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VetInfo Digest July 2006

Table of Contents:

Seizure Control

This Month's Note:

A client came into our office this week and loudly announced to my receptionist that his dog Duke was in for a yearly physical, "Even though Dr. Richards told me he was going to die three years ago." What I actually said, at least according to our records, was, "I think that there is only a 50% chance that we can save Duke." I hardly ever say that a pet's death is completely inevitable, except when I think it is going to occur within a few minutes. Most veterinarians have a miracle pet or two in their practice - dogs or cats that really seemed to have an illness that would kill most pets but which this one individual lives through. I don't know any vets, personally, who would take it as bad news if a client called to say their pet defied the odds and lived through a tough time with a little help from us or possibly all on its own when our choice of treatments wasn't likely to have helped with the disease that was present. In any case, there are times when it is great to be wrong. If you have one of these pets who has lived through a dire situation make sure that you tell the whole story if you have a crowd of listeners stuck in your vet's waiting room!

Seizures and Seizure Control, continued from last month.

When and how to use seizure control medications has been a topic of discussion among veterinarians for a very long time. There is no strict consensus at this time but it is possible to at least outline some of the controversial points in order to try to understand how these decisions are made.

Over the years I have seen a number of reactions from clients when their pets have experienced a seizure. Some of my clients want me to start medication immediately, hoping that there will never be another seizure ever during their pet's lifetime. Other clients try to delay using seizure control medications even though their pet is having seizures very frequently or having seizures of long duration. Like many things, it is probably best to be somewhere between these two positions. How you react to the seizures may influence your veterinarian's decision making process regarding seizure control so keep this in mind if you are either excessively disturbed by seizures or if they don't bother you at all. Making treatment decisions based on the client's perception of how bad a seizure is for a pet is usually a poor approach to the decision making, so it is helpful if you make an effort not to let your personal feelings about the seizures show too much.

Seizure activity can cause a number of changes in the brain of animals who experience epileptic seizures. The brain uses oxygen and energy to function, just like muscles. However, the brain is limited to using glucose as its source of energy. If a seizure goes on long enough it uses up the available glucose and oxygen and brain cells are damaged. This is the reason that a seizure that goes on for more than 5 minutes is considered to be an emergency. It is also the reason that multiple seizures occurring within a single day are considered important enough to warrant the use of seizure control medications even if they are the first incidence of seizures, as long as there is not an discernible underlying cause that can be treated separately. In really severe instances, severe seizures can lead to blood flow changes in the brain that can cause large areas of the brain to be damaged. While this is rare, it further justifies the use of seizure control medications for long seizures and when seizures occur repeatedly within a short time period.

Seizures that are of short duration but which occur on a periodic basis also can lead to changes in the brain that can have an effect on seizure activity in the future. For some time neurologists have known that the presence of a group of cells prone to inducing generalized seizure activity (a seizure focus) in the brain will cause other clusters of seizure prone cells to occur and will also lower the seizure threshold in some patients. This is usually referred to as "kindling" seizures. In addition, a seizure focus in one side of the brain will tend to induce a similar seizure focus in the other hemisphere of the brain in some patients, a process referred to as "mirroring". These changes can lead to increased seizure activity over time or even to early death in some pets. For these reasons, some veterinarians feel it is important to control seizures as soon as it is evident that they are going to be a recurrent problem. I think that there would be universal agreement with this position except for the fact that there is no really ideal seizure control medication, free of side effects and risk, at this time.

It is easiest to list the side effects of seizure control medications on an individual basis but in general it is fair to say that the balance between the potential harmful effects of seizure control medications and the potential harmful effects of allowing seizures to go on uncontrolled has a strong impact on the decision as to when to control seizures. Veterinarians who have had patients who suffered severe adverse effects tend to want to hold off on seizure control while veterinarians who have had patients who developed serious consequences or died as the result of uncontrolled seizures are quicker to use medications. Due to this problem, there is not a really strong consensus, even among seizure control experts, as to exactly when seizure control should be considered. There is also a strong incentive to try to identify underlying causes for seizures that might be controllable without anti-seizure medications or to find alternative therapies that do not seem as toxic, at least.

There are differences in the way that dogs and cats are treated for seizure disorders due to the fact that the medications vary in their effect on each species. It is important to keep track of which species you are dealing with when considering seizure control therapies and I will try to make the differences clear as I go along in the listings of seizure control medications.

The Seizure Journal

Last month I talked about keeping a seizure journal as part of the decision making process for determining when seizure medications might be indicated. Before discussing those medications it is important to point out that keeping a journal is equally important when attempting to regulate seizure control medications. It is extremely important to document whether the seizure activity is being controlled and keeping a log is the best way to do that. When seizures do occur try to note how long the seizure itself went on for, whether there were early warning signs and how long the recover to normal behavior took after the seizure occurred. If there were any changes in routine, diet or activity levels that might have contributed to the seizure make note of them. Make a note of what was happening right when the seizure occurred, especially whether it occurred during a rest period or while your pet was active. In the log it is also important to note when medication doses are not administered, for whatever reason that might occur. It is amazing how often people bring a pet in who has been doing well on seizure control medications but who have a break in seizure control after skipping one or more doses of phenobarbital over a short time period. Most people assume this won't matter but sometimes it does -- and having a record of when seizures occur and when medications haven't been given can aid in detecting this problem.

Your journal helps your vet determine several things. It can aid in determining if the seizure control medications are working. It can also help determine if dosage changes are needed. In some cases it will help to determine an underlying cause for the seizure activity. It also helps you to recognize when seizure control goals are not being reached so that you can notify your veterinarian. For some pets seizure control might be adequate if they have less than one seizure a month all of low intensity, but for others the goal may be two seizures a year, for instance. Having the journal reminds you that the goal usually can't be complete control of all seizures but rather a goal of reducing seizure intensity and the frequency of seizure episodes.

Phenobarbital

Phenobarbital is a well known and widely available medication that is inexpensive to use. For some time it was considered to be the first choice in seizure control for both dogs and cats by most veterinary neurologists. This is changing some at the present time as neurologists are becoming more and more comfortable with the use of potassium bromide as a first line seizure control medication in dogs. In cats phenobarbital is still thought to be the first choice in seizure control for most situations.

Phenobarbital is a barbituate. This group of medications is physically addictive. This worries many of my clients but addiction in pets is not the concern that it is people. Pets can't hold up the 7-Eleven to get more drugs when they want them! Dogs on phenobarbital often do show signs of addiction with some of them becoming very insistent that they get their daily dosages on time but they do fine as long as they do get their medication daily. It is a bad idea to abruptly stop phenobarbital once a pet has been on it for more than two or three weeks due to the strong possibility that severe withdrawal signs will occur, including severe seizures.

Dogs with seizure disorders are usually started on a dosage of phenobarbital that is between 1 and 3mg/kg every 12 hours. Most dogs will require a dosage in the upper end of this range so a good starting point is about 2.5mg/kg every 12 hours. Dogs vary widely in their ability to absorb, process and respond to phenobarbital so it is necessary to monitor serum levels of phenobarbital and to adjust the dosage as necessary based on the response to therapy and the serum level of the medication.

It takes approximately 2 weeks for phenobarbital to reach a steady state of metabolism in the body. This is the point where the medication is present in constant enough levels in the blood stream to adequately control seizures. This is important to remember when first starting phenobarbital, as seizures in the first few weeks phenobarbital is being used are not unusual, since there are times the medication levels are below the serum levels necessary for seizure control.

Failing to monitor blood serum levels of phenobarbital can result in poor seizure control or missing phenobarbital levels that are in the toxic range. Veterinary neurologists suggest testing phenobarbital serum levels 2 weeks after starting seizure control medications, then again after 45 days and 90 days. If the seizures are controlled and the serum levels are within the recommended range of 20 to 40 ug/ml then further testing is recommended at 6 month intervals. If the dosage has to be adjusted due to the results of any of these tests the recommendation is to re-test after 2 weeks, repeating this process until the seizures are controlled and the dosage is in the recommended range.

There are some dogs who appear to respond to phenobarbital at dosages slightly below the recommended range. If seizures are well controlled and the serum phenobarbital level is 15ug/ml or greater, it is likely that the medication may be providing at least some degree of seizure control. Sometimes we have a dog come in the clinic whose seizures appear to be well controlled who has phenobarbital levels of 12 ug/ml or less. We usually recommend gradually withdrawing the phenobarbital in these dogs as it seems likely that it is not effective at this dose range and that the seizures have disappeared for other reasons.

There are also dogs who require phenobarbital levels greater than 40 ug/ml to get good seizures control. At the present time most neurologists seem comfortable with serum levels of phenobarbital up to 45 ug/ml and some will push this further but the risk of liver damage begins to dramatically increase when serum levels exceed 45 ug/ml. In most cases in which phenobarbital fails to provide control of seizures when the serum levels are adequate the use of a second medication, usually potassium bromide, is indicated. Most veterinary neurologists recommend attempting to test the phenobarbital serum levels when they should be lowest, which is right before administration of one of the day's doses, in order to be sure that the level is within recommended ranges throughout the day. It is likely that phenobarbital levels are stable enough after two to three weeks that drawing the blood any time during the day is acceptable, though.

Phenobarbital has lots of adverse effects. It makes dogs drink more, it makes them urinate larger volumes and it keeps most of them hungry enough that they will bother you a lot in the hopes of getting an additional allowance of food. When first used it makes most dogs seem very depressed or moderately intoxicated. This effect usually lasts for about 3 weeks. After that, the liver learns to process the drug better and the dog becomes tolerant of the effect of the phenobarbital enough that most dogs seem normal, although their owners sometimes feel that there is a long term very slight lethargy, at least compared to the dog's previous activity levels, while on phenobarbital. These effects are more aggravating than serious.

In a smaller number of dogs, probably slightly less than 5%, phenobarbital causes more serious problems. Liver damage is the most common serious problem and it is a good idea to monitor liver enzyme levels on a periodic basis while using phenobarbital. Rises in alkaline phosphatase levels, one enzyme associated with liver disease, are induced by phenobarbital directly and do not indicate that liver damage is occurring. Rises in other enzymes associated with the liver, such as alanine transferase (ALT) or in bile acids, could be due to phenobarbital damage to the liver. It is probably best to monitor the liver enzyme levels at the same time that phenobarbital serum levels are being tested.

Phenobarbital use in cats is very similar to its use in dogs. The recommended serum levels are a little different and not as well established but a guideline of 10 to 30ug/ml has been published by Shell and Dyer. The recommended starting dosage is usually 2.5mg/kg in cats. Testing intervals are the same according to most neurologists but Dr. Shell believes that once yearly testing is satisfactory after the initial dose is established. Cats have the same side effects as dogs, although liver damage seems to be much less common in cats. Phenobarbital can be given IV initially to ensure that blood levels are high enough to control seizures and then maintained orally almost immediately, which allows phenobarbital to be used to rapidly gain control of seizures in cats, which is an advantage for the use of phenobarbital in cats over dogs.

Phenobarbital use frequently causes rises in serum alkaline phosphatase (SAP) in dogs. Increases in this enzyme can signal the presence of liver disease, hyperadrenocorticism (Cushing's disease) or bone cancer, as well. It is important to keep in mind that a rise in SAP alone associated with the use of phenobarbital is usually a normal finding and not to get too worried about the other possibilities unless there are either clinical signs or other lab values that make them more worrisome. This problem has not been shown to occur in cats. This is an important difference between the species because it makes it important to investigate changes in SAP levels in cats even though they are currently on phenobarbital for seizure control.

Suddenly withdrawing phenobarbital after a pet has become dependent on it can cause severe withdrawal symptoms, including death. It is very important to taper the dosage of phenobarbital over several weeks when stopping the medication. Plan ahead for weekends, vacations and other times when you may have a hard time getting in contact with your veterinarian for prescription refills so that you do not run out of the medication.

Phenobarbital is a controlled substance. Your vet must continue to keep a veterinarian/client/patient relationship in order to sell or prescribe this medication. Do not assume that you will always be able to get refills without having your vet examine your pet or without having serum phenobarbital levels checked when it is appropriate to do so.

It is really critical that you tell any veterinarian who may not be fully familiar with your pet's medical history that your pet is on phenobarbital whenever treatment is necessary for any other illness. It is a good idea to say something like, "Don't forget that Velcro is on phenobarbital." even during visits with your regular veterinarian. Phenobarbital interferes with some medications but more importantly a number of medications cause changes in phenobarbital serum levels that can be important. Among these medications are chloramphenical (antibiotic), tetracyclines (antibiotic), cimetidine (Pepcid AC tm) and ranitidine (Xantac tm).

At the present time we still use phenobarbital as our first line anti-seizure medication for both dogs and cats. Many neurologists have changed over to potassium bromide as their first choice for seizure control, primarily to avoid the potential for liver damage that is present when using phenobarbital. We may make this change at some point in the future.

Potassium Bromide

Potassium bromide is not an approved medication for use in pets. Most veterinarians who use potassium bromide prescribe it through compounding pharmacies who package the chemical in flavored liquids or capsules. Potassium bromide has been recognized for its potential to control seizures for a very long time but it fell out of use in humans when the discovery was made that it led to dementia when used long term. So far this has not been a problem in pets.

Potassium bromide is now the first choice for seizure control in dogs for many neurologists. It would probably be the first choice for seizure control in cats, too, except for the fact that it causes asthma in about a third of the cats who are treated with it. This is a serious complication that limits its use in cats to situations in which there appears to be no practical alternative.

The major advantage of potassium bromide over phenobarbital in dogs is a lower long term risk of serious adverse complications, especially liver disease. Potassium bromide is excreted through the kidneys without causing damage to them. Another advantage for many pet owners is that potassium bromide can be administered once a day after the initial induction period.

Like phenobarbital, potassium bromide causes signs of intoxication when first used. The length of time these signs last varies with the method used to start the medication process. When it is not necessary to gain control of seizures rapidly it is reasonable to start potassium bromide at the estimated maintenance dosage and to wait for it to obtain steady state serum levels, even though this takes approximately 3 to 4 months. When seizures are occurring frequently enough that seizure control needs to be obtained quickly it is better to start with a loading dosage of potassium bromide that brings serum levels of the drug up very quickly but which may also produce very pronounced signs of toxicity, such as lethargy and incoordination, usually one to two days after the initial loading dose. Potassium bromide also causes an increase in appetite, increased drinking and increased urine volume so there is little difference between it and phenobarbital for these side effects.

There are a couple of published loading dose protocols for potassium bromide but regardless of which one is used, it is important to test potassium bromide serum levels after the first few days of use (typically on the 3rd day) and then to re-test serum levels in two weeks. Adjustment of the dosage may entail using additional "mini" loading doses if the serum levels are low or skipping administration of potassium bromide for several days if the levels are too high. There was a time when it was hard to find a laboratory that could accurately test potassium bromide levels and some general practice veterinarians still feel that this is a problem but for the most part this is no longer true.

When using potassium bromide for seizure control it is important to establish a diet that contains the same amount of sodium chloride (salt) every day. This usually means picking a particular dog food and sticking with it and feeding the same amount of the chosen diet and the same type and number of additional treats every day. It is much harder to regulate potassium bromide levels effectively when dog owners can not stick to a regulated diet. This is also helpful in preventing weight gain due to increased appetite. If dietary changes must be made due to other health concerns it is important to measure potassium bromide serum levels about 6 weeks after the dietary change and then again in 3 months. As a general practitioner, I think that most of my clients are unable to maintain a constant diet and this is the major reason that we have not switched to potassium bromide. Veterinary neurologists tend to see clients who are more highly motivated than most veterinary clients and it makes sense that they would have more success with this aspect of potassium bromide dosing. Think about this issue before choosing potassium bromide as the primary seizure control method for your dog.

The recommended serum levels for potassium bromide are 20 to 25 mmol/L. The steady state is usually reached about 3 months after initiating therapy and also after changes in dosage. It is important to remember that changing serum levels is a slow process when using potassium bromide since seizures that occur during the interval between dosage changes and obtaining increased steady state serum levels shouldn't be considered to be a failure of the medication or an indication that the dosage should be steadily increased. At the present time most neurologists seem to be comfortable with potassium bromide serum levels up to 30 or 35 mmol/L and some will go for even higher levels if necessary to control seizure activity, as long as the patient tolerates the dosage acceptably. The realization that higher dosages could be used when necessary to control seizures seems to be part of the reason that neurologists are switching to potassium bromide use as their primary seizure control method.

There is less problem with withdrawal of potassium bromide abruptly than with withdrawal of phenobarbital. The major reason for the difference appears to be the very slow changes that occur in potassium bromide levels over time. Stopping the medication causes serum levels to slowly decline over several weeks and lessens the potential for withdrawal seizure activity.

Obtaining potassium bromide in consistent formulations can be a little difficult, at least from a local source, in most areas of the country. It may be necessary to deal with a veterinary mail-order compounding pharmacy in order to obtain this medication. This isn't necessarily a big stumbling block but it does mean that you have to remember to order the medication in sufficient time to get it before you run out of it since it isn't possible to run to the corner pharmacy or local veterinary practice to get it.

Combinations of phenobarbital and potassium bromide

When seizures are very difficult to control there is some benefit to using phenobarbital and potassium bromide at the same time. In some cases it is possible to use lower doses of one of the medications when using them together. If this is the case it is probably better to try for potassium bromide levels in the normal to high end of the therapeutic range and phenobarbital levels in the normal to low end of the range. We have found that for our patients with seizures that are difficult to control we have to keep both medications in the normal to high end of the serum levels to get adequate seizure control, though.

There are no shortcuts when using both medications. You still have to monitor the serum levels of both medications just as you would when using them alone for the best results. You still have to control the diet to get good regulation of potassium bromide serum levels and you still have to avoid using medications that interfere with phenobarbital levels.

The use of phenobarbital and potassium bromide together is still less expensive than using the newer human seizure control medications, though. Due to this, the combination is generally the next step up in seizure control for any dogs who are not responding to either medication adequately - after reevaluation to ensure that epileptic seizures are the dog's problem.

Diazepam

Diazepam (Valium Rx) is a good short term seizure control medication in dogs and can be used long term for seizure control in cats. Diazepam is the first drug of choice for stopping long duration seizures in both dogs and cats and for controlling persistent cluster seizure activity in dogs.

In cats diazepam is generally given twice daily when it is used long term for seizure control. Some cats have very few side effects from diazepam use while others show signs of lethargy or seem to have slight personality changes. A small percentage of cats are susceptible to severe liver damage that occurs within a few days of starting oral diazepam. It is very important to monitor liver enzyme levels when using diazepam due to this problem. Even with early recognition of this problem some cats will die from the liver damage. This is not a common problem but its severity makes most veterinarians look at diazepam as a second choice for seizure control in cats, especially since phenobarbital doesn't seem to have the propensity to cause liver disease in cats that it can have in dogs.

When a dog or cat is in status epilepticus or is having repeated cluster seizures diazepam can often stop the seizure activity. This shorter term use and the routes of administration seem to be less likely to cause liver disease in cats.

In the veterinary office diazepam is usually administered intravenously by rapid injection to control seizure activity and then maintained by a controlled intravenous dose administered over the course of 6 to 8 hours before an attempt is made to lower the dosage. This administration requires a fair amount of attention to detail and will probably require transfer to an emergency or critical care facility from any veterinary practice that does not have 24 hour a day staffing.

It is possible to administer diazpam rectally and to obtain good blood levels and good control of cluster seizure activity. This enables most pet owners to administer the medication themselves at home, which is a real advantage when pets are prone to cluster seizures. Being able to medicate at home can eliminate the need to rush to an emergency veterinary hospital on weekends, nights and holidays, which is inevitably the time that cluster seizures occur. This is something that you should talk over with your vet if your dog or cat is prone to cluster seizure activity.

Diazepam breaks down quickly when exposed to light and it is absorbed into most plastics rapidly so your vet will have to dispense diazepam for injection in its original bottles, even though it is intended for rectal use. The alternative is to use specially prepared rectal solutions made for children with cluster seizures but these are prohibitively expensive for most pet owners. You should not draw the diazepam into a syringe for administration until it is time to use it.

To use diazepam to control cluster seizures, you will need to be willing and able to draw up an accurate dosage in a syringe and to administer it rectally during or shortly after seizure activity and then to administer three to four additional doses at 20 minute intervals. Most of my clients who have attempted this have been able to handle it satisfactorily. It is a relief for my clients to be able to handle seizure control on their own. I think that just knowing that they have medication available makes them more comfortable since cluster seizure activity can be very upsetting. We have also used this method of therapy for a small number of dogs prone to repeat episodes of status epilepticus and it has worked well, so far, to allow time to get these patients to us or to the emergency clinic for further care.

Alternative seizure control medications

There are several newer seizure control medications that are approved for use in humans that can be used in dogs and cats. These are particularly good for some canine patients with partial seizure activity but they are very costly and for the most part it is better to consult with a veterinary neurologist prior to considering one of the newer medications. I will try to give a short overview of these medications in the next VetInfo.

Seizure Enhancers

When your general goal is to reduce seizure activity it is important to avoid using medications that may lower the seizure threshold unless they are absolutely necessary. There are a few medications which have the reputation for lowering the seizure threshold and therefore making it more likely that a pet taking them will experience a seizure. It is best to avoid these medications if possible.

The medication we associate most strongly with inducing seizure activity is acepromazine. This is used as a preanesthetic and also as a sedative to treat thunderstorm anxiety and motion sickness. Other medications that may lower seizure thresholds include ketamine (an anesthetic agent), amitriptyline (sedative, behavioral modification, itch or pain control), aminophylline (bronchodilator), terbutaline (asthma in cats), theophylline (bronchodilator), xylazine (anesthetic agent) and estrogens (incontinence). As you can see from this list, the main things to consider are sedatives, anesthetics, bronchodilators and estrogens, so be sure to remember this short list for pets who seizure and remember to remind the veterinary staff that you pet seizures prior to any procedure that involves anesthesia.

I know that many of you don't have pets with seizure activity but I think it is important to cover some of the other medications and some of the alternative treatments recommended for seizure control in the next issue. Hopefully there will still be room to move on to at least one other topic, too.

Thanks for your Support!

VetInfo Digest

P.O. Box 476

Cobbs Creek VA 23035

All opinions in this newsletter are those of the author, Michael Richards, DVM