Welcome to this session on new therapeutic options for refractory epilepsy or for our patients with refractory epilepsy. Yeah, this is a, a challenging topic because we rely heavily on medication and during this session, we will talk about the medications that are available to us and also how we may use them. To try to deal with our very aggressive seizure patients, and by aggressive, I mean the amount of seizures that they have and how uncontrolled they can be in some cases.
But let's, let's step back a second and talk about what refractory epilepsy actually is. When we talk, when we talk about refractory epilepsy, we're, we're often looking at the human definition, and the International League Against Epilepsy, this human group have described refractory epilepsy as the persistence of seizures, despite the use of at least 2 anti-seizure drugs when used at effective or supposedly effective, efficacious daily doses. And in the human world, less than 15% of people with epilepsy actually become seizure-free if your first two drugs fail.
And that's important because we know they have a lot more drugs available to them than than we have for veterinary medicine. And so it's likely that many dogs are going to be in a worse off position than the human world. So if 15% of humans become seizure, less than 15% become seizure-free, if the first two drugs fail, we're probably dealing with a lot more dogs that, Can't get controlled by the use of two or more drugs.
This is an important point to drive home with the owners when we talk about management of their expectations because we often look at the addition of another drug or a third drug as being potentially as successful as the first, and we shouldn't do that. Our best chance of controlling a dog with epilepsy is the first drug that we use. The longer things go on, the more likely they are to become resistant to drugs.
As we mentioned, there are a lot of drugs available in the human world and less so in the veterinary world, for, for use of controlling epilepsy. And this means that we are gonna be more challenged than the human world. These drugs have different mechanisms of action, so you would think that they would be synergistic, but still there is a high failure rate.
Now what do we know about the prevalence or the definition of, of refractory epilepsy, in veterinary medicine? Well, we, we don't have anything unfortunately we, we base it on. Several factors that we know can be challenging.
So the number of seizures that their patient experiences, as well as the severity. So what is it that's going to be a problem to us? And we, we would suggest that at least one every 3 months, and we'll talk about this when we talk about selection of medication a bit later, but.
11 seizure every 3 months is, is too much. Now, that is going to depend on the severity and what that means is perhaps you have one every 3 months, 1 every 4 months, 1 every 5 months, but at the time that you have seizures, you have multiples, so clusters, status epileptics, and that, that can impact whether we'll think you're afractory or not. The number of drugs that we've made mention of that, but once we, once we use more than 2 drugs.
We start to consider we're getting in trouble. The dose of the drugs, how high are these drugs, are we starting to enter into the realm of side effects with these drugs? The therapeutic levels, it's important with some drugs that we can monitor with therapeutic levels, particularly.
Phenobarbital, potassium bromide, that we make sure that we're using the drugs at an appropriate therapeutic level, make a bit of mention of that with phenobarb. How long the treatment has been going on, so we're unlikely to call a dog refractory if they've only been treated for. A few weeks, we need to give each drug an adequate period of time to monitor the effect of it on the seizure frequency and severity.
What does the owner expect? We've had some owners who say my dog has several seizures a day, and this is better than it used to be, and so I'm quite happy versus I don't want my dog to have any seizures. And so that's going to play a part in what our consideration of refractory.
Epilepsy is, and, and, and quality of life as well. What is the quality of life when the dog is on these medications and is having seizures and this is going to again be in part down to owner perceptions. So we need to have long chats with owners about what they should expect, what they want out of the treatment.
All of these things will impact our individualised definition of what refractory is. So we can't just go with, well, you failed two drugs, your, your refractory. It may be, it may be a slightly different case.
Now, what about the prevalence of refractory epilepsy in people up to a third of human adults, not doesn't matter where you live, but 1/3 of human adults with epilepsy will be refractory to medication, and this has been shown to depend on. What age you, you initially present with epilepsy, how frequent and long the seizures are at the time of presentation, whether you have status epileptics or not, whether you have symptomatic epilepsy, right? So that's epilepsy due to a structural disease of your brain versus idiopathic epilepsy where.
There's no structural disease. It's a, a chemical abnormality, and whether you have a genetic syndrome for epilepsy, which are, which there are several in human medicine, and these are, being discovered recently in veterinary medicine as well. So we would imagine that there are several risk factors in veterinary medicine.
We do know that there's a similar prevalence, so up to 30% of dogs are considered refractory to medication. Whatever, again, that definition truly is, we know that there's gonna be a decent amount of dogs here that are not responsive to medication as the owner wants as we want, and overall. All based on the literature, less than half of the dogs end up being seizure free without side effects from those medications.
So we do have a huge challenge on our hands. Why do dogs become refractory or several, several considerations here. Certainly there are changes in the brain that are responsible in part.
The brain can become less sensitive to medications with time. And so initially the medications may work and with time, they become less effective, and this is thought to be due to receptors in the brain becoming less sensitive and transporters in the brain, kicking the drug out, that blood brain barrier that we hear about sometimes, can actually, end up kicking more drug out with, with time. And so there are some molecular mechanisms that have been described.
That explain why in some dogs, you will not be well controlled. There's also this concept of inherent disease severity, and we see this in veterinary medicine that some breeds of dog appear to be. More resistant to medications, have a more severe, disease.
Australian shepherds, border collies, they have a high prevalence of drug resistant seizures, and from the start, we need to talk to owners, with those breeds. Anytime I see a collie, border collies especially, anytime we see a shepherd, Australian shepherds especially, then we'll talk to owners about the fact that this may be a challenge. Insufficient drug dose, that's always a reason that we need to look at, are we using enough drug?
And we'll talk about the concept of are we using it as frequently as we should as well. We've always looked at increasing drug doses as being a way to try to control our challenging patients. Sometimes it's increasing the frequency that we give that drug.
So we'll talk about that shortly. It's important to recognise that most drugs are not anti-epileptic. What's that actually mean?
Where we often use the term anti-convulsant, when we talk about these drugs, because that will stop the seizure activity at the time or reduce that seizure activity. Anti-epileptic in its truest sense, means that it helps the brain control the progression of the seizure focus. So with time, the more seizures you have, the more you're going to have.
Your brain. Actually allows the seizure focus to grow. The more you have, the more you're going to have, it's, it's almost like .
Like getting a boxing injury, the more, the more damage to the brain that there is, the more likely that that, is going to, to cause clinical signs. The more boxing matches you have, the more damage there's gonna be. So, so a vicious cycle here.
So the more seizures you have, the bigger the focus and our drugs are not anti-epileptic, so most of them cannot prevent that spread. So with time there will be a bigger seizure focus. Our drugs will be less effective.
And then there's this, you may not have epilepsy to begin with, and this takes us back to really square one, with the evaluation of our, our, our dogs with epilepsy is, do you actually have epilepsy? Sounds like an odd thing, but we often rely on owner descriptions of seizures to help us understand whether you have epilepsy or not. Sometimes the descriptions can be very.
very accurate and help us, believe, yeah, this dog had seizures, sometimes video footage, can accompany these descriptions and again increase our confidence levels that there is seizure activity, that it is epilepsy, but sometimes it can be difficult. So let's review, why this may be a problem. Obviously, if you don't have epilepsy, the drugs aren't gonna work, and we could get into a cycle where we keep increasing the doses and adding numbers of drugs to this patient.
When really they were never gonna work in the first place, so this is an important area to focus on. When we talk about epilepsy, we're talking about dysfunction of the brain. Now there are 3 gross areas of the brain that we should consider that could be affected.
You've got your motor areas, your sensory areas, and your autonomic areas. So motor controls your motor movements and your sensory that receives all of the sensory input, so your smell and your hearing and your vision. And perceives that, and then your autonomic areas that control your heart rate, respiratory rate, and depth, your urination, defecation, etc.
Now, in a generalised tonic clonic seizure, perhaps the most common type of seizure that we'll see. Then we will have all three areas involved. So generalised, the whole body is involved in this, it implicates the whole of the brain is involved as well.
And so here we see a generalised tonic clonics. So, we've got motor dysfunction, sensory dysfunction, so a perceived loss, decreased consciousness, and autonomic dysfunction here seen with salivation. So generalised tonic clonic, the tonic is rigidity, clonic is some sort of paddling that's going on.
And so this is our classic seizure, and it may not be difficult for an owner to describe this to us, and for us to have some confidence that we're dealing with this. We can move on to the next step of considering should we start medication. The other thing that's important here to note is this post it to period where there is going to be some period of, of, mental change.
This can be exhaustion, behaviour changes, there can be these involuntary movements. It can be ataxia as well, could be blindness. This post ital period is important again to ask about because it may improve our confidence that we're actually dealing with a seizure in the first place.
Now, seizures may not be generalised, they may be focal and they may affect one or two of the areas that we've talked about motor, sensory, autonomic, and manifest and slightly differently. So if just your motor area is involved and that motor area controls your masticatory muscles, for instance, we have what's sometimes called these chewing gum type seizures here. You can see there's an autonomic component in this dog as well, with excessive salivation.
But this is a more focal motor seizure. Again, maybe it's, it's not difficult for an owner to describe this to us, but it becomes a little bit, more complicated, and we may start to consider there's other, there's some other type of event going on. These could be even more difficult when just there are, there is motor dysfunction of a certain area of the body that is difficult for the owner to describe.
We've got, in this case, a focal motor, what's sometimes called myoclonic seizure, where there is Muscle spasm. See, seen commonly in older cavaliers, but in many, many breeds of dog, you can see these spasms, sometimes present without salivation, urination, defecation, without a change of consciousness that's really perceptible to us. And this can be tough for us to know, is it a seizure or not.
There are other differentials to consider. I is this dog have a pain focus? Does it have muscle disease?
. Is this another type of movement disorder that we'll we'll mention briefly? So focal motor seizures can be tough. Focal sensory seizures, even more so.
A classic focal sensory seizure are the fly biting or fly catching seizures where we believe they're seeing something, that's not there. In human medicine, if you have a sensory seizure, you see things that aren't there, you may hear things that aren't there, you may smell things that aren't there, and that's obviously can be very difficult. For us to establish without the use of electroencephalography or EEG in dogs.
Those are, those are electrical tests that look at the brain waves in our dogs, and at the time of an event, it would be very difficult, challenging for us in most cases to, to look and see that this event is correlated with an abnormal brain activity. This could be a behavioural abnormality. And so we need to look into that.
In some cases, we may even need to rule out visual abnormalities as well. So focal sensory seizures can be difficult for us to be comfortable, with there actually being seizures and not something else. So let's look at what the something else could be, and these are things which might mimic or be twins with seizures, so to speak.
paroxysmal events, these means sudden onset, sudden offset events, and they could mimic seizures, and these are things we need to rule out when an owner describes an event to us. In an otherwise normal dog, all of these things here, in, in black, as opposed to the grey, all of these things here can appear in otherwise normal dogs when you examine the dog could be normal. So we've got syncope, movement disorders, gonna show some videos of these narcolepsy, cataplexy, sleep disorders and compulsive behavioural disorders.
These things can look like seizure activity, particularly the focal forms. Hopefully, with these, episodic events, intermittent vestibular disease, myasthenia gravis, causing a collapse, and a painful focus, hopefully we would find something on neurological exam, physical exam with these patients at the time, and they're not able to hide anything there. But sometimes not.
So these are, are, are things which could mimic and in the main don't respond very well to anti-convulsants, if at all, and so it's important that we establish whether these are possibilities. Obviously syncope is, is one of our most common causes of. Episodic collapse, and we often see that that's associated with excitement or activity as we see in these, this dog here running around the garden, sudden collapse.
It's a tonic. There's no movement, and the dog is up and although maybe slightly confused, at the time. Of a recovery, it doesn't have the postal changes that we saw in that last dog.
So. The nature of this event, is slightly different in that it's atonic. There's no movement associated with it, which generally implies that it's not a seizure.
It's associated with exercise, generally implies it's not a seizure, because most times seizures occur at rest or during sleep. And the fact that the dog is up quickly without any evident, postdictal changes that we described before, again, generally means we should be thinking of, of other things. Now there's, there's been an area of veterinary medicine that's expanded quite rapidly over the last 10 to 20 years, and this is called these, this area is called movement disorders.
Occasionally you'll hear. This called paroxysmal dyskinesia, and this means sudden onset, sudden offset, abnormal movement. So it's kind of a broad term here to cover some abnormal movements.
In human medicine, paroxysmal dyskinesia or abnormal movements can be too many movements, so the poster child for that could be Parkinson's, tremor disorders, they can be consistent, abnormalities or persistent abnormalities. And, and then, but they're also freezing movement disorders, so you move too little, cramping type movement disorders, and they may receive less press, than the, excessive movements, but they are equally debilitating. What we've seen in dogs with these, overall is a generalised collapse.
They can be focal in some, in some breeds with one limb being affected, but a generalised collapse as we see here in this border terrier. With increased muscle tone. Very much like seizure activity.
However, they maintain consciousness, so they're awake. The owners can speak to the dog. They can appear responsive, but for all intents and purposes, this event could be described as a seizure by the owner, and this could be, this could be a problem because we may start treating this dog with anti-convulsants if we are unaware that there is a slight difference in this dog's case, that is awake.
This can last for minutes, but in some cases for over an hour, so it can appear as, as, as the dog is having status epileptics, but it is not a seizure activity. There's usually no precipitating event. Some breeds, such as the Cavalier King Charles, can have excitement or activity as a precipitating event, so that can complicate things and make it look like singerbe, but usually no precipitating event, which is what, what we expect with seizures.
There are now multiple breeds affected, so if we got the border terrier here, but it's also seen in Labrador retrievers, in Jack Russell terriers, in the Bichon Frise, German, smooth haired, pointers. So, to name a few, we've got multiple breeds that now are affected, worthwhile plugging it into the internet. If you have a dog that, that looks like this, a collapse with cramping, with rigidity, often bringing the front leg up to the head, look at the breed and see whether it's been documented with paroxysmal dyskinesia.
The advantage of video is obviously, you can send that off to someone to get a second opinion to say, what do you think this is, because it can be important before we start medication. Treatment of these sometimes can, can be anti-convulsants, the Welsh terriers, for instance, seem to respond to the levetiracetam. The German shorthaired pointers can respond to fiobar, but more, more often they don't, and we have to look at other treatments, gluten-free diets, so the hydrolyzed diets can help some, such as the border terrier.
Acetazolamides, that diuretic, can affect calcium channel function, so can be successful at helping paroxysmal dyskinesias. The serotonin reuptake inhibitors can help some patients. Clonazepam can help, some patients, particularly cavaliers.
So we end up going through a treatment trial approach, but it's important to know that we suspect we're dealing with a paroxysmal dyskinesia. Another type of movement disorder that we may see are these idiopathic head tremors in dogs that can be that can be a side to side movement or an up and down movement. So, a no movement like we see here in this dog, versus an up and down yes type movement.
Now these head bobs that we may see are intermittent, they're not persistent, so they can be the dog could be normal when they, when they see you, when you examine it. These are sudden onset. They're often short lasting, and they, they see most commonly in three breeds of dog bulldogs, boxers, and Dobermans.
If seen in other breeds of dog, it would be worth investigating for an underlying cause. But in these breeds, rarely do we see that it's an idiopathic problem. We believe some sort of neurotransmitter problem.
No identifiable treatment for them. They don't seem to respond to anti-convulsants very well. Maybe it's an anxiety response.
There's there's some belief about that, that this is a movement that comes from anxiety, because in some breeds, particularly the Dobermans, there's a high prevalence of concurrent behavioural abnormalities that that are suggestive of anxiety. As well. But these, most of the time don't have an underlying cause.
Need to rule that out first, and do not respond to anti-convulsants. Narcolepsy, you may have seen videos of this. This is again a sudden atonic collapse, much like syncope.
Precipitated, not, not necessarily by activity, but yes, by by excitement, often that is feeding time, someone coming to the door, and that, that can be something which, as we see in this video, hopefully shortly, if we see, we'll see that. There it is, excuse me for a second as I try to get this going. We see a sudden collapse again, that's atonic.
There's no movement here. There's a loss of consciousness, and, that was precipitated by excitement. And so many times the owners will then try to comfort the dog, so when it wakes up, they'll get excited again and so it can be a.
A vicious cycle. There are medications which can help with these, so serotonin reuptake inhibitors and noradrenaline, drugs, . Ritalin, so methylphenidate can help, so stimulants.
So there are drugs that will help, but anti-convulsants really won't. So again, important to identify these cases that have a sudden collapse as being narcolepsy in this case, because they will not respond to anti-convulsants. This is usually seen in younger dogs.
It's often inherited in most cases dachshunds, Dobermans, Labradors are high up on the list of dogs that are affected by this disorder. Again, a neurochemical disorder, nothing that we can end up finding on MRI or CSF tap. Then we've got this group of disorders, these compulsive behavioural disorders in people called OCD or obsessive compulsive disorders, we're, we're not sure what they're actually thinking, so we, we can't call them obsessive, but.
These are repetitive behaviours that can include circling, tail chasing, pacing, jumping in a place, chasing light, and that sort of thing. These are the locomotive versions, the oral behaviours, these can manifest as as leg or. Chewing, self licking air or nose licking, as we can see in this dog, blank sucking.
And so there are, there are behaviours that can manifest as in this case, that's similar to focal motor seizures that could be interpreted as a focal motor seizure. Now, this dog will stop this event if the owner speaks to it. And that's not possible with a, with a focal motor seizure.
Focal motor seizures are involuntary. These behavioural disorders are not necessarily voluntary, but they, they can be broken by the owner intervening, and so. That's worthwhile asking about to try to establish your confidence level with with what is going on.
So we end up with these questions that I that I've alluded to along the way with these videos that are important to ask the owner, once they've described the event, to help you with whether this is a seizure or not. Again, in some cases, the owner may have articulated the event, so. Beautifully that you are able to say, yes, this is sued for activity.
But sometimes that's not the case. We rely on the video and these questions and the history. So we ask, what was the dog or cat doing at the start of the event?
If there was any excitement or activity then. Probably not seizures. Was there any limb rigidity?
We often rely on the presence of limb rigidity to say it's a central nervous system problem. Now we saw with paroxysmal dyskinesia, you can have limb rigidity. So it's not, these aren't absolute questions.
but limb rigidity makes us think, yes, because we saw with syncope, a tonic collapse, narco narcolepsy, a tonic collapse, so no rigidity there. Did the dog urinate or salivate? So we're looking for autonomic abnormalities here.
This is important because, again, it helps us try and separate it from the other events. Some dogs will have urination at the time of syncope, but most of the other events won't have an autonomic component. Was your dog or cat responsive to you during the event?
Now, this is unlikely during seizure activity, as we said, this, often consciousness is affected, these are involuntary, you can't break them. Whereas with other events, then that's not the case. Narcolepsy, the dog is not going to respond.
So again, these are not absolute questions. Was the dog cat, what what was the dog or cat like immediately after? So if the owner can describe some post Ital abnormality in terms of their behaviour, in terms of their gait, in terms of their vision, then that may be something which increases our confidence level that is seizure activity.
So we use these questions to help us out. With improving our confidence, and this is so important when we're dealing with refractory epilepsy, the first thing we're gonna do is say, do you have epilepsy? Sounds like a crazy stupid question, but we need to be confident that this is seizure activity.
It's the first thing that we're gonna look at because maybe we're medicating something that looks like a seizure, and the reason that it's not responding is it's not a seizure. Seizure therapy, normally, we've got to look at indications to start, and as we said, the more seizure activity you have, the more you're going to have your brain will have a larger focus. Like being in this boxing match, your brain will get damaged, the more boxing matches that you're in.
More your brain will get damaged, so we're gonna have an ischemic focus in the brain, which, enlarges with time. So the more, the, the earlier you treat, the better. But we need to see a pattern to be able to know that our medications are working.
So it's a careful balance here. There are some consensus statements available that suggest one seizure every 6 months, should be an indication for starting medication. It can make assessment of success a little tricky, but.
We know that once these are every, every month is probably too much. So once these are every 3 months is where we'll settle out. This is a kind of sliding scale.
It really depends on what the owner is comfortable with, but this is an area where we'll say we should probably start medication now. If you've got a breed, that we talked about, the shepherds and the collies that have an aggressive seizure focus, the sooner you start, the better. And in some cases, in some of those dogs, particularly the young, younger, patients that present of those breeds, we may even start them on two medications at once.
We can always back off one of those medications or stop them, but it's difficult to play catch up if they don't respond to just the one medication if we start that. Now, that's, that's not a common approach, but, many times we've started to adopt that because we know those breeds will have a very difficult focus for us to to treat. If the dogs have status epileptica, so, seizure more than 5 minutes or cluster seizures where there's multiple seizures in one day.
And there's no indication that this is a toxicity or a metabolic disease like hepatic encephalopathy, then we'll start long-term medication. Obviously, if there is an intracranial disease, irresponsible, so a stroke, a previous head trauma, for instance, then. The presence of seizures tells us we need long term therapy.
So it's important to know when we start, and then what do we use? We've got a lot of options depending on whether you're a dog or a cat as you see here. Now we'll often go with .
Phenobarbital. And the reason for that, as we'll start off, in a second talking a bit more about is its efficacy. There is no other drug on this list that that comes close to the efficacy of phenobarbital, and it's important to get success early on with controlling seizure activity.
Now, it's not always the most popular choice because of the adverse effects that are associated with the use of this drug. and obviously efficacy is not the only factor considered. We've got cost, we've got those adverse effects.
We've got how often during the day do they these drugs need to be given, and so there are other, other factors here, but we'll often go with venobarbital based on its efficacy of over 90% compared to, as we'll go through here, lower efficacies, . With these other drugs. If we can't get this seizure focus under control quickly, we're more likely to have a refractory situation.
And when we know that over 30% of dogs will have refractory epilepsy, this is a big problem. For us to try to head off. So start quickly, use your most powerful drug.
Now, if there are some side effects, we could always switch later on, or add a drug and then wean down phenobarb, but the choice you make to begin with can be really important. It's not all about drugs. We're gonna start talking about those right now, but, and we know that we initially will increase doses to to effect and to avoid side effects.
We'll increase the frequency of therapy which you've made a brief mention of and talk more about in a second, and we need to be aggressive from the start and that involves using. Effective doses quickly and potentially using two medications in those breeds, collies, shepherds that may present at a young age and have a tough to control future focus. There are other options we'll mention in this talk, so the use of Diet, recently neurostimulation, let's talk about that, use of cannabis, surgery, acupuncture.
All of these at this stage are treated as more adjunctive therapies, in some cases, palliative therapies in in humans. They have a role, certainly, and they may, spare your medications slightly, so they may mean that you can use less doses, but on their own, probably we shouldn't expect them to be effective entirely. And so they're always adjuncts to drug therapy.
Let's let's talk briefly about these drugs and what how we can manipulate them in our first line as our first line treatment and then as our refractory cases. So as we mentioned, Fenobar will often use this as a first choice. Again, people have concerns about its use because of the adverse effects which we'll we'll, we'll mention shortly, but it's because it, it's effective in a high percentage of cases.
Some studies. Say 94, 95% of dogs, whatever the cause of seizures, idiopathic versus a tumour or a stroke, etc. Whatever the cause, this is, there's some effect.
That doesn't mean complete effect. That doesn't mean eradication. Eradication of seizures may be seen in only about 50% of dogs with this drug, but there'll be some positive effect in up to 9 out of 10 cases.
We have to wait about 10 to 14 days. So let's say 2 weeks, we have to wait before this drug is at its maximal levels and it's consistent, and that's what steady state means, maximal consistent. For the dose we're using, we start off at 2 to 4.
I'll often start at 4 mg per gig every 12 hours. Again, you can wean down, but we need to control these seizures from the get-go, . Now, we often think that if the drug doesn't work, so after 2 weeks, we can start monitoring.
It may start working well before 2 weeks, but after 2 weeks, we know that it is maximal and it's consistent, so we start monitoring after 2 weeks. At that time, if we think, well, this hasn't had a sufficient impact, whatever we believe that to be. Seizures per week, per month, severity of seizures, side effects, whatever we believe, then we can increase the dose and we'll often increase the dose by 25% arbitrary, but we'll increase it by 25% and then we'll wait another 14 days before we can start to re-evaluate the effect of the new dose.
We'll use, as we'll mention in a second. Serum levels to guide us with this drug, but it's important to know that in some dogs they won't respond as well to an increase of the dose, as they would to an increased frequency of the dose, and this is because this drug. As with others, can be, can be, less effective with time.
You may have heard of this so called honeymoon effect, which is seen with other drugs like levetiracetam, but it's seen with all anti-convulsants to some degree and it means that the drug is effective, to start with and over time becomes less effective. Now we, we, we made mention at the start that one of the . Causes origins of refractory epileptic, are molecular changes in the brain.
The brain can start pushing drug out of the brain of itself with blood brain barrier. It, it can become less sensitive to the drug with less receptors, less sensitive receptors in the brain. But this drug is more of the architect of its own downfall because it increases the metabolic capacity of the liver, and the liver breaks phenobarb down.
So with time, it can become less effective because there's a lower serum level. It's breaking its it's, it's breaking, being broken down by the liver. And so increasing the dose could be effective, but spreading it out to 3 times a day could also be very effective because instead of this drug lasting 12 hours in a in a case where the liver now is super, metabolic, has a high metabolic capacity, then Potentially, it, it needs to be given more frequently.
It's worth mentioning because this is something we see in other drugs as well. So if you're not having great effect with increasing the dose, but you have more still room for movement, maybe change the dose to 3 times a day if obviously, the owners can deal with that. Now, there is, as we said, a serum concentration that we look to use to help us in making those adjustments.
How do we use that? Well, we begin with giving 2 to 4, let's say 4 mg per kg twice daily. We wait 2 weeks for it to be, maximal and consistent, and then we take a blood test.
Now, the reference range of most labs, will be given with your, your analysis, so let's say 15 to 45 mcg per deciliter. This is a target range, this is where 60% of dogs will be well controlled. 20% of the dogs will need higher, but we can't give them higher, as we'll talk about.
20% of dogs will be fine giving them a low, at a lower, serum level. So we don't treat the serum level, we treat the dog. We look at how many seizures you're having.
Do you need more control? Where is your . Serum level.
If you are getting towards the high end, certainly if you're over 35, getting towards 45, we shouldn't give you any more drugs because of the risk of liver disease. If you're in the low area and you're well controlled, I don't need to give you any more because you're well controlled. I don't care about your serum level.
If you're in the target range, well, that's great, but there's a lot of room for movement here. So if you're 717. You still have too many seizures.
Perhaps I'm gonna increase you by 25% so that I can get you higher in that therapeutic range, and you can then be better controlled. So just because you're in this therapeutic range doesn't mean that, there's no more room for movement. And as we said, sometimes, instead of increasing the dose, we'll look at these patients and try and push them to 3 times daily if the owners can deal with that.
And it has been established with clinical trial to show that our clinical study, I should say, to say that, 3 times a day can be very effective in some dogs when using phenobarb. But obviously not everyone's favourite because of the adverse effects. Most of these are idiosyncratic, which means bad luck, meaning that.
It doesn't often come down to the dose that you're using, and, and also the length of time that you, you're using it, although we, we'll mention that in hepatopathy in the next slide. Hyperapability affects a few dogs. It's pretty crazy to see these dogs will be panting, pacing, howling.
You have no other option really but to take them off this drug. It's a very quick onset if it is gonna happen. Liver disease, mentioned in the next slide, bone marrow, issues.
There may be suppression of one cell line or all three cell lines here, neutropenia, anaemia, thrombocytopenia may be seen, important then to monitor these. It's suggested to be an idiosyncratic. It was thought to be immune mediated, but they meant to be more of a toxicity really, as the cause of it, and they can regenerate if you reduce the dose or in some cases, take them off this drug.
Lymphadenopathy, not common, seen more commonly in cats on this drug, and skin disease, cats and dogs, it's a necrolytic dermatitis, not common. But is, a, a major problem again, will respond to reduction, potentially removal of, of the drug itself. But liver disease is the one that receives the most press.
However, we're not really sure of the prevalence of this, how many dogs on phenobarb, get this, are at risk of this. Well, based on the one study that's out there, we do know that it is reversible. So if we keep an eye on our patients.
This doesn't have to be a fatal disease. If we don't, it will be a fatal disease if they get, liver dysfunction. It's most likely if your phenobarb level is above 35 to 40, so we try to keep the phenobarb levels down.
In this one study, The levels were actually around 60 to 70 in most cases, so very high levels. So we do know that we can do something to reduce the chance of liver disease, and most of the dogs in that study were on phenobarb for over a year, so it's not going to be an overnight, situation. You're not going to start a dog on phenobarb, and tomorrow it's going to go into liver failure and you have no control over it.
So the, the situation here is it's chronic and it's high it's, it's high serum levels. So. That is something to to look for.
We often don't look too closely at liver enzymes when dogs are on phenobar because, as we said, the, the liver can be souped up really, on this drug on this drug. So liver enzymes will be induced, particularly alkaline phosphatase, less so ALT, because this drug inducing the, the. Enzymes means that now this organ has higher metabolic capacity and so as we said, it can actually mean that will reduce the levels of phenobarbital.
So it's the architect of its own downfall, but we expect these liver enzyme elevations, they don't mean anything in terms really of liver dysfunction. We always have to rely on a functional liver assay. And so every 6 months.
It's important to monitor phenobarb's serum concentration. That will be a good historical data point for us to look at because we can see in dogs that aren't controlled anymore what's been going on every 6 months you've been at this range and now you're too low or you're too high. So we, we can, we can make determinations based on history, but it also helps to say, hey, it's going too high.
This is, this dog's at risk of liver dysfunction. Haematology, as we said, we look at our cell lines every 6 months if possible. Serum chemistry, less important.
We don't look at, really the enzymes. We don't too bothered about those. You could say we are bothered about liver function, we look at albumin levels, cholesterol, that sort of thing, but, a little insensitive for us to be too reliant on it.
So we'll look at functional liver assays, bile acids, probably most commonly every 6 months if we can. Every 12 months at a minimum, if the owners can't afford every 6 months, we need to, so there's some labour intensity with the use of this drug, but it's very efficacious, and can be used to, to help many, many dogs with aggressive seizure focus early on. Now, other drugs that we'll talk about are often considered as adjunctive drugs.
They can be used as soul therapies as well, so we'll talk about their efficacy in that capacity. Potassium bromide, is the oldest of our anti-convulsants, was first used in people in the 1800s. Was then withdrawn because of some psychopathic murdering tendencies in people, but in this day and age where, if we forget history, we can recreate it, it's been shown that that this, this, this drug now based on its efficacy is worthwhile putting back on the market so.
There are humans, people out there on potassium bromide. I'd stay away from them if I were you, because they may murder you and get away with it. Now we don't see that in dogs, that we know of, but there are some behavioural abnormalities that we can see.
But otherwise a very safe drug because it's not metabolised. It's excreted by the kidneys, even if you have renal insufficiency, you're not going to cause toxicity, may just mean you need to use a lower dose. Seems to be synergistic with being a barb, acting in a slightly different manner.
And on its own controls about 50 to 60% of cases, so fairly good. efficacy nowhere near the 90% of phenobarb. Those that are refractory to phenobarb, it seems to control about 8 out of 10 of them, and it is the preferential drug for clusters.
Not many drugs have been shown to work in in dogs on a long term basis that have cluster activity. Short term, we're looking at, obviously, benzodiazepines and levetiracetam, but, for, . Long term control of clusters.
It's really, really, this is the drug that's, that's had, although limited, has had some success compared to other drugs. Now, this is used on a once a day basis, so for some owners, that's fantastic. You can divide it if you want, and We often start quite high if we're using it on on its own, 40 MB per gig per day.
Again, we can back off. The problem with the use of this drug is it's not very flexible. It takes a while to get to maximum levels, up to 6 months in some cases, most dogs about 3 months before it's consistent, it's maximal.
That doesn't mean it's gonna take that long to work. It just means that long before we. Can really rely on it, right?
So it may work after a week, but not maximally, not consistently. Again, we can use serum concentrations, so blood levels to actually help us out, but these, this is even more of a target range than the Fenobar because you can go way over the top here in some cases, as long as they don't have adverse effects that affect the quality of life. We can keep on increasing.
So the reason to take this is just to see how much more room for movement we've got, in some dogs, particularly if they're on phenobarb, well, we may need to push the serum concentration really high, like 3000, 4000, but we're just looking at this as, as an aid to making adjustments. Remember, treat the dog, don't treat the serum level. Adverse effects are not as common, not as, problematic as with phenobarb.
We can see the one, the transient ones that are seen with phenobar like PUPD, polyphagia, ataxia sedation. Those things can be seen with this drug when used alone and also exacerbated by this drug when combined with phenobar, so it can be a real problem for quality of life. In our refractory patients.
Very rarely will see pruritus, very rarely hyperactivity, see some behavioural abnormalities, maybe not murdering tendencies, but some behavioural abnormalities, . Occasionally rarely, pancreatitis, particularly if combined with phenobar, so we need to watch out for that. Rarely megaesophagus.
We don't use it in cats because there's a relatively high prevalence of feline asthma like signs, and in some cats, it can be fatal. So we, we don't use in cats, but can be an effective drug in dogs. Unfortunately, not as flexible as you would like it to be because it's not a quick onset, quick offset type of drug, but shouldn't be cast aside just because it's an older drug, and it's not as flexible as you'd like.
Compared to this, a newer drug or relatively over the last couple of decades or so, and, a safe and very flexible drug. This isn't metabolised in the liver again, excreted in the kidneys, and metabolised by serum esterases. This can be a drug that we need to increase its dose when used with phenobarb.
Phenobarb will increase the activity of serum esterases and so can kick out levote so it may not be as effective as it should be or we would like to be. When you use with phenobarb, often we'll use this 3 times a day, so there is a management issue here unless you can get hold of the extended release, which can be given twice a day, and can be as effective. Extended release version lasts in the serum above the supposed seizure threshold for for serum levels for over 12 hours, whereas the standard release, 8 hours is, you're lucky to get that amount.
It can be 6 hours in some dogs. And so in some dogs on the standard use, we've actually had to go to 4 times a day. Again, not something that many owners can do, but it is, it does again emphasise that it's not all about increasing the dose.
It's sometimes about increasing the frequency of use so that when drugs are metabolised quickly, they can be replenished with that frequent use. Overall, some people will say, as an adjunct, 50% control, but we're gonna talk about monotherapy in a second, useful in emergencies, obviously we're not talking about that today, but, the parental version here. It's very successful as emergencies and minimal side effects, so ataxia sedation, but no, no other really concerning things besides that.
It, in a monotherapy trial, there were some concerns raised because a small trial, but, levitrestan was put up against phenobarb, and unfortunately, when looked at on its own, there was no significant difference in the monthly number of seizures before and after treatment with Levoresan. Whereas obviously Pheobarb had, had, a, a more significant effect, so fewer seizures after treatment. 5 of the 12, phenobarb treated dogs were classified as true responders, where they're having over a 50% reduction in seizures per month, whereas none of the Levitrassan dogs.
So monotherapy, this may not be the drug for most of our cases. However, This was a standard release version of Levaretem, and so again, it may be that the, the reason for failure, is, is the fact that it actually needs to be given 4 times a day. Again, not that that is feasible for most people.
So the XR may be more efficacious as a monotherapy if you can, obtain that. Zennisima is becoming people's favourite. It actually seems to be the new age phenobar really, in that it, it, it has some similarities with the fact that it is a twice a day drug, 5 to 10 mg per gig, twice a day.
It can affect your thyroid axis, hypothyroidism seen with high doses. This may just be biochemical hypothyroidism rather than the clinical signs associated with it. And it and it ends, it elevates liver enzymes and can cause liver dysfunction.
So very similar to phenobarb, it is metabolised in the liver. We need to watch liver function closely here. There's also a sulfonamide based drug, so you may see some sulphur related side effects, with the, with the use of this.
So worthwhile watching that. And when used together with phenobar, we'll need to use a higher dose because phenobar will increase the clearance of this drug, mainly again because it's metabolised in the liver. So what, how, how efficacious is this drug?
Well, when there's a couple of studies out there looking at monotherapy. 10 dogs, with idiopathic epilepsy were looked at twice a day therapy, and 60% were favourable responders. And so that means over 50% reduction in the monthly frequency of seizures.
So that, that was, an initial monotherapy study that said, OK, this could be successful when used in dogs, not, . Not as efficacious as phenob are, but it's, it's, certainly worthwhile considering. And then more recently, this paper looking at the clinical efficacy and tolerability of sinniamide monotherapy, looked at 56 dogs, newly diagnosed, idiopathic epilepsy, so no structural issues, and showed that 3/4 of them had over a 50% reduction.
And over half of them achieved siege of freedom. So that's, that's good. There were some side effects seen, so 13% in this study had, reduced levels of activity, decreased appetite, vomiting, and limb weakness.
This was seen to be mild, temporary, dose related. So, so is a worthwhile drug to consider as monotherapy, perhaps, again, a useful adjunct as well in our refractory drugs. Less commonly used are our gabapentinoids, so gabapentin and pregabalin.
Obviously we use these more now for neuropathic pain. However, they are, relatively safe, even though they're metabolised in the liver. No liver dysfunction has been reported 3 times a day again, so again may be an issue for some owners.
And there is, as an adjunct some report that gabapentin at least can have 50% improved seizure control associated with its use with minimal side effects. A note not to use the proprietary liquid formulations. You can certainly have it .
Recompounded and it can be OK as a liquid, but some liquids will contain Xylitol, and obviously we don't want to use Xylitol in dogs because of its toxicity. So just be careful about using a liquid formulation if you, if you do want to use gabapentin as an adjunct. Pregabalin is the next generation of gabapentin is a, binds the receptor a little stronger, a little longer, so a little bit more efficacious, less side effects, .
Sedation ataxia are really the only ones that are seen with some GI things occasionally again shown to decrease seizure frequency by about 50% and may be efficacious as a twice a day drug in some dogs, in, again, metabolites in the liver but seemingly pretty safe. So we look at these as again potentially. Adjuncts, just because now they're more commonly used for neuropathic pain doesn't mean that we might, we shouldn't consider their use.
They were initially designed as anti-convulsants in humans, but because they're off label use, found some success with neuropathic pain, with diabetic neuropathies in people. Now that's kind of where we we place these drugs in terms of their utility. Obviously, Mitoin has a role again, potentially as a soul therapy, twice a day.
With minimal side effects, and, and also dual effect, right? So it's not just a, an anti-convulsant also has some anxiolytic properties. If it is licenced, if it is available in in your country, then it, it is something that could be considered.
It's a partial agonist at Ben ZP binding site. So binds, where diazepam binds and so is very has a very rapid on. And this is supposedly paving the way for newer drugs that are going to have a similar mechanism of action, meaning that within a day, it's efficacious.
Now, levitream 3 to 5 days, niamide 5 days before they get to steady state. So a lot quicker than phenobarb, a lot quicker than bromide. Gabapentin pregabalin, then maybe about 3 days.
This is 1 day, 24 hours, and you are at a, a therapeutic level. However, there are no therapeutic monitoring recommendations. You don't need to take blood levels to monitor this drug, I should have said, but you don't need to take them either for, for pregabalin gabapentin, and niamide, and levatiracetam.
There's no correlation with serum levels and with efficacy in those drugs. And the efficacy is variable depending on what study we read of apotoin, but to some degree up to 75% of dogs have been, benefited by this, with epilepsy, and then eradication seen in about a third of those dogs, so eradication of seizure activities. But it has been shown that a follow up with time, the .
Efficacy dwindles a little bit. Same with all drugs that we're using for seizures, really. You can see that after 6 months, 21% seizure free compared to early, early part of the study, 33%.
So with time, less efficacious, and it has again been documented to not be effective for clusters, as we said, bromides probably the major drug that we'll use long term for clusters. So we, we've got all of these drugs to use, and we use them as a polytherapy. We use them at higher doses, we use them more frequently.
These are all the tactics that we will use, but then as adjuncts, there's other things that we can now consider. The use of diet in various forms, which we'll go through briefly now, neurostimulation, cannabis surgery, acupuncture. So we'll make brief mention of, of, of these as we finish off here.
So dietary change, this is a big thing to owners of epileptic dogs. A recent survey, looked at over 250, owners, and 2/3 of these owners reported that they changed their dog's diet. After receiving an idiopathic epilepsy diagnosis for their dog, and nearly half of the owners reported giving dietary supplements, in addition to a change of diet, and the most common being coconut oil, or medium chain triglycerides.
So what's going on here? Medium chain triglycerides come from coconut oil or palm oil. And it has been shown, although it's not completely understood, that these can be anti-convulsant.
They provide an alternative energy supply to the brain, and in epileptic dogs then energy metabolism is, is, insufficient, is, is not as, it's not normal as in a normal dog, and so an alternative supply of energy. Potentially through these medium chain triglyceride is helpful. It also changes neurotransmitter levels and it's been shown to be an antagonist to glutamate, which is the excitator excitatory neurotransmitter in the brain.
So it's, it's, it's an antagonist to the major excitatory neurotransmitter. So potentially that's a reason for it being anti-convulsant. Now this was incorporated in a commercial diet.
I'm not meaning to advertise any diets, but it's, it's this diet that it's in. I don't work for Purina, but I'm just showing you the results of a trial where this diet, which contains medium chain triglycerides, and essentially those purported to be these AMA receptor antagonists, and AMA is one of the receptors for glutamate, was used in 21 dogs with refractory seizures. Now, again, remember these are dogs that are unlikely to be helped by many things.
Remember, right at the start, we said less than 15% of people. Will be controlled by the use of any other drugs if they failed two drugs. So here we have a group of dogs that potentially have a very serious seizure focus that maybe nothing will help.
We've used now this diet here in this study for 3 months versus a placebo. And they found that their seizure frequency was lower. Now, now, not too much lower, right, 2.3 per month versus 2.6 per month, so it doesn't look great there.
But when you know that 10 of the dogs had more than a 50% reduction in seizure frequency, that's quite dramatic. 6 dogs didn't have any response. So an expensive option.
It's 3 months of use before you can kind of write it off or before you can see what success it's going to have. It may have absolutely no response in an individual dog, but it may be enough to actually improve the quality of life of some dogs. Now, there's a lot of research going.
On us to various mechanisms of delivery of these medium chain triglycerides that are alternate to the use of this diet. But right now the the dose, for instance, of coconut oil is not well known. The side effects of using that high fat.
Solution in dogs can be anticipated, but not well known. And so we have to be cautious with owners getting on the internet and saying, well, I'm just gonna give my dog coconut oil. There can be problems, but that's where research is going right now, so more information will be forthcoming shortly.
Hypoallergenic diets, in people it has been shown that there is a role, a contributory role rather than a primary role. Of food allergies, in humans and potentially, therefore in dogs, in, in children that are, that have dairy sensitivities, it's been shown that there's a higher prevalence of epilepsy and changing the diet can potentially improve their epilepsy control. So potentially the use of a hypoallergenic diet, the ones that are commercially available, may again be something that we could consider.
Again, unfortunately expensive. You need to use it for 3 months, it may have no effect, but it's a trial and error. Worthwhile mentioning this though, the ketogenic diet.
Now this is the Atkins diet, supercharged. It was found that children with epilepsy. Who were put on this traditional ketogenic diet, on a, on a traditional ketogenic diet, so a high fat, low carbohydrate, had a significant seizure reduction compared to children on a controlled diet.
About 40%, so 4 out of 10 children had over 50% seizure reduction. And maybe about 5% of children actually had more than 90% reduction in seizures. So refractory epilepsy in children can be managed with this ketogenic diet.
It induces ketosis, lactic acidosis. And these things are actually anti-convulsant. The reason that most seizures end after 90 seconds is because there is a buildup of lactic acid in the brain, and that's been shown to be anti-convulsant.
So essentially the ketogenic diet is, is mimicking that. Unfortunately, and, and obviously there is a high risk of pancreatitis, if you're using this diet in dogs, and it's very difficult to induce ketosis in dogs unless they're diabetic. So, unfortunately, this isn't an area that we are able to, pursue, but owners will come in and say, what about the ketogenic diet?
So just important to say that is a non-starter for dogs. No talk on refractory epilepsy is now complete without a bit of discussion on cannabis, so let's go with the kind of overview here, . There are a couple of species of the cannabis plant cannabis sativa and indica that are most commonly used to manufacture marijuana and hemp, and it's hemp that we talk about when we're talking about cannabis, we're talking about hemp because this is .
Now that the part of the plant actually that contains less than 0.3% of THC, that's the psychoactive component. So it really has, has negligible effect on the brain in terms of, psychoactive issues that have been associated with it.
So hemp is what we're, what we're using now. There are over 120 metabolites, so called cannabinoids. Within hemp and marijuana, and one of them is cannabidiol.
So you might have heard of CBD, that's cannabidiol, that's one of 120 metabolites of cannabinoids. And it's been shown that these, in humans, can be effective for anxiety, for improving sleep, for nausea, for pain, and for seizure activity. We'll get into that in a second.
But it is important that now these are kind of widespread. They're on the market owners get them from anywhere, important to advise owners, regardless of your local legal issues, and it's important to stress that that. There are legalities involved in prescribing this and suggesting it and discussing it, depending on where you live.
Regardless of that, it's important to advise to owners that what you get in that package may not be efficacious and safe. One study looked at 29 products, of, of hemp derived CBD. So low THC and there was a poor quality in most of these products with, with only 18 of the products being appropriately labelled, and two of the products had zero CBD in them.
Some of the products actually had heavy metal contaminants in them, so that's concerning. Another study. Looked at CBD extracts sold online for human use and revealed that there was major labelling inaccuracy.
Only a third of those products, and there were over 80 products evaluated, were accurately labelled. 43% in that study were under labelled, 26% were over labelled, so. We can't rely unless it is a certified product from a respected or a an approved manufacturer.
We can't rely on what's in there and it actually may even be dangerous. How's it, how does this work? What, what is the, what is the thought about its effectiveness?
Well, there are receptors for cannabinoids all around the body, so-called CB1 and CB2. CB1 receptors are in the brain, central nervous system, and these, correlate with effects on cognition, your behaviour, your appetite, your emotions, your memory, because we have endogenous cannabinoids. And then this is then supplementing their, their efficacies.
There are CB2 receptors. These are, these are less common in the CNS are more highly concentrated in the peripheral nervous system and the immune system, and they, play a role in inflammation and pain regulation. How they work is less well understood.
There are, there are a couple of receptors that they'll target on the pre-synaptic terminal. Overall they seem to reduce calcium, mobility, which reduces excitatory neurotransmission, so decrease glutamate, and changes adenosine uptake, so inhibits that adenosine uptake. There are some issues.
With its efficacy based on how it's given, in people, it needs to be given with a fatty meal, and that's obviously a problem in dogs, and so you'll see that that's some. Solutions will be combined with an oil. We don't know the exact dose, we'll make comment on that in a second.
There's, but there is a low bioavailability, so like up to 20% that's crossing over. So, again, dose is gonna be important and it's metabolised pretty quickly, extensive first pass metabolism. So, so it's important to know what products you're using.
It's important to know the dose, it's important to know what it's combined with, and these are all areas of research, and there's a couple of studies out there that look at CBD. This study in 2019 looked at dogs with refractory seizures. Again, tough crowd, right?
CBD infused oil was used at 2.5 MB per gig twice a day versus a placebo and for 12 weeks. 9, were in the CBD group, 7 in the placebo group.
And the seizure responders were were the same in each group, so that's not great, but it was shown that there was overall a 3rd 33% median seizure reduction in the CBD group. So the number of cases that responded with the same in placebo, so saying, well, that, that, that doesn't fill me with confidence, but there's some hint of efficacy here in that there is a median seizure reduction in that in that group. Which was statistically significant.
Now, more recently, this, study again looked at refractory seizures. Again, tough crowd, used CBD and, a version of CBD, CBD acid, . In sesame oil, so you'll see different oils that come with these preparations, versus placebo, again, around 2 mg per gig, 12, every 12 hours.
They looked at a crossover 12 weeks, found that there were 6 out of 14 seizure responders versus 0 for placebo placebo, and overall these dogs went from 8 seizures over 12 weeks down to 5 seizures. So again, a hint at efficacy there, more work to be done. Certainly not something that could be used on its own and expected to reduce or or or stop seizure activity.
Let's make a brief mention of neurostimulation. This is where things may go in the future, a lot of work being done in people where the delivery of electrical or magnetic pulses to the nervous system may alter neurochemistry. The precise mechanisms that are really poorly understood.
It has been shown with, however, these pulses are delivered intracranial or transcranial, so from the outside, that the effect seems to increase with time, peak effect in 2 years, that's going to make studies difficult, but it, it seems to become more efficacious with time. These are currently used as third line strategies in people, so we've got medication, we've got diet, and they're currently considered as palliative rather than, anything, anything, more substantive. And the versions of these are vagus nerve stimulation.
Deep brain stimulation, transcranial magnetic stimulation, and really there's very little data on these latter two here in dogs, so we, we're gonna kind of skip over those and go to vagal nerve stimulation just to give you an idea, because this is getting some press at the moment. Now, the vagus nerve, why are we stimulating it? Over 80% of the vagus nerve is sensory, right, so it carries information from your body, from the viscera towards the brain.
These are afferent fibres going to the brain. Only 20% of fibres are actually motor or efferent, so you could use the vagus nerve to send messages to the brain, and it has been shown. That stimulating the vagus nerve actually increases some vital neurotransmitters that are inhibitory, so serotonin and and GABA and GABA.
So these can, as well as dopamine and your adrenaline, but these can really then calm the brain down. It, it's also been shown that it changes blood flow and regions that correlate with seizure reduction. And so there's potential efficacy, related to multiple mechanisms here.
And you can, based on human work and on dog work, implant these pulse generators. So you, you've got like a human cardiac pacemaker here, buried under the skin with a lead that attaches to the vagus nerve, sends messages into the brain, calms the brain down. In people over 50% seizure reduction with very mild and reversible effects, very expensive though, right?
So these, this equipment, is not being recycled as quickly into the veterinary market as cardiac pacemakers, were and are, so it's expensive and demands a small surgery to to implant them. Some, some studies out there, 10 dogs were with, idiopathic epilepsy that was refractory again, were, underwent surgery for implantation of this pacemaker device and the lead wrapped around the left vagus nerve, and it was shown that some dogs did experience a reduction in seizure frequency, and that infrequency, it, it, that positive effect increased with time. So again, something that needs to be noted is they're not going to be as efficacious as they, as they could be straight out of the gate.
It's gonna take some time. A more recent study looked at really this the sort of feasibility and side effects here. 16 dogs with idiopathic epilepsy, showed that this was at least well tolerated.
And the current was increased slowly, so, the dogs were OK with its use, showed that coughing was a problem that was dose related. Obviously, the, vagus nerve is, it gives rise to the recurrent laryngeal nerve, and so there's, there's input to the larynx with some of its motor fibres, and so you can see some effect on that. But overall fairly safe.
We actually looked at a handheld . Vagus nerve stimulator, so a non-invasive stimulator manufactured as gamma core, for the treatment again of refractory seizures. We looked at 14 dogs and took it out, for a few months and showed that 9 of those dogs had seizure reduction.
4 of them were considered good responders. So again, a reasonable adjunct here, for the handheld version. But a lot more work needs to be done on what dose you're delivering, how long, how frequent, etc.
So, cannot be advised at this stage, and again it is also quite expensive. And then lastly, or nearly lastly, the surgical treatment, this is, this plays a big role in people who are refractory to all mechanisms of, of, anti-seizure therapy. Essentially, you're trying to localise the origin of the seizure with.
EEG or electroencephalography, you find out where that structural abnormality is, with EEG and then you can resect it. Most of the surgery, resects a specific area, but in dogs, that's been very difficult to do. And so the research that's out there has focused on two types of palliative surgery.
A temporal lobectomy, as we see here, here's the temporal lobe on an MRI of a dog here, and this can be cut out, and suggestive that it is responsible for some versions of seizure activity. And also a corpus callusectomy. And one study here, or corpus callosum is essentially what joins two hemispheres together, right?
So, the left speaks to the right through this corpus callosum. So if you can cut it, you can disturb the spread of seizure to the other hemisphere. Now there are some side effects that could happen with that because you need the left side to speak to the right side and vice versa.
But in this study, 6 dogs with refractory seizures were treated, 2 dogs died. There was a pretty significant seizure reduction rate though. So it's out there.
It's still, I'd say, experimental. This is not mainstream treatment at this stage, and it would be considered, fairly radical, because of the side effects that can be noted with it. but lastly, acupuncture again, as an adjunct has been shown to have some effect.
There are supposed accu points, the base of the ears, and, people who are qualified in this would be better. It's suited to talk about this, but, the versions of acupuncture that can, that you can have, it's probably best to start with the temporary versions, so the needles, versus the sort of more permanent implantation of gold beads. That can be advised just to see whether the temporary version actually works.
There really aren't any controlled trials. There's anecdotal evidence that it can work. I've had some cases where it seems to have had effect in the right hands, so it could be considered for refractory cases, but we should emphasise if it does appear to work, do not reduce the medications dramatically because they are dropping the control of seizures up.
So you can add into problems if you do that, but it can be a useful adjunct to consider for refractory cases. OK, thank you for your attention. I'm sure that if there's a way you can send some questions, I'd be happy to field them.
We do have a website that is free. It's worth going to for further veterinary neurology education worth visiting. But thanks for attending and hopefully you've got something out of this to.
I deal with this very challenging disease phenomenon. Thank you.