, of the left adrenal, on the other side, the right adrenal, may be, normal sized or small, and, it's, it's worthwhile making sure that. You'll try to identify that that right adrenal if you can.

Having found the left adrenal, then ultrasound is, is absolutely essential for looking for whether this is a surgical case or not. So if we see this, this vascular invasion into the caudal vena cava, then we know That the surgical risks of, of, of trying to remove this are greatly increased and at least if this was my own dog, I probably wouldn't let a soft tissue surgeon have a go at this. Whereas if it was just that left adrenal mass I showed you originally, then absolutely surgery is, is, is the way forward in the hands of a of a of a good surgeon.

That it represents the most cost efficient and longest, likelihood of, a happy life. Sometimes we, we, we see cases that are trying to stay resistant, sometimes there are adrenal tumours, but some pituitary ones are, are, are seen as well. I think we sometimes say they're triota resistant, but actually we've got to remember that, that starting doses of riota have trended downwards over the years.

We used to start at 5 mg per kg. We now start at 2 Migs per kg and some people will start at 1 mg per kg. But as a result of that, it is inevitable that most dogs will need an increase in their dose.

And I think we should be fairly generous on our increases in dose, in, in terms of preserving client confidence in us, and confidence in the, in the drug, and just saving costs on the, on the monitoring. But my recommendation is that we increase doses by a minimum, a minimum of 50%, and I'm quite happy. If a 30 milligramme trite capsule isn't working, I'm quite happy if the dog's a large dog to go up straight up to a 60 milligrammes.

If we've had no effect with 30 milligrammes, you're quite, quite happy doubling the dose to 60 milligrammes. You don't need to go, and I see a lot of people going from 30 milligrammes to 40 milligrammes to 50 milligrammes, and it's very expensive to do this, and it's not necessary. It's not in the licence to do it.

It's 30 to 60. obviously, if the 30 is having some effect and is, is, you know, there's somebody, then, then a slower approach is, is, probably sensible. But if it's having no effect, then I think you can be, a lot more confident about moving forward more quickly.

Clearly effective monitoring is the key, and particularly by the owner of recording the weight of the dog, the appetite of the dog, the thirst, the activity, and making sure that when you do these dose increases that the owners know what they're looking for and so that they, they're ready to respond to that if you do go too far. You need to provide good owner support during this time, and, and careful examination when you see the dog. Laboratory tests are a, a useful add-on, to help you in this decision, but it doesn't replace the owner monitoring and your monitoring.

As travestine starts to go up in in sizes, then the costs start to mount. By the time you hit about 7 to 10 milligrammes per kilogramme, and many cases can meet that level of dose, then actually triosta is now often more expensive than using mitotane. And M attain is still a really good option.

If you've not used it, then get some advice on how to use it, but it is still really a very good option, and I think we are missing a trick here if we are not using that. In the original studies on Triosta, about 10 to 15% of dogs did not respond to risine despite enormous doses. So that means that if you've got 10 crushing eye dogs in your life, then you should have at least one of them on mitotane.

So we've talked a bit about those adrenal tumours and trans resistant dogs. What about the pituitary macroadenomas? We, we know about 10% of dogs when we do MRIs and CTs of their brains actually do have quite large pituitary tumours, and for the most part, they are not significant.

But if they start to grow rapidly, and this can happen when you start to remove the cortisol secretion using triota or mitota. Then you can see a, a, an, a more rapid increase in tumour size. And these can cause dogs some problems with, with, depression, apparent blindness.

They will bump into things, soulence in the sense that they'll be hard to wake up, and, and then sometimes you have to, to shake them awake, and the dogs may be be ataxic. What you don't see is seizures. If you have a dog with Cushing's disease with seizures, then there is some other cause.

I've never come across a dog where the pituitary has been the only cause of the seizures. It's, it's important to recognise, however, that when we see these images like these with here a 3D CT reconstruct and here an MRI of, of really quite large pituitary tumours, that actually there is no real correlation between the endocrine effects, the neurological effects, the prognosis and the size of the tumour. These are like pictures of a car and me asking you how fast is the car going.

You can't tell from one picture. You need two pictures with a defined time interval between those two pictures in order to say how fast the car is going. And so it is with tumours.

We don't know how fast they're growing and we don't know what hormones they're producing. The faster growing ones may in fact be producing less hormones and therefore may have less clinical effect. and so it's important not to get too carried away with CTS and MRIs, and we reserve those for cases where there are clinical signs of central disease, and, and therefore we need to take some activity.

And where we have those signs of, of, those neurological effects, then, we have to think very carefully about how we manage them. Radiotherapy is effective, but obviously it's quite expensive. But also, conversely, of course, although it may not be counterintuitive, using steroids may, may slow, slow down some of the brain swelling associated with the rapidly growing tumour.

And although the dogs will still obviously suffer from Cushing's disease, the more serious neurological effects may, may, may go into remission. Finally, then we'll talk a little bit about concurrent conditions, and, the, the real biggie here are the difficult, those difficult cases where they have Cushing's and diabetes. Obviously, Cushing's glucocorticoid excess causes insulin resistance and therefore, there is a distinct link between the development of Cushing's and diabetes.

Interestingly, although Cushing's probably is the cause of the diabetes, in most cases, it's the diabetes that is diagnosed first. And then the Cushing's is diagnosed afterwards. and that, of course, throws some challenges because at the point of diagnosis, then these animals are often unstable diabetics and therefore may have abnormal responses to ACTHDs and low dose acts.

And it's important therefore that we spend time stabilising these diabetics a little bit before we try to diagnose Cushing's and I, and I will always say that the dogs have to be at home and eating well and drinking well, even if they're not wonderfully stable, and maintaining their body weight, before we can say for sure that we, we've got a stable diabetic and therefore we can do an ACTH stent. If the owners are short of cash, then undoubtedly the diabetes is far, far more important than the Cushing's. It, it used to be saying that thought that, that, we should reduce the dose of, insulin when we start to dog on Trilotine.

That's not my, my belief now. There seems to be little consistent effect on, on insulin dose, with the treatment with Triistine. And therefore, it, it is more sensible to continue on the normal insulin dose, but be alert to the need to change it, if you need to.

We know that no matter what the the treatment regime really, the fact that, that is that dogs that have Cushing's and diabetes have a shorter life expectancy than the ones that just have Cushing's. And indeed, if you compare this data to those that have . Just diabetes from other papers, then you, you'll, you'll see that that actually Cushing's and diabetes is definitely worse than either condition on its own.

And it's worthwhile being honest with owners about that upfront that, that we haven't got a perfect answer. These are difficult cases. My current protocol is to administer insulin and Trilota twice daily, in, in all cases.

And I use clinical signs more than anything else to, to monitor these conditions, particularly the water intake. And I use continuous glucose monitoring systems to establish, that, they're on the right dose of instance. So here I'm talking about freestyle Libras and things like that.

Urine glucose, haemoglobin A1C are are useful and, ancillary aids for the monitoring of these conditions. And, a pre-veteral cortisol between 40 and 140 seems to be fairly, reliable, for the control of, Cushing's in these patients, but that's not published. And, I, I think we have to be fairly careful with these, these things, not to overinterpret them.

It is the clinical signs that are number one. The other group of conditions that we see are those that are steroid responsive, that when we treat them with, with, for their Cushing's, we start to see. The commonest examples of those are arthritis and A to B.

So we have dogs that, that, have not been itchy for years, or the, or that have been running around quite happily, or, or be it PUPD, and we treat them with their, for their Cushing's and, and now they start, with chronic ear diseases, with, yermas, or with lameness and stiffness. Other cases like, that IBD I was mentioning to you and even a case of lymphoma that was held in check by the Cushing's disease have been reported. We have to offer the owner 3 options, really, don't treat either.

Treat the condition, but not the Cushing's, i.e., use the, the, Cushing's to control the condition as far as possible, or treat both.

And, and certainly, my experience is that by and large, if you go for treating both, then you get a better result because you, you're using, using Cushing's to treat a disease is likely to cause problems because Cushing's doesn't give you a nice regular supply of steroid. It fluctuates and it's not necessarily the right dose every day. So you can, I find often to use triosta and then to use meloxicam on top, and I'm quite comfortable with that.

I've never had a problem. Meloxicam and, sorry, risine and cyposporin for the atopic dogs. And even in some cases, yes, it sounds counterintuitive, but a small dose of prednisolone and trilasan works quite well in these cases.

Other concurrent conditions, heart disease, unequivocally, heart cardiac function is worse with Cushing's. I am more keen to use Trista in these cases and more aggressive with my congestive heart failure medications in these cases. These definitely both need to be treated together and, and pretty aggressively too.

In contrast, in, in, in complete contrast, is, is kidney disease. Cushing's makes hypertension and urinary tract infections worse, in, in dogs with kidney disease. And equally at the same time, the, appetite and thirst of dogs with Cushing's disease and renal disease are better than those with just renal disease on their own.

So in these cases, I tend to avoid using the trial of spa, but focus on trying to control the hypertension and control the urinary tract infections. I find if you start treating dogs that have Cushing's and renal disease and you start treating them for their renal, for their Cushing's disease, their renal disease gets worse, they go off their food and they usually end up in a black bag rather too quickly. You're better just letting things be.

Liver and bili tract diseases, again, the appetite and thirst are better if they've got their Cushing's. You give them rista, that goes off. There's little evidence that treating the Cushing's disease will improve mucoces, but equally, if you're going to remove the muccocele, then the surgery may be less risky if the Cushing's is treated for a few weeks beforehand.

There's not much published on any of this, and so much generally my, my, my feeling has been with the mucous seals, is, is to, to, to give only enough ridosta to control the worst of the effects of the Cushing's but not have any pretence that it's going to alter the, the mucous seal. So in those 55 minutes or so, I've I've run through some clinical scenarios where difficult cases of Cushing's are presented. I don't want you to go away from this thinking that this is, is normal.

Most cases of Cushing's respond quite well to medication. They're relatively easy to diagnose, and the outcome is very good. This is, this is about those oddities rather than the norm.

Dogs like Missy and so forth respond very well for, for their treatment and, don't need, a huge amount of, of, of effort or difficulty. but lessons to take home from this, presentation would be, please think about the necessity necessity of diagnosis and treatment before you start and discuss those with the owner. If the diagnosis is challenging or unusual, then rely more on clinical signs, clinical pathology, and diagnostic imaging than on the endocrine tests.

Alter your thresholds of the diagnostic test, the endocrine test, to help you make a diagnosis. Do understand the endocrine test you are using and be prepared to ignore a result that doesn't fit. Try to decide if these dogs are pituitary or adrenal dependent cases because it has both prognostic and therapeutic implications.

Consider the effects of pituitary masses that we develop with time and the fact that you can actually do something for these animals, for quite some time, if you just take your foot off the, the trista and, and, and use other, other medications, to help you through. And do consider the effects of concurrent medications on dogs and tests. Some conditions may need more management of their Cushing's, whereas in contrast, some may actually need less.

I hope that was, useful. I appreciate it was a, a quick run through through quite a lot of information, and I'd be happy to take any questions now. Thank you very much.

Ian, that was absolutely fantastic and fascinating. I, I really do think that everybody on tonight will have learned a considerable amount. I know that I have, and, I was quite relieved in the end when you said that these are the exception and not the rule, because I was starting to become a bit worried.

Yes, yes, absolutely, you, you, you know, working in a referral practise it sometimes, easy, easy to see the zebras and, you, you know, actually, actually, there's an awful lot of horses out there just. And the standard, things that, you, you know, we don't get to see. But, I hope by, by sharing some of these with you that, we, we've got, a group of people out there who recognise some of the issues and problems around it.

I must say, for me, one of the, the biggest eye-openers of tonight was the fact that, you know, you can adjust what the lab says based on the number of clinical signs. And the more I thought about it, the more logic it seemed to me, and I, I, I was kind of battling to understand why I never thought of it before. But it does make sense.

Yes, yeah. I, I, I mean, I think, I think the, the, the problem is in, in today's world, we are figured driven, and, and we, we set so much store in, a, a number that we forget the basis of that number is a, a distribution within a population and they, they've drawn a cutoff to suit you most of the time. But, but there are times when it simply does not work and does not suit.

So you have to be prepared to say, no, I, I, I, I am prepared to change the threshold on this occasion. And, and that's where some experience comes in, and, and not necessarily experience of that condition, but experience of, of, of all veterinary work, because of course, this, this doesn't just apply to Cushing's, it, it applies to a whole load of other things that, the more we do in life, the more we realise that these things are not set in tablets of stone, and, and it's not black and white and it's not a computer programme, and, and actually, the, the, there's a bit of Black magic, black art, if you will, in, in, in, in being a vet. And, and this is one of them.

And, and that's to look at a set of biochemistry results and say, or endocrine results and say, you know what, we're nearly there, but it's nearly, nearly as good enough for this case, nearly good enough for this case. I think the other thing that you've also left out there is the, the important factor of knowing which phone number reaches somebody like you. Yes, I guess, and I, I'll go for, I, I, I, I, I thank you for that.

But actually, I, I think it's actually about talking to colleagues. And I think if, if you are going to bend the rules, as it were, my advice is always to get two others to bend them with you. Even if they, you just colleagues in practise, to say, hey, can you just have a look at this case?

Can you just sense check me on this? I'm saying this dog has Cushing's. Do you agree?

Even though the result isn't quite right, are we nearly there? And as long as you have agreement. Then, then actually, if there's any comeback and everyone's worried about being sued, in fact, no one's ever been sued for this.

No one will ever be sued for this because you've taken a, a, you know, a reasonable approach and providing you've discussed it with the owner and it's not doing it behind the owner's back, then there's no way that they could, could sue you anyway, because after all, don't forget, what is a dog that's sick with Cushing's actually worth? And the answer, of course, is nothing. You could not sell a dog with Cushing's.

So, you know, no one's ever going to sue you for this, and, and we've got to just step back and say, you know, this is not gonna happen, it's, it's about doing right by the patient. And it makes sense to sense check. And it, it, you know, the thing I have, which perhaps other people is every morning and evening, I have to sit in rounds and I have to explain my decisions to my colleagues, and they have to explain their decisions to me.

And that is a very powerful tool. Now, OK, we're doing it for teaching purposes, but hey, you can do that for a single case in any primary care practise. You can get a couple of people around and say, look, let's just look at this.

And, and if everyone agrees, then you don't need to phone me up. You can just get on with it. Yeah, and I, I'm not going to try and quote the quote word for word, but, some famous person previously said, the power of two brains together is way greater than the sum of the two individuals.

That's absolutely right. I, I, I don't know. I don't know.

I can't tell you who that quote was, but I have heard that one before. Yeah, fantastic. Ian, it's been an absolute pleasure once again to be listening to you.

All the questions that have come through, you have answered. In between those are all the accolades for what a fantastic, lecture this was and how fantastic it was to learn from somebody, of your knowledge and who is prepared to give up their time to share with us. So thank you so much for your time tonight.

Thank you very much, Bruce, and thank you everyone for listening. Thanks folks. Thanks for joining us on another member's webinar to fill my controller in the background.

As always, thank you for making things happen seamlessly and from myself, Bruce Stevenson, good night.