---start---- betsy dayrell-hart VMD diplACVN private practicioner in Va formerly on faculty here she will discuss epilepsy Seizures = convulsions = fits: a sign of brain dysfunction; the cerebral hemispheres participate, but need not be the site of dysfunction. The causal lesion may be within the brain, or might be elsewhere in the body and affecting the "normal" brain adversely. 1. are paroxysmal events 2. usually self limiting 3. generally characterized by: disturbed muscle activity and posture; disturbed consciousness; disturbed autonomic activity; possible anomalous behavior; abnormal EEG activity not a disease itself but a sign of a problem. to make a seizure occur, all kinds of things either within or more likely outside the brain can go wrong, affecting neuronal activity and causing synchronous discharge, so that we see activity relating to this abnormal synchronous activity. other paroxysmal events are conditions which might mimic a seizure - eg, peripheral neuromuscular, vestibular, cardiac, respiratory, and metabolic dysfunction or collapse. NB: must be distinguished from "false epilepsy." anything causing syncope, tremors, etc. epilepsy: a condition characterized by recurrent seizures. true epilepsy: idiopathic = primary = cryptogenic = true epilepsy false epilepsy: symptomatic = secondary epilepsy --> there is a cause (tumor, encephalitis, insulinoma, etc. think about a neuron and imagine this diagram as a brain neuron. there is a cell body, within which there is an electric potential maintained about -70 mV. to be able to d/c it has to have polarity, so it can depolarize. the neuron has inhibitory and excitatory inputs from other neurons. these create the EPSP and IPSP to move the neuron toward or away from threshold. eventually threshold is reached, it depolarizes. if you measure resting potential, -70 mV (-60 on this chart), and you put + charge into the cell, it gets closer to the threshold - it gets hypopolarized or, less negative. if you keep putting current in, making it less negative, it will reach threshold and depolarize. but if you hyperpolarize it, make it more negative, you take it further from threshold, make it harder to depolarize. so when you think of how a neuron decides to depolarize synchronously or not, remember you can do a number of things to hypo or hyperpolarize the cells. think of group of neurons in the brain - an ensemble - in the cortex, are columns of neurons. there are cells - if this whole thing is the cortex and the surface is the top, there are neurons in the IVth layer - remember those layers you saw? there are cells in those layers - remember the pyramidal neurons, those are the ones. they are in a column, and input and output activity in cortex is columnar, so all these ones in a column are participating in the same activity. when active, there are inputs from deep in the brain to the cells, from the cells to other parts of the brain. the dendrites tend to run perpendicular to brain surface. excitatory cells can send afferents to the pyramidal cell dendrites - if enough of those do that, cell will depolarize. other cells tend to be inhibitory, shielding one column from nearby activity. so there are IPSP and EPSP; these clels have dendritic potentials developing up near the surface; when there are enough inputs to get cell to threshold, it will discharge. normally, if you want to move your hand, messages go to the motor neuron to bring it to threshold so it will depolarize and you move your hand. nearby neurons are quiet - you don't move your hand and foot. but if there are too many collateral connections, or loss of inhibitory synapses, then you may get depolarization of cells in series or in parallel to the neuron which is supposed to depolarize. when you try to remember something it gets easier and easier to do b/c you form new pathways. but sometimes the balance b/c normal synaptic interconnections and those that should be shielded breaks down - either you take away some negative, GABA mediated influences or you add too much positive input, and you activate some neurons you weren't supposed to. if this happens, and they fire repeatedly and get nearby neurons to fire repetetively then there is synchrony. EEGs: rarely done for diagnostic purposes in vet med. if you record a surface EEG - from the scalp - the same way an ECG records remotely what is going on in the heart from the surface, you're recording general electric potentials of the brain from the surface. you're getting potentials that are mainly developing from the superficial parts of the brain. there is some deep activity but the further you are from the source, the smaller amplitude you pick up. so normally, you see group currents, lots of currents happening outside a whole bunch of neurons, mostly dendritic potentials. now, if you can record the activity occuring in those cells nad surrounding area and you look for evidence of synchrony, as collections of neurons fire together you start seeing larger and sometimes very characteristic potentials. sometimes a surface electrode actually will pick up a spike instead of a normal squiggly low amplitude thing. ECoG - electrocorticogram - you expect a known latency after a stimulus to see a response from a brain. if you record from inside a cell, you see large amplitude potentials. from just outside that cell the potentialls are smaller in amplitude. from further away, still smaller. the EEG is looking for these "paroxysmal depolarizing shifts" and repetitive discharges. these shifts happen when you hyperpolarize a neuron which has a tendency to depolarize - even as you depolarize it it has this shift. superimposed on this are spike discharges which occur as the neuron stays close to its potential. those are repetetive discharges. you look for these. surface EEG is again lower in amplitude than intracellular recordings. we see a spike and then a period of quiet, and then a bunch of repetitive discharges which show up on the EEG as spikes. during the seizure, there is abnormal activity in the brain, repetitive spike discharges, as more neurons get involved it is synchronous. in people and animals with epilepsy, there are also inter-ictal spikes. when the siezure is happening, you see many spikes. if there is a single spike of activity but it doesn't spread, you see no seizure but you see this on the EEG. or if you give a convulsive drug, you may start to see these one at a time, then more and more, until a seizure occurs. so abnormal electrical activity occurs even between clinical periods of siezure. but we don't do EEG in animals very much b/c the amplitude of the spike is influenced by resistance b/w electrode and tissue - from CSF, meninges, skull, muscle, skin. humans do not have so much resistance but dogs and cats have more resistance. also if you put eeg leads on your own head you can keep still and follow commands. a cooperative patient isn't the rule in a companion animal practice. it takes a long time. blinking, twitching ear, can make spikes but those aren't epilepsy. Threshold: the beginning point stimulus or insult to homeostasis point beyond which a seizure occurs every animal has one does it change during life? is it inherited? think of each brain as having a threshold. imagine all the things you can do to bring a neuron closer to thresholds - those things could induce seizures. if you get enough of some convulsant stimulus - drug, low glucose, whatever - it will cause a seizure. in animals, it may change over course of life (maybe, not sure). everyone has a siezure threshold that is probably inherited in that some animals are more susceptible to spontaneous seizures than others (dogs more than cats, people mroe than horses). as you near threshold the cells we talked about before start to discharge - it can send collaterals to get other cells to fire with it. it may cross corpus callosum to other side of the brain, or from there to more parts of the brain. when we talk about categories of seizures - they may be focal - in one small area without crossing corpus callosum - so we see activity related to that area of the brain - or it may start deep in diencephalon and go out to all areas. it may be generalized. we depend on activity we see during the seizure to decide if it is focal or generalized. classifications: generally based on what structures are involved, behavioral manifestations you see, or EEG findings which is experimental in animals. consider animals who have seizures. think about the threshold everyone has. there is a bell curve. some animals are born with really high seizure thresholds and never have seizures. others are born with low thresholds. maybe not always responsive to the same stimulus. but some animals have epilepsy and are normal in every way but have spontaneous seizures. if you breed those animals, they probably will produce more epileptic animals. clinical and historic features to cover: prior history of patient, of events, of onset, of gender interictal history, PE, labwork appearance, symmetry of events there is usually a preictal phase, ictus, and postictal phase. pre-ictal: spikes developing but no overt activity seen. when owners report this in dogs, they say the dog comes to be with them or does something to make owner think dog knows it will have a seizure. then it enters ictus where it is having the seizure - if in motor cortex, may paddle, thrash, exhibit clonus (rhythmic contractions) and tonus (rhythmic extension); paraysmpathetic activity (SLUD, vomiting), etc. that is the seizure activity, the ictus, during which there are many spike discharges in the brain. then, there is post-ictal phase which may be a brief quiet phase and then rapid return to normal; or may be very quiet phase, involving blindness, confusion, slow respiratory rate, or other abnormal sign but after the actual seizure. seizures may be: partial, focal - spikes only in one area Jacksonian seizures are typically in this category: the activity begins in one limb, or one body part - same part each time - maybe paddling right foot first - then the activity marches across the body and sometimes become generalized, but the focus of abnormal activity begins in one spot. focal seizures are not usually idiopathic. idiopathic epilepsy is usually generalized. it may start in front and spread back or back and spread front but is usually bilateral. when we see focal seizures, we want to know what's going on in that area of the brain. generalized, tonic, clonic, tonic-clonic: typical grand mal seizures - there is genrealized activity, the whole brain goes at once, not part first. petit mal - activity is generalized but so brief that people don't usually even use posture but have just brief memory loss. this may occur in dog/cat but we see it less common than grand mal, perhaps b/c we just don't notice it. psychomotor - behavioral - complex partial motor seizures: animals have "running fits" - have no control over what they do but do not lose posture - may run around and bark while turning in circles. may fall over and have generalized seizure after that. limbic lobe seizure - fly biters, floor lickers. it's hard to separate these things from other behavioral problems. especially if they do not lose consciousness. if we had EEGs, we might be able to tell if there were focal discharges. why do we care if seizure is focal or generalized or petit mal or whatever? well, if we see jacksonian seizures there may be a structural cause. or other times in people, the kind of seizures which occur, even if idiopathic, the part of brain involved may influence what drug will work. some seizures occur b/c of insufficient GABA; others b/c of too much excitatory NTs or biogenic amines. those need different drug types. usually we don't find anything about the seizures in animals that helps us to figure out what drug to use. but now that we have a few choices, we may figure that out. so first - is it idiopathic or symptomatic? then, find out from the owner, the history of what happened before, what the events look like (so you can see if generalized or not), what inter-ictal phase is like because generally if idiopathic is normal inter-ictal but sick animals aren't normal in between; PE helps us to find maybe a tumor in abdomen which could have metted to brain, or maybe we find nothing on PE. we like to do some labwork in most animals - more than often in idiopathic epileptics this is entirely normal but we need to do at least a CBC, Chem, UA so as not to miss some obvious disease process not evident on PE. also ask about appearance and symmetry of events. owners may come in and say "dog is having fits." and you say ok and find nothing wrong at all and you say ok, it's idiopathic epilepsy. but then if you ask what aniaml was doing they may say it was doing something that wasn't a "fit" at all. people often get tired of this. they come to you because they are SURE the dog is having fits. they do not want to describe it to you. but if they tell you he had a head tilt, fell down, thrashed from side to side for 5 or 6 days, then it wasn't a seizure. it was vestibular disease. but to the owner it was a seizure. do not ask LEADING questions. if you say "did he do this, did he do that," clients often say "oh, yeah, he did" but you should instead ask "what exactly did he do" and figure out if it was a siezure or not. there is a list in the handout of the kinds of things that can happen when it isn't idiopathic epilepsy that might bring an animal closer to threshold. ever wonder why an animal who is sick and dying of sepsis or toxemia has seizures? well, probably b/c as metabolic processes go on and body is poisoned, brain is losing ability to maintain normal resting potential - it gets closer to threshold. why do dogs convulse? brain homeostasis is disrupted. provocation can be minimal. different causes, same result. list in handout of many things that influence brain's ability to keep its homeostasis. glucose - low glucose - in very young animals that are not fed, hypoglycemia occurs - small breeds in first few days of life who miss 2 meals may convulse. they are generally treatable with glucose. they get better, they are fine as long as you feed them. this is a metabolic problem, symptomatic epilepsy. or, in old animals with insulin producing tumors, hypoglycemia can occur, and often in these animals there are some signs prior to the severe hypoglycemia which causes a seizure which indicate the problem - hunger, shakiness, wooziness, possible history of fasting and then seizure, and some owners even come in and say "i think the dog is hypoglycemic and has an insulinoma b/c he has seizures when I feed him once daily but not if i feed him four times a day and I know what it is b/c i looked it up on the internet." but there are other causes - polycythemia, other tumors, sepsis - but basically something is taking away glucose from the brain. sometimes people think that when a dog has seizures, in and of themselves, the seizure causes glucose to drop. this is not really true. if you cause a convulsion in a dog, the glucose usually goes up during the siezure due to release of cortisol and epinephrine. a normal, healthy dog who has a seizure will have a slightly elevated BG maybe around 200-250. liver disease is another problem that can cause seizures. young animals with shunts, portosystemic anomalies, small livers not working well, can have seizures perhaps due to circulating toxins or increased ammonia levels, but they have them and typically the young animals born with abnormal circulation have seizures shortly after they eat and they also may have hx of looking abnormal based on protein content of diet after they eat. the more protein they eat, the worse they look. sometimes before they have a seizure from hepatic encephalopathy they drool, look dull. usually smaller than siblings. require medical or surgical tx or some can't be treated. on the other hand, old animals usually have acquired liver dz. usually they look sick even when they are not immediately post meal. they may be icteric, may have livers that are large, may have tumors somewhere, something somewhere will look wrong. if you think about all the things you look at on a chem panel, almost any of them can induce a seizure if out of whack enough, just by changing the milieu around the neuron so it can't maintain polarity toxins lead, other heavy metals strychnine many things like this can cause seizures, stop brain from maintaining itself or body is ok but brain is sick: brain tumor, brain inflammation, inborn error of metabolism in the brain; if you see an animal who is normal outside the brain and has a problem in the brain causing seizures, where in the brain is the problem? the cerebral cortex and diencephalon. this seems obvious now but sometimes people think they come from the cerebellum. they do not. they come from cortex. if you've been through the whole list of other things that can happen to body and brain and induce seizures and those aren't occuring in your patient, your patient probably has idiopathic epilepsy. it's generally a diagnosis by exclusion. we have a set of criteria we use to help us confirm this: young at onset of siezure - > 6 mos, < 3-4 yrs. routinely normal between seizures if you looked at brain, cells would look normal seizures tend to be centrencephalic or generalized - probably start deep, hit both sides of brain at the same time. beyond that, it's hard to profile a generalized dog with idiopathic epilepsy. almost any breed - many mutts. some breed groups think some breeds are predisposed but it seems that whatever you see most often has the most epilepsy. maybe 0.5-2% of dogs have seizures - the majority have idiopathic epilepsy. so you see this normal dog which is convulsing. what do you do? you have to give something to stop the seizure, right? when do you start, what do you use, how much do you give, what does it cost? how long do you give it? almost always you treat for life. most dogs have seizures and keep having them. ----break---- seizure mechanisms: voltage dependent ion channels GABA mediated-inhibition acidic amino acid-mediated excitation (excitatory AAs) drugs to treat seizures: there comes a point when you find a young, healthy, normal animal with recurrent seizures. there are many reasons why you start earlier or later with some animals. in children at least, if they are treated prior to the 10th seizure there is easier control than if they are not treated until after the 10th seizure. we don't have this data in dogs, aren't sure if the disease is the same in dogs. there may be some number of seizures beyond which it is harder to control seizures in dogs, but you have to remember the problems getting those stats and also that we have fewer drugs available b/c dsome do not work well and b/c some are just too expensive. we also have a different view of "what is seizure control" - a dog with idiopathic epilepsy can be a perfectly fine pet even if he has a seizure once a week or once a day. now, some people freak if the dog has one more than twice a year. so that's different for each owner. the dog has to do different things than a person has to do. people need jobs, need to drive cars, read, learn things. dogs may have a job, but may need only not to make too much of a mess in the house. so goals differ, outcome may differ - adoption, giving away, euthanasia in animals are options. so seizure control has other things influencing it than what the cause is. main goal: minimizing seizures - rarely, we make them go away. can try to make them shorter, less violent, less frequent; or if dog has clusters of seizures maybe we can make them go from 12 per cluster to 2 per cluster goals shift drugs are limited animal metabolism of drugs is different from human metabolism of drugs. mechanisms which change cell's ability to stay polarized: voltage dependent ion channels GABA mediated-inhibition acidic amino acid-mediated excitation (excitatory AAs) so we'd like the drugs to stop letting positive charges in ion channels, or enhance GABA mediated transmission, or change how many excitatory AAs can bind, or change something about dendritic potentials, or stop the repetitive depolarizations, those would be good. more specific. Slide: liver of dog who has had phenobarb - nodular hyperplasia and fibrosis/cirrhosis medical management - what drug we pick, how we pick it, when we give it, when we start, when we stop, who decides - all vary per patient. out in the Real World, we do xyz - something you hear often. but the university world is also Real. a sense of unreality in private practice comes from owners who think the dog has seizures b/c it is controlled by aliens, or the phase of the moon causes it, or veterinarians who treat animals without ever trying to make a diagnosis. that's somebody's reality. but not ours, hopefully. try to make a diagnosis, treat based on what the goals can be, and lose the distinction b/w whether you are in the university or not as a method of choosing a treatment. if you are awake and eyes are open, you are in a real world. anticonvulsant drugs: phenobarbital: our goal is to minimize number/frequency/violence of seizures by choosing a drug effective in the species we treat with minimal toxicity and which is inexpensive, dosed conveniently, etc. some drugs do this. one is phenobarbital, an oxybarbiturate coming in a number of sizes of tablets, elixir, and injectable. dose: to effect, usually about 5 mg/kg/day but may go much higher, need serum concentration of 15-35 micrograms/ml in serum. reasonable dose based on body weight. loading dose: 15-20 mg/kg IV for animal in status epilepticus untoward effects: acute/chronic - some animals have untoward effects; may be worse if animal takes other drugs. there are some animals - this is a low number - but some get liver disease and get cirrhosis. it's a low frequency effect, but can occur. we used to see it more before KBr was out. dogs metabolize phenobarb (and some other drugs) about 4 times faster than humans do, so you have to give drugs with a long half life, cutting out many other anticonvulsants suitable for use in dogs, so we would be giving really high doses - up to 60 micrograms/ml in serum. at some point sedation would occur, in which case the owner usually said to cut the dose back. but some dogs would develop liver disease before sedation effect was seen. don't panic over this but keep in mind that this drug CAN make dogs sick but usually does not. reasonable monitoring is key. Primidone (mysoline) - similar to phenobarb, is turned into phenobarb and PEMA in the body (phenylethylmalonamide - an anticonvulsant in people but not in dogs) - dogs on primidone with seizure control all have therapeutic serum levels of phenobarb; dogs with no control on primidone don't have control on phenobarb, etc. toxicity is the same as with phenobarbital. can't use this in cats. more expensive than phenobarbital. few dogs take this drug rather than phenobarb b/c why use a drug that needs to be converted in the liver? but sometimes people think it works better than phenobarb so they use it. Pentobarbital: sedation/anesthesia. given by injection for status epilepticus, no oral form. beware of aspiration when you sedate animals to stop the seizure. return to consciousness is rocky. paddling, vocalizing, and panting may be mistaken for seizure activity. starts a vicious cycle - needs close attention and monitoring. fairly long acting drug. animal stays asleep a while and as animal wakes up and goes through the prolonged transition to consciousness you think it is having seizures and you give more drug and it is a vicious cycle. if patient is sedated/anesthetized: intubate maybe monitor breathing, HR, temp, support with IV fluids, express urinary bladder as needed, EKG monitor, turn and lubricate eyes. treat as anesthetized patient. drug interactions with barbiturates: chloramphenicol (will get increased, toxic levels) cimetidine (increased or decreased levels) phenytoins (increased or decreased levels) digoxin (increased or decreased levels) metronidazole (increased or decreased levels) steroid antiinflammatory drugs when you use these things together you really have to monitor drug levels of both. chloramphenicol you can't give with phenobarb, it's dangerous. Steroids also increase liver metabolic activity so you have to monitor closely. there are other drugs that may be involved. other anticonvulsants: KBr - potassium bromide - 250 mg/ml reagent grade dose: 25 mg/kg/day or more once daily in food. it's the bromide that works. blood levels: 1 mg - 2 mg/ml ?? untoward effects: acute/chronic can order from pharmacy, get it beef or tuna flavored. once daily dosing. it takes a long time for it to work, though. you can't inject it. most of us do not use sodium bromide so it's not generally available by injection. most often used only by mouth and may take 2 mos to get to steady state bromide in the body. usually takes 2-3 weeks to see benefit so sometimes use twice daily for first few weeks to speed it up. if giving it by itself - doubling dose x 2 weeks at first doesn't seem to affect dog. the dog usually only looks a little sleepy if it gets too much but maybe in time we will find there are side effects. haven't seen them yet. Br- is an anion. giving it to a dog with seizures often reduces the frequency/violence of seizures dramatically. mechanism is thought to be via exchange for Cl- and hyperpolarization of neurons. not sure though. this drug is often given after treatment with phenobarb for initial control. when you start using bromide in dogs already on phenobarb, you give both at full dose then start to withdraw phenobarb. have owner keep journal of what drugs are used and what seizures are like. start when owner first brings dog in. KBr is not metabolized, not protein bound, is exchanged for chloride, causes chem screen artifacts. after a drug change, wait at least two average seizure intervals before evaluating response. if once weekly, wait at least two weeks. when we give bromide we can measure it in the serum - usually look for 1-4 mg/ml in the serum; a recent JAVMA article from November suggests that when used with phenobarb the concentrations of both can be lower, but the upper and lower levels of therapeutic range for bromide are hard to assess. if animal is doing well and level is under 1 mg/ml, don't change the dose. same with phenobarb. if level is lower than you expect but control is good, don't change it - unless you know this animal has very severe seizures or there are other things to think about. Diazepam - one of the Benzodiazepines (clorazepate is another) used by injection to control status epilepticus. short acting, usually works. comes in tablets, suppositories, injectable dose 0.25-1 mg/kg IV for status; 0.5-2 mg/kg PO in digs, cats this is good for cluster seizures - give rectal suppository at the start of a cluster and it is well absorbed, enters blood quickly, 10-15 minutes onset, can abort the cluster or at very least relax the animal so it can go to the hospital. diazepam mainly used for status epilepticus, or in some dogs orally with other anticonvulsants. if animal comes in in status, if you give diazepam it will stop that seizure, then you figure out what to do next. if you determine it is idiopathic epilepsy you can start phenobarb. but some animals come in with a first siezure, get some valium, seizure stops, and you don't give anything else until you figure out why it had the seizure. not a good maintenance drug in dogs. in some cats, is reasonable maintenance drugs. except for a few cats which have idiosyncratic liver necrosis, of course. many cats can take valium longterm for seizure control .idiopathic epilepsy is less common in cats than dogs, easier to control, probably a different process. benzos, when they work, seem to do so by potentiating with GABA inhibitory neurotransmission (hyperpolarization). GABA + benzodiazepines are more effective than GABA alone. benzos alone don't do anything. we think most anticonvulsants are GABA-enhancers. other anticonvulsants: gamma-vinyl-GABA (vigabatrin) - gaba transaminase inhibitors - produce more GABA around the neuron by decreasing degradative processes. coming on the market soon (available in europe, etc). effective in some dogs when phenobarb doesn't work. few toxic effects, although hard to tell for sure. phenytoin - drug that when combined with phenobarb or primidone causes toxicity. commonly used in people. in dogs, degraded really fast so if you give it by mouth you can't get good serum levels. it can't be given to cats - huge half life in cats. such a long half life in cats, it can induce irreversible liver disease really fast. half life is in days. in dogs, if you could get a long enough acting form, and you don't have a problem with causing some liver dysfunction, you might be able to give one of the drugs in this class along with bromide and be useful in dogs. valproic acid, carbamazepine - expensive, possibly hepatotoxic, not that useful, not really used in dogs. in referral institution you see animals coming in who aren't doing well on maintenance. there may be animals out there taking these and we don't know b/c we don't see them... after trying phenobarb and bromide, if dog doesn't respond to those or can't tolerate them, we have to try other drugs, in combination. may be expensive. will require serum monitoring though maybe we don't know therapeutic levels. if they are toxic they may not have the same toxicity that showed up in the beagle tests done by the company. lots of stuff goes on in pet dog life that doesn't in lab beagle life, too - surgery, plane rides, vaccinations, meds... we like to monitor these animals, see them every six months at least to do a PE and basic bloodwork. if something is going wrong with blood or liver or kidneys we may pick it up with routine screening this way. if they are having trouble, if seizures are not controlled, we see them more often. if they are sick, or showing toxic effects of the drug, that's difficult to define - sedation could be considered a toxic effect. dog may be sleepy, quiet, scuffing hind feet. client may say dog has degenerative myelopathy. but this could be just sedation. they may be really really sedate, so sleepy they fall asleep during PE, and may have hyperreflexia, may have nystagmus, may be undergoing toxicosis from the drug which is possibly reducible if you withdraw the drug. or there may be longterm changes occuring in brain, liver, or other organ b/c drug has been exerting some effect over time. that is harder to diagnose and deal with b/c lots of things happen over time nad the changes you see may or may not be drug induced. are changes due to seizures? drugs? something else? toxin? etc? concurrent renal disease? who knows. it helps to do some reasonable monitoring. keep in touch with owners. it isn't good to start therapy and never see them again, or see them only once yearly. ----end----