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The Neurotransmitters: Clinical Neurology Education
IM Board Prep #4: Seizures and Epilepsy
Hello and welcome to our mini-series designed to help prepare internal medicine residents get ready for the neurology section of their board exams!
While it is aimed at IM residents, it is a good review for anyone feeling a little rusty on the approach to seizures and epilepsy.
In this episode, we'll be talking about the evaluation of first-time seizure, seizure types, epilepsy syndromes, treatment of epilepsy, as well as management of status epilepticus.
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The views expressed do not necessarily represent those of any associated organizations. The information in this podcast is for educational and informational purposes only and does not represent specific medical/health advice. Please consult with an appropriate health care professional for any medical/health advice.
Hello, dear listener, and welcome back to The Neurotransmitters. I'm your host, Dr. Michael Kentris, where we talk about everything related to clinical neurology. Today we are continuing our series for internal medicine board review, obviously on our neurology subject, and our specific subject today are seizures and epilepsy. So let's start off with some definitions again. What do we mean when we say seizure? So we're usually talking about a clinical manifestation of an over-excitation or failure of the normal breaks, if you will, on excessive excitation or hyper-synchronization of electrochemical activity in the brain, causing some sort of clinical event. Contrast this with the definition of epilepsy, which is essentially the tendency to have unprovoked seizures or, to use our proper definition, to unprovoke seizures more than 24 hours apart. Or one unprovoked seizure with one of the following abnormal EEG MRI or someone who has a known syndrome preexisting that is associated with epilepsy. And we'll talk a little bit more about what that workup looks like. But first, when someone comes in and either the patient or a family member says they've had a seizure, the first question you need to ask yourself is was it actually a seizure? Because there are other things that can mimic them. So, as with so many things in medicine and neurology in particular, it does come back to the history, always the best place to start. So you often need history from both the patient as well as, hopefully, a witness to the event, because very often people's memory may have been impaired during the event itself. The best place to begin is at the beginning. So you want to ask how was the patient feeling prior to any loss of consciousness or any more dramatic clinical event that other people noticed? Did they feel like they were in their usual state of health? Do they have any strange preceding symptoms in aura, if you will? And that aura can present differently depending on what part of the brain is involved. Some of the classic temporal lobe auras could be something like deja vu, a strange feeling in the stomach, a quote rising epigastric sensation end quote towards the face. That is a very common one as well. It's unpleasant smells or a feeling of impending doom or panic.
Dr. Michael Kentris:As you might presume based on some of these questions, these are not things that most people think to mention necessarily. So, as opposed to our usual open-ended questions, these are very directed questions, although you do have to have a grain of salt and put it into the appropriate clinical context. Hopefully the event in question was witnessed by someone who can give you a good collateral history, because very often people are coming in after an episode of loss of consciousness and with most seizures there can be some degree of amnesia regarding the event, either pre or post as well. So you do need someone who witnessed it to really get the full picture. And things that you're going to ask about is did they have any kind of cry or scream that ictal cry at the beginning of an event, particularly as they go into a tonic-clonic seizure? How long did the event last? Most seizures should last less than five minutes, usually around one to two minutes.
Dr. Michael Kentris:How was their behavior before and after the event? Perhaps they were having some unusual automatisms Again, we'll talk about those in a little bit or kind of a staring off before or maybe they had some unusual behaviors. They tried to run out of the room after a tonic-clonic seizure so-called post-ictal leaving or fleeing behavior Other things that will help you point more towards an epileptic seizure. Did they have their eyes open during the event? A lot of times you'll have ictal eye opening, did they? If it was a tonic-clonic seizure, did they have a lateral tongue bite, not very sensitive as a sign, but pretty specific? In the appropriate context and as I hinted at a little bit earlier, is this truly the first event or going back? Have there been these little strange spells in the past that have not risen to the point of medical attention that may imply that this was not in fact the first seizure, if in fact it is a seizure. So really digging back for those other past events that may have seemed somewhat innocuous at the time to the person having them may point you in a more clear direction.
Dr. Michael Kentris:So what other kind of things belong on our differential diagnosis for potential epileptic seizures? Other things that we think about are syncope. Now, that can result in loss of consciousness, of course, but the thing that a lot of people forget is that it can also result in some brief convulsions, usually some mild myoclonic or twitching in the limbs. Some of the key factors in differentiating convulsive syncope from an epileptic seizure is that it tends to have a typical presyncopal prodrome. What do I mean by that? Well, someone might feel a little woozy, dizzy, lightheaded. They might have some flushing, might be a little diaphoretic. Maybe it happened as they stood up from a lying or seated position. The duration of loss of consciousness tends to be much more brief than what we see with an epileptic seizure and similarly there really isn't any post-ictal confusion like what we would expect to see with an epileptic seizure.
Dr. Michael Kentris:Another entity in our differential diagnosis are non-epileptic spells. These were previously called psychogenic non-epileptic seizures. They are now called functional seizures or dissociative seizures, but essentially they are events of non-volitional movement that closely mimic a seizure. The clinical features that can help differentiate non-epileptic versus epileptic spells is that the events with non-epileptic events tend to be less stereotyped, that is to say, it isn't the same time after time in terms of the movements, the pattern of involvement of various face, limb, legs, etc. There tends to be more forced eyelid closure, that is, if you are evaluating someone during an event and they squeeze their eyes shut when you're trying to check their pupils for light reflex. The limb movements tend to be asynchronous, as opposed to more time-locked and rhythmic like you would expect with an epileptic seizure. You can see side-to-side movements which are not typical of epileptic seizures. The spells themselves tend to be on the longer side and they will not infrequently have this start-stop-start-stop kind of pattern to the event. So you'll have this intervening period where they might appear fatigued or disoriented, potentially even lucid, and then the event will resume and this kind of goes on for a period of time.
Dr. Michael Kentris:The pattern of breathing itself can also be very helpful in differentiating. So after an epileptic seizure we expect more of this sturtorous breathing, that is to say, very heavy, wet, kind of like someone with bad, untreated sleep apnea, where it just sounds like their throat's trying to close up. The breathing pattern after a non-epileptic event is usually more akin to someone with hyperventilation. They're breathing very quick like they just ran a race Again. It is important to remember that any one of these signs by themselves is not enough to really hang a diagnosis on. So it really is collecting multiple of these signs, both historical and clinical features, to help you differentiate epileptic versus non-epileptic events.
Dr. Michael Kentris:Some other things that we want to think about also right. We have to think a seizure is something with a quick onset, quick offset and often with a relatively normal physical examination in between episodes. There are, of course, exceptions to that. So a few other families of neurologic disorders that can fit this quick tempo of onset and offset migraines, different kinds of auras, confusional migraines, things like that can also present with this kind of rapid onset and offset. This has helped historically if someone tells you they had a migranous headache either pre or post event.
Dr. Michael Kentris:Another event that can happen is a limb shaking, tia or transient ischemic attack. So you can get these episodes of shaking, often in the arm or the leg, and this may be a precursor to a stroke. So, again, very important to get that history down. Different kinds of movement disorders think of things like hemifacial spasm or blepharospasm. Different kinds of ticks, tremors, especially if they're asymmetric, especially if maybe someone has a history of a stroke and maybe they only have a tremor in one arm or one leg. Various sleep disorders are things to think about as well. Different kinds of parasomnias, people who walk in their sleep, people who have REM sleep behavior disorder, where they're acting out their dreams, sometimes violently. You can have people, often children, with confusional arousals. Basically, they wake up from sleep and they're more disoriented, confused, than what we would expect them to be. So there are a number of things to think about.
Dr. Michael Kentris:Not everything that shakes is a seizure is a good maxim to think about when we are evaluating for potential seizures. So let's say, we've taken our history, we think, yeah, this sounds like it was an epileptic seizure. So what are the things that we need to know to help decide Is this person at risk of future seizures, ie epilepsy, or is this a one-time event and we just kind of have to take a watchful, waiting approach? Just like a broken record? I'm coming back around to you guessed it the history. So there are different risk factors, both familial, historical and otherwise, that can help us try and risk stratify this person to see if this is someone who might be at risk for epilepsy, because the question at this point is why did this seizure happen?
Dr. Michael Kentris:Well, what are some different risk factors for developing seizures or epilepsy later in life? These are somewhat variable based on the stage of life that the person is developing epilepsy during. So we tend to see epilepsy most common in the very young and the very old, with a slight dip in mid-light. So in the younger end of the spectrum we see things that are related to complications around birth history. So someone maybe had a perinatal stroke or some hypoxia requiring a time in the NICU, things of that nature. A little bit older, we start seeing issues with genetic syndromes creeping in and then we might see some developmental abnormalities and things of that nature. As we get a little bit older, into childhood, adolescence, we see things like concussions, typically with loss of consciousness or traumatic brain injuries becoming more common, cns infections like meningitis and encephalitis as we get a little bit older, cns neoplasms or different types of brain tumors, and then, in the older end of life, we have patients who have history of strokes or dementia, and all of these can increase the risk of developing seizures and or epilepsy.
Dr. Michael Kentris:Another question we want to ask ourselves during the evaluation of someone with a first time seizure, or even someone with a history of epilepsy, is is this seizure provoked or unprovoked? Provoked meaning a few different things, depending on what you're looking at. So we have what are called acute symptomatic seizures, and those are seizures that occur within seven days of some sort of injury to the brain, like a traumatic brain injury, a stroke, meningitis, something of that nature, whereas a remote symptomatic seizure we'll talk about a little bit later. A provoked seizure can also occur in someone who's been put on a new medication, also certain kinds of medications like tramadol, yourpropion, cephapim, someone with alcohol withdrawal. These are provoked seizures and they are not necessarily counted towards a diagnosis of epilepsy per se.
Dr. Michael Kentris:Now, someone with a history of epilepsy can also have a provoked seizure and that may be related to maybe missing a dose of medication, someone who's been under more stress and has had some sleep deprivation, maybe they have another active medical issue, like maybe their septic from some sort of systemic infection, and that causes them to have a quote breakthrough seizure. So those are all provoked seizures, both in patients with no history of epilepsy and someone with a history of epilepsy, and the management of a provoked seizure can be different than an unprovoked seizure. So an unprovoked seizure is essentially when you find nothing in recent history for this particular person that should have caused a seizure. Because if we have someone who has a seizure and has one of these historical risk factors, he might still consider an epilepsy in the appropriate clinical context. So we've gotten our history, we think it's a seizure.
Dr. Michael Kentris:What kind of workup do we need to do so? First of all we want some kind of head imaging. A lot of times people, when they come in with a first-time seizure, they've already gotten a CT of their head without contrast. That is good to rule out some of those more acute things like a mass or an intracranial hemorrhage, but it's not going to see a lot of the other causes of seizures or epilepsy. So ultimately we will want an MRI of the brain, very often with and without contrast, if there is a concern for infection or a neoplasm.
Dr. Michael Kentris:In addition to these routine images, you will also sometimes get what is referred to differently at different institutions but is essentially an epilepsy protocol, quote-unquote. What that often entails are thin coronal T2 flare slices. Looking at the hippocampus and amygdala for signs of mesial temporal sclerosis, as this is one of the more common causes of adult onset temporal lobe epilepsy, temporal lobe epilepsy being the most common form of focal epilepsy in adults. Two other etiologies that are important to keep in mind are cortical dysplasias, which that's why we want really clean images, and a lot of times a 3-tysola is better than 1.5 tysola for evaluating for these. And then cavernous malformations are also well known to be an epileptogenic vascular abnormality, but certainly not the only one.
Dr. Michael Kentris:Our other primary test is an EEG or an electroencephalogram, so it's important to know what is the utility of my EEG in evaluating for epilepsy. Sometimes the spell in the history is not so clear-cut. It could be a seizure, maybe it's something else, or maybe you don't have good collateral witnesses to tell you more about what happened and the person doesn't remember. So if you have an abnormal EEG that shows some epileptiform discharges like spikes or sharp waves that can really clue you in a direction. But what is the sensitivity? So it's generally held to be around 50% for a routine EEG. That's around a 25-minute recording, give or take 50%, not great. The specificity often over 90-95% depending on what studies you look at. So quite good. So if you have a normal EEG it does not rule out epilepsy, but if you have an abnormal EEG it rules it in. Quite well. Now, repeat studies or a prolonged study can raise that sensitivity up to around 80% or so. And if you're still having an unremarkable EEG, then if the patient is still having recurrent spells maybe this is more on the outpatient side of things doing spell capture in an epilepsy monitoring unit is the way to go. You'd really need to catalog what is going on on a video EEG recording. The other primary utility for EEG is for ICU monitoring and we'll talk about the utility of that later on.
Dr. Michael Kentris:Let's talk a little bit about seizure type. So seizure types typically fall into one of two camps. We have focal onset and generalized onset. So just to worry about the nomenclature as I know this trips people up a lot. So in the previous nomenclature simple partial was equivalent to a focal, aware seizure and a complex partial is a focal seizure with impaired awareness, generalized onset, still generalized onset, and that includes some of our other seizure types like absence, myoclonic, tonic, chronic atonic and tonic tonic, although tonic clonic can occur after a focal seizure spreads bilaterally as well. Why do we care about where the seizure starts? Well, we do have narrow spectrum, that is to say medications, anti seizure medications that only work for focal onset, and then we have broad spectrum, which work for both focal and generalized onset seizures. So it is important to know what kind of seizure the patient is having, as that will help you to decide in some cases on specific therapies that may be more or less effective. So we've talked a little bit about some clinical manifestations of seizures, and we're talking about focal seizures specifically.
Dr. Michael Kentris:The kind of appearance that we see clinically does vary based on what parts of the brain are being involved in the seizure, whether that's near the beginning, the end or somewhere in between. So let's talk mostly about temporal lobe epilepsy or temporal lobe seizures, as these are going to be more common in the adult population and, just on your exams, tend to be something that you see a little bit more often. So the common auras that we see for temporal lobe epilepsy include things like deja vu, that rising epigastric sensation that we mentioned earlier, or the feeling of panic or dread, unpleasant smells. Other autonomic symptoms can be associated, so sometimes drooling, pilo erection, things like that. That may be more insular but it does vary a little bit person to person.
Dr. Michael Kentris:As things progress beyond the aura with retained awareness, we may see a behavioral arrest, kind of looks like someone just press the pause button on a person. They just stop in the middle of whatever they're doing. You can also see automatisms. These can involve either the mouth or the hands, what we call manual or oral automatisms. So a manual automatism is what we call a manipulative, non-purposeful. So let's say we've got someone that got their lunch tray in front of them and they start picking up their sandwich. You think they're going to take a bite, but they just start pulling it apart. Right, it's not purposeful, they're just kind of manipulating the things in their environment. Classic oral automatisms are kind of a lip-smacking chewing type of behavior that can often come along with different temporal lobe manifestations. You may also see some speech arrest or speech difficulties with involvement of the dominant temporal lobe, typically the left side for the majority of people.
Dr. Michael Kentris:I want to mention about staring spells. Now, this is something that trips up people very often when we talk about temporal lobe versus abscess seizures. So a lot of times I'll get a call and there's like, oh, the patients have an abscess seizure. I'm like, well, they're 60 years old, do they have a history of epilepsy? No, like, it's probably not abscess. So let's dive into because temporal lobe seizures and abscess seizures can both have staring spells. Now, with temporal lobe seizures, which is what we usually see in adults, there's usually some degree of impaired awareness, usually lasts maybe a minute or two and you might get these other automatisms like we were just talking about, and oftentimes afterwards there will be some post-acid confusion. Abscess seizures usually we're talking seconds, like less than 15, 30 seconds on the long side. The impaired awareness very brief and there's usually no post-ictal confusion. And, as it would say, the most common type of abscess, usually childhood abscess, which we'll talk about with some of our epilepsy syndromes later. It is important to recognize the difference between these two phenomenon, as the treatment is different and the prognosis is different, especially depending on the time of life that you're capturing this behavior during.
Dr. Michael Kentris:A few quick words on other focal onset seizures. Frontal lobe seizures these are kind of the most challenging seizure type to recognize clinically. They often present with bizarre hypermotor types of behavior weird speech patterns, swearing, bicycling type movements of the legs, very, very strange, often thought to be some sort of psychological manifestation. But they are very stereotyped. They are very brief and the confusion afterwards often very minimal. So they can be very challenging to pin down. Periatal lobe seizures very often we think sensory abnormalities, paristhesias, pain, things of that nature. If it's in the association cortex you might get some visual perceptual abnormalities. Oxypital lobe seizures our primary visual cortex you can get different geometric shapes, colors, usually nonformed visual hallucinations.
Dr. Michael Kentris:As for generalized onset seizures, we talked a little bit about absinthe. Myoclonic are kind of these quick, lightning-like jerks usually involving the face or arms. Tonic seizures generalized tonic seizures are usually extension and or abduction of the arms. Atonic or sometimes known as drop spells patients will have a quick abrupt loss and muscle tone, often falling to the ground. Very commonly will result in injuries to the face or head. And then chronic seizures where you can get chronic jerking a little bit more regular than myoclonic and faster than tonic. Kind of sits in that middle space there a little bit. Just a few epilepsy syndromes I want to go through. So we mentioned temporal lobe epilepsy above. We're also going to talk about idiopathic or generalized epilepsies. These are also sometimes referred to as genetic generalized epilepsies.
Dr. Michael Kentris:So one of the more common ones that we see in children is childhood absence epilepsy. Now, obviously this is defined by having generally normal development, typically between the ages of six months to six years, although that number does vary a little bit depending on the literature that you look at. It is defined primarily by normal development and the presence of absence seizures. Now, very often these kids will grow out of the absence seizures. However, there can also be associated generalized tonic-clonic seizures and or myoclonic seizures and these other seizure types they may not grow out of as they get older. So you do have to select your medication based off of what seizure types they have within a specific syndrome. So, for instance, with absence seizures, ethosuxomide is kind of the classic treatment, but ethosuxomide does not work for tonic-clonic or myoclonic seizures, it only works for absence seizures.
Dr. Michael Kentris:The other very common generalized epilepsy syndrome that we will see in practice is juvenile myoclonic epilepsy or JME, and again, this is usually onset in adolescence, associated with myoclonic seizures. Very often they will have associated tonic-clonic seizures and, occasionally, absence seizures as well. So, similarly to childhood absence, we need to select a medication that will cover the seizure types that are occurring. And this is where, on the test, sometimes it'll give you a little twist. So if this is a young man, the first-line medication is generally recommended to be valproic acid. Now, if this is a young woman, because valproic acid is often very tereogenic, they may recommend levatoracetam instead. Now, very often in real life, we will trial levatoracetam instead because it does, on average, have a more benign side effect profile.
Dr. Michael Kentris:One of the hardest things about a first-time seizure is deciding do I start this person on long-term anti-seizure medications or not? So deciding to treat is when we get all of our work out right Our historical data. Is this actually the first-time seizure? Maybe there's an event in the past? Is there an abnormality on the MRI or the EEG? Are they both normal? If they are both normal, we typically won't start anyone on long-term anti-seizure medications if they have no risk factors, normal testing. And the reason for this is that about one out of 10 people in the US will have a seizure at some point in their life. Now the majority of those will not go on to develop epilepsy. About 2-3% will and the general number is about 1 in 26 people in the country have epilepsy, which is pretty similar to those numbers. But what that means is that if you start everybody who has a one-time seizure on anti-seizure medications, you're going to be over treating a large number of people. So you do have to use your discretion and appropriate risk stratification to decide who are the people who are at risk and who are the people who we can take a watchful waiting approach.
Dr. Michael Kentris:Now, regardless of whether or not you are starting anti-seizure medication or not, there with few exceptions are going to be some safety precautions that are recommended. So driving restrictions is kind of the most financially as well as socially burdensome, and these laws do vary based on what state you are in. So I recommend checking out the Epilepsy Foundation's website. The Foundation has different legal restrictions based on what state you're in, different times, different durations of how long or what kind of reporting you have to do, things of that nature. So I do recommend checking that out based on what state you are in. Other general rules of thumb for safety include avoiding open heights. Avoid bicycling in traffic, operating heavy machinery, swimming unattended or taking a bath in the tub. Unsupervised showers are usually fine. Avoid cooking over open flames.
Dr. Michael Kentris:See any situation where a loss of consciousness could lead to injury to that person or someone around them, and you kind of have to use your judgment in some of these situations. If you are diagnosing someone with epilepsy, then you do need to counsel them on SUDEP, which is an acronym that stands for Sudden Unexpected Death in Epilepsy, and this is around 1 in 1,000 patient years overall. Now this goes up to 1 in 100 if you have uncontrolled generalized tonic-clonic seizures, nocturnal seizures or you're on multiple anti-seizure medications for epilepsy control. It is important to counsel people on this, as it is one of those things that is frequently never mentioned to people with a new diagnosis of epilepsy. When deciding on an anti-seizure medication, you need to pick a medication that is appropriate for the seizure type or, if you have a syndrome, the syndrome type, and there are broad spectrum versus narrow spectrum. Right Broad spectrum will work for both generalized and focal onset seizures, whereas narrow spectrum typically only is going to be effective for focal onset, and in some cases a narrow spectrum used on a generalized epilepsy may actually exacerbate the seizure frequency. So you do have to be cognizant of those contraindications.
Dr. Michael Kentris:Now. There are a lot of anti-seizure medications available on the market right now and there are a lot of idiosyncratic side effects as well as drug interactions between these. So I'm going to focus on the ones that are likely to be the most high yield for your examinations. So oxcarbazapine and carbamazapine. They have a risk for hyponatremia and this is very age-related as people get older, the risk for hyponatremia goes up, so you do have to watch out for it. It kind of looks similar to SIDH Acid. So many side effects. The main ones that they want you to be aware of are thrombocytopenia, but of course, be aware of its liver toxicity issues also. It is also a COIP450 inhibitor, so it will affect metabolism of other medications.
Dr. Michael Kentris:Some of our strong COIP450 inducers phenitone, carbamazapine and phenobarbital. There are others. Those are dose-related. These are the ones to remember, thank you. Rashes can be common with again with fenitone, carbamazepine, phenobarbital and lamotrigine. Lamotrigine is kind of the one that they always grill you about because it does have an association with Stevens-Johnson syndrome and that is why we titrate it so slowly to reduce that risk.
Dr. Michael Kentris:If you have a patient of Southeast Asian heritage, you do want to check HLAB1502, as this can affect their metabolism of carbamazepine and predispose them towards different side effects. With leviteracetam, good ol' capra, it does have about a 10% incidence of neuropsychiatric side effects, including depression, anxiety, agitation, things of that nature. That usually shows up in the first couple of weeks of starting it for most people. Parampinol we don't see this one used as often, but it does have a black box warning for homicidal ideation, so you do have to watch out if you have a patient coming into you on that. So Pyramid, a medication used for epilepsy, migraines as well as in combination for some weight loss formulations. It can cause a lot of different side effects. So weight loss, obviously. It does have a little bit of a carbonic and hydrase effect, so it predisposes towards kidney stones as well as these parasthesias around the fingers and the mouth, and in some cases it can also cause mood disorders, cognitive fog, psychosis, things of that nature. So be aware of these less common side effects for Pyramid. Conversely, lamotrigine and Valproic acid are both mood stabilizers, so those can have some dual benefit, depending on the patient population.
Dr. Michael Kentris:Monitoring serum levels of anti-seizure medications is sometimes questionable and it will depend on who you ask. But who is it most likely to be useful for. So routine screening. Not super helpful for most things, although it can be useful with some of these older anti-seizure medications think about your Valproic acid, phenytoin, things that have a lot of variability, different interactions, serum protein binding, etc. Etc. So those older anti-seizure meds, it is reasonable to check on those every once in a while. I would also check drug levels somewhat routinely on someone who is on multiple medications who I know is going to have interaction issues, or if they are having new medications added on for another medical reason that also may have an interaction. So those are the situations that I think about.
Dr. Michael Kentris:You also want, with certain medications to check, like Lamotrigine and Leviteracetam during pregnancy. One of the other main reasons to check serum levels is that you are worried the patient is not taking their medication as prescribed and they keep having breakthrough seizures. So you wonder, do I need to increase the medication? Do I need to emphasize adherence to the medication regimen? And so that can be helpful in that particular situation. What I don't do is I don't check more modern anti-seizure medication levels Leviteracetam, for instance, in a patient who is not having any worsening of their renal function in this case, or if he was hepatically metabolized, or liver function if their kidneys and livers are working the way they always do. I'm not routinely checking a Leviteracetam level or a lecosamide level and I'm certainly not adjusting the dose downwards in someone who is tolerating the medication and is well-controlled, with no reported seizures. Unfortunately, I will see folks come in from nursing homes where this is exactly what happens Someone gets a kepper level it's high, quote unquote. They drop the level down and the patient comes in with a seizure. So what I'm saying is don't rock the boat In these situations. You really need to be thinking about what you're going to be doing with that result before you order it.
Dr. Michael Kentris:Let's say we have someone who's been doing well. They were diagnosed with epilepsy, they've been taking their medications as prescribed, they've been seizure free for years now and they want to know can they come off their medications? So the answer is sometimes so if someone has been seizure free for between two and five years, been easy to control, didn't take a lot of medication management. They're only on a single agent, sometimes two question mark, you may be able to successfully wean them off their medications. Now there are situations where we try again to risk stratify before we make that decision. So if they have an abnormality on their MRI, let's say an old stroke or an area of encephalomalacia from an old head injury or something of that nature odds are it's probably not going to be successful in the long term. Or you get a repeat EEG and you still see epileptiform activity from the previous area. Odds are they are not going to be successful in staying off of anti-seizure medication long term. And this is complicated by the fact that during this period of weaning and being off of anti-seizure medication for six months from the time that they discontinue it, you do have to institute those same seizure-safe precautions, which can of course interfere with someone's ability to drive and work, depending on what their occupation is. So you do have to factor in these very important financial and lifestyle considerations.
Dr. Michael Kentris:One other unique situation is in people who have a history of juvenile myoclonic epilepsy. We typically do not recommend weaning off of anti-seizure medications as the vast majority of those patients will have recurrence of their seizures. That is usually, unfortunately, a lifelong diagnosis. But what if we're talking about the opposite situation? What if we have someone who has been hard to get under control? They have what we call medically intractable epilepsy. So what does that mean? It means that they have been tried on two or more appropriately selected and appropriately dosed anti-seizure medications which have failed to control their epilepsy. Something that is important to keep in mind is that these medications were not effective, not that they were stopped due to tolerance issues, but that they were ineffective at controlling seizures. So if someone meets the criteria for medically refractory epilepsy or quote-unquote intractable epilepsy, then they should be referred to an epilepsy center where very often they will have an evaluation in the epilepsy monitoring unit for spell capture, because we need to, one, make sure the diagnosis is correct and two, if it is, then try and localize where in the brain the seizures are coming from to evaluate if they are possible candidates for different types of epilepsy surgery. Another option that is sometimes considered in these patients are vagal nerve stimulators and as well as ketogenic diet in the appropriately selected patients, oftentimes children. So both of these are kind of more palliative options and they do not typically lead to complete seizure control.
Dr. Michael Kentris:A couple points about specific populations that may develop seizures or epilepsy. So in the geriatric population we have to keep in mind, like in so many medications, they have decreased protein binding clearance, both renal and hepatic will decrease and as they have more medical issues, the potential for medication-medication interactions increases. We also tend to see a history of stroke or dementia as more common risk factors in this population. As we mentioned earlier, with certain organ dysfunction you do have to modulate the dosing. So for kidney failure or kidney impairment you need to modulate the dose of gabapentin, pregabalin and levatoracetam those are kind of the big ones and for liver failure, carbamazepine, phenytonin, phenobarb and valproic acid. There are of course others. There are over 30 different antisezure medications available, but I think these are some good ones to keep in mind.
Dr. Michael Kentris:People with seizures that occur post-traumatically these can also occur with stroke, traumatic brain injuries. So after a severe TBI with or without intracranial hemorrhage, subdural hemorrhages, depressed skull fracture, etc. Or if they even have a neurosurgical procedure, they will usually be on at least a week of a prophylactic antisezure medication. These days it's very often levatoracetam. With these patients you do have to watch out for the difference between acute symptomatic seizures versus remote symptomatic seizures. So if this seizure occurs in the first week, that does not necessarily mean that they are going to be on lifelong antisezure medications or even long-term antisezure medications. But if they have a remote symptomatic seizure, that is to say a seizure occurring more than one week out from the episode, from the traumatic brain injury, from the stroke. Now we're calling this a remote symptomatic seizure and that risk for seizure recurrence curve starts to bend upwards and they are in that high-risk camp and we will typically start antisezure treatment at that point in time.
Dr. Michael Kentris:The final patient population I want to talk about are women, so a few different things that we need to think about with women in particular, particularly women of childbearing age. Obviously, one of our main concerns is with complications that may occur during pregnancy. There is some thought that certain medications, in particular valproic acid, may be associated with increased difficulty of becoming pregnant, as valproic acid in particular is associated with a polycystic ovarian syndrome and potential anovulation. We do know that some antisezure medications do have a higher risk for major congenital malformations. These include valproic acid, phenobarbital, phenitone, topiramate and carbamazepine. This can be dose-dependent, so you do have to weigh the risks and benefits of someone having, say, like, a generalized tonic-clonic seizure versus in-utero exposure. Now, it's always better to have these conversations in advance of a pregnancy so that you can make decisions and take time with any dose adjustments or medication adjustments that may be desirable. So, that being said, around 50% of pregnancies in the United States are unplanned, so it's always good to have that conversation about contraception as well, which we'll get to in a moment.
Dr. Michael Kentris:In terms of major congenital malformations, the risk is higher with polypharmacy versus single agent therapy. Specific agents valproic acid is associated with neural tube defects, lower IQ as well as other major congenital malformations. Phenobarbital also major congenital malformation risk and a lower IQ to pyramid cleft, lip and palate. The two anti-seizure medications with the lowest incidence of major congenital malformations are lamotrigine and levatoracetam. This is ironic as they both require a bit more monitoring than other anti-seizure medications during pregnancy. So lamotrigine is epitably metabolized and as estrogen levels increase during pregnancy, its metabolism will go up, so the dose may need to be increased by around 50% or so over the course of the pregnancy. So it is recommended that if the person is well-controlled on their dose of lamotrigine, pre-pregnancy get a baseline level and then, over the course of the pregnancy, check that level monthly so that way you can titrate the dose to the level. This is one of those few times where you'll actually look at the level to help guide your dosing in that particular chronic fashion. Now, after delivery, you'll have to go back to that pre-pregnancy dosing within just a couple days, because those levels will rebound quite high and can result in some significant toxicity if you don't stay on the ball. Similarly, levatoracetam also drops during pregnancy. This is thought to be due to increased renal clearance, but the evidence isn't quite as good. However, we do still tend to kind of watch this one pretty closely and titrate as needed.
Dr. Michael Kentris:As far as nursing after pregnancy, generally it is thought that the benefit of breastfeeding outweighs any risk of exposure to antisexia medications in breastmilk, in particular, because this was the same medication that the mother was taking during pregnancy, so the infant has already been exposed to it in utero. One caveat to that would be some of these more sedating medications, the most common one being something like phenobarbital Aware. On contraception, a lot of oral contraceptives can have decreased efficacy due to enzyme-inducing antisexia medications. So you do have to keep in mind what medications they're on and whether or not there's going to be interaction. Similarly, in the other way, estrogen-containing oral contraceptives can diminish the efficacy of lamotrigine as well. So a lot of times in women with epilepsy, you might consider recommending an intrauterine device or IUD as well as barrier methods.
Dr. Michael Kentris:The final point I wanted to mention is that you can sometimes see fluctuations in seizure frequency or seizure burden around women's cycles when they have epilepsy. This is called cadmium epilepsy or cadmium seizures, and this can happen at different points in the cycle for different women, whether that is around the time of menstruation, around the time of ovulation or for an anovulatory cycle. The last, but certainly not least topic I wanted to talk on for our review today is on status epilepticus. Status epilepticus is a true neurologic emergency resulting in significant comorbidities and mortality risk, and it is defined as ongoing seizure activity for five minutes or more than two seizures without return to baseline level of consciousness in between. Like so many things in life, as well as on the exam, the first things to address are your ABCs, so make sure those are addressed first. You'll also be working to establish IV access giving thiamine, glucose if they're high glycemic, checking, routine blood work like a CBC and CMP.
Dr. Michael Kentris:Now on to status epilepticus specific management. So our first line treatments are going to be benzodiazepines, traditionally lorazepam, although diazepam and medazolamp can also be used. Our second line agents are more of our traditional anti seizure medications, so think of things like phosphenitone, valproic acid, levatoracetam, and you do want to make sure that you're administering these weight-based. A lot of times I'll get a call and say oh, we gave them a loading dose of levatoracetam. I'm like how much? Like a thousand milligrams? That's just a regular dose. A loading dose of phosphenitone is 20 milligrams phenitone equivalents, or PE, per kilogram with a max of around 1500, some might say 2000 milligrams per dose. Don't go higher than that as it can cause bradycardia and other cardiac issues. For valproic acid, we're giving 40 milligrams per kilogram with a max dose of 3000 milligrams typically, and for levatoracetam, 60 milligrams per kilogram with a maximum of 4500 milligrams.
Dr. Michael Kentris:Now in the algorithms they will say first line and second line, and that's great on paper. In real life, a lot of times we are working in parallel and as we are giving benzos we are asking for the pharmacy to send up a second line agent, because those benzos buy you time to make sure that there isn't a seizure right now. But it may lead to seizure recurrence if we don't get a second line agent on board. Not always, but it definitely is something to keep in mind as you're managing these patients in real life. Our third line therapies are usually going to be our IV anesthetics and this is the point where the patient has been intubated. We are working on getting them attached to continuous EEG monitoring and we are starting some agent like Propofol, madazolam, ketamine, pentobarbital. Now the reason why we need that EEG is that it is not uncommon for the electrical seizure activity to continue even though you may not be seeing physical manifestations of that any longer. Also, you need to make sure they are not continuing on in non-convulsive status epilepticus after treating the convulsive status epilepticus. So it is definitely something to keep in mind as you work on these more challenging patients.
Dr. Michael Kentris:You can also find non-convulsive status epilepticus in a couple other situations as well. One is someone maybe with a pre-existing diagnosis of generalized epilepsy, maybe some sort of absence epilepsy, and they will have what's called the quote unquote walking wounded. Look, they walk around, they're a little disoriented, not acting like their usual selves, but not comatose. A lot of times these will break with treatment with benzodiazepines or a loading dose of another medication like Valproic acid. We also see this in comatose patients, typically in the intensive care unit, and this can be due to a variety of different reasons. One of the more common ones is in someone who had a cardiac arrest and is suspected to have an anoxic brain injury. The outcome in these comatose patients for non-convulsive status epilepticus is really more related to the underlying etiology. So this is like if they have a history of epilepsy versus if they had a cardiac arrest. The outcome for the cardiac arrest patient tends to be much worse than someone with a pre-existing diagnosis of epilepsy, because we have a reason for why they would be having seizures as opposed to a suspected new brain injury. And that is where we are ending on our internal medicine neurology board review for seizures and epilepsy.
Dr. Michael Kentris:There's a lot of information here, but believe me when I say I tried to pare it down as much as I can. There is so much more that we could have talked about, but I know doesn't represent the fundamental stuff that people need to know for their IM boards and in-service exams. So thank you all again for listening. If you enjoyed this, found it helpful, share it with your friends, share it online, leave us a five star review and do check us out. You can find us online. I am on twitter, slash ex at drkentris drken-tris. You can find the neurotransmitters podcast also on twitter, slash ex at neuro underscore podcast, and you can find more information and other resources at the website, theneurotransmitterscom. Thank you again for listening, really appreciate it and we'll see you next time.
