Hello, and thank you so much for this opportunity to present at SCCM 2022. And I'm Neha Dandaij. I'm an assistant professor of neurosurgery and neurology, and the research director for neurocritical care and recovery, systems director for neuroemergencies management and transfers for the Mount Sinai Health System in New York. So I'm going to talk to you about Carpe Diem, recognizing and preventing occult seizures in severe traumatic brain injury. So this is how we're going to walk through this challenge of recognizing and treating occult seizures. We'll talk a little bit about epidemiology, pathogenesis, right from the early post-traumatic seizures to the possibilities of developing post-traumatic epilepsy, recognizing and some challenges in recognition and monitoring, seizure prophylaxis, and then just some general thoughts about treatment of seizures and status epilepticus. So when you take a look at this slide and you walk from left to right, as you're thinking about these patients, which of these patients do you think are going to develop early post-traumatic seizures? So on the left side of the screen, we see this patient who is a 54-year-old motor vehicle accident victim whose GCS is five, and he presents with severe traumatic brain injury. On the extreme right-hand side, we see a 42-year-old man who's developed head injury after falling from a height of about 20 feet, and his GCS is about 13. Now while he's behaving like a moderate TBI patient, and the first patient is behaving like a severe TBI patient, both of these patients are at a risk of developing early post-traumatic seizures. Then what about all these patients who seemingly have mild TBI? What is their risk of developing early post-traumatic seizures? And then what does early mean? So post-traumatic seizures and post-traumatic epilepsy, only about 4% of all epilepsy cases can be attributed to trauma. The likelihood of recording seizures once you use continuous EEG monitoring increases in these patients, particularly in the first 72 hours. And the majority of these seizures in the patients in whom seizures are recorded, which is about a third of adult patients with moderate to severe TBI, will be non-convulsive seizures, which are very difficult to recognize clinically. Either the patients may be in a coma, or they may have some very subtle signs like twitching of the angle of the mouth, or nystagmoid movements, or some twitching of an extremity or the corner of their lip, et cetera. So these are very difficult to recognize unless you have continuous EEG monitoring. And once you have continuous EEG monitoring, in patients with moderate to severe TBI, the findings on EEG monitoring have been shown to change treatment in more than half of these patients. So classifying post-traumatic seizures, this is the conventionally accepted definition. Within 24 hours, seizures that occur after moderate to severe TBI would be categorized as immediate seizures, within 24 hours to a week, early seizures, and then more than one week, late seizures, or post-traumatic epilepsy if these seizures are recurrent. Why is this happening? So in TBI, there's the primary neurological injury, then over days, months, and perhaps even years, the development of secondary neurological injury, and then there's that cohort of patients who remains at risk of developing post-traumatic epilepsy. When patients suffer from primary neurological injury, contusions, intraparenchymal hemorrhage, diffuse axonal injury, diffuse vascular injury, vasospasm, delayed cerebral ischemia, and post-translational modification of synaptic proteins all exposes patients to this risk of developing seizures. As part of the secondary neurological injury, as patients remain at risk of developing hypoxia, ischemia, excitotoxicity, oxidative damage, activation of this neuroinflammatory cascade, worsening cerebral edema, et cetera, this predisposes patients to developing seizures in the early phase or post-traumatic seizures, that is, seizures that occur within a week. How do patients move from TBI to post-traumatic epilepsy? A lot of different changes occur, and the mechanisms, potentially the pathogenetic mechanisms may really hinge on oxidative stress, activation of an inflammatory cascade, and perhaps these are the reasons why the post-traumatic epilepsy patients have seizures that are very difficult to control. But there is a window of opportunity. When we think about the epileptogenesis that comes with acute neurological injury or the primary neurological injury, so there are some disease-modifying interventions, particularly treatment and definitive treatment of the underlying traumatic brain injury, whether it's a subdural hematoma, epidural hematoma, and using anti-seizure medications or anti-epileptic medications for prophylaxis, so on and so forth. What are the consequences of early-onset seizures? Early-onset seizures are harmful. They increase the incidence of subsequent risk of developing epilepsy, risk of increasing intracranial pressure, hypoxia, physical injury, increased lactate-pyruvate ratio, suggestive of a metabolic stress on the brain, and worsen outcomes, including increasing mortality. So how do we manage these? The most important thing is a high level of clinical suspicion. We are monitoring these patients with continuous EEG monitoring, AEDs or anti-seizure medication prophylaxis, and counseling patients. So let's take a step back and look at what do current guidelines say. So in this review that included 63 guideline statements from across 29 countries, only three guidelines addressed post-traumatic seizures and post-traumatic epilepsy. There are lots of challenges to practical implementation of clinical practice guidelines in epilepsy. They may not be applicable. Frontline providers may not be aware of these guidelines. There may be a lack of agreement in who to treat and who not to treat, who to prophylax and who not to prophylax, a lack of motivation or guideline-related factors where there are contradictory recommendations, and then, of course, environmental factors and resource utilization. So studies that examine the barriers and facilitators to the application of various kinds of clinical practice guidelines, particularly in understanding which patients with TBI will benefit from monitoring prevention and treatment, will be helpful. So let's take a look at a couple of key guideline statements. So from the American Academy of Neurology, for adult patients with severe TBI, prophylactic treatment with phenytoin beginning with an IV loading dose should be initiated as soon as possible and continued for the first seven days, but should not be continued beyond seven days. And also, for the same patients, clinicians should advise that there are clinical factors which may be associated with the risk of recurrent seizures, including a prior brain insult such as stroke or trauma, as well as patients who have EEGs that have epileptiform discharges. What do the guidelines say for brain trauma foundation? So for brain trauma foundation guidelines, the conclusion of the authors was there was insufficient evidence to support a level one recommendation for prevention or treatment of seizures. Prophylactic use of dilantin or valproic acid, according to the brain trauma foundation guidelines, is not recommended for trying to prevent late post-traumatic epilepsy. Phenytoin is recommended to decrease the incidence of early post-traumatic seizures, but the overall benefit, only in those patients in whom the overall benefit seems to outweigh the complications. So let's take a look at some head-to-head comparisons of anti-seizure medications versus controls or AED versus controls. So specifically looking at phenytoin versus placebo, no difference in the incidence of early post-traumatic seizures was reported in one of the earliest studies. Subsequent studies where phenytoin was continued for 18 months, again, no difference in the incidence of late post-traumatic epilepsy or post-traumatic seizures. In this study that showed phenytoin being used for about 12 months in a two-year follow-up, a significant decrease was seen in early post-traumatic seizures, but no difference in late post-traumatic seizures. And in this study that looked at phenobarbital between one month post-TBI for up to two years, at five-year follow-up, there was really no difference in incidence of late PTS. And then in another retrospective study that looked at valproic acid, one-week follow-up, no difference in the incidence of early PTS. And then phenytoin versus placebo, one-week follow-up, no difference was seen in the incidence of early PTS. What about comparing different AEDs, dilantin versus valproic acid or dilantin versus levetiracetam or phenytoin versus levetiracetam? And as we see, there is really no difference in the incidence of early PTS, and perhaps the side effect profile or the adverse effect profile of levetiracetam may be more favorable. So despite no difference in the incidence of early PTS, it may be preferred. In other words, for post-traumatic seizure prophylaxis, we know that prophylaxis works, but do not continue it for beyond seven days. What about EEG findings? So in this study, which was a post-op analysis of intrepid conducted over 20 level one trauma centers in the United States, they classified EEG findings in over 150 patients, looking at what was happening with the background. And with a normal background versus some intermittent sharp waves versus some rhythmic discharges or burst suppression. These were categorized as abnormal backgrounds. And then ictil-interictal continuum findings were described as a rhythmic delta activity or a lateralized rhythmic delta activity or seizures. So when we look at the spectrum of the probability of poor outcome in all comers, in all different kinds of patients who are at risk of developing electrographic seizures or ictil-interictal patterns, generalized rhythmic delta activity, lateralized rhythmic delta activity, generalized periodic discharges, lateralized periodic discharges, and seizures. And as you can see, as we walk from left to right, the incidence or association of these patterns with increasing burden of electrographic seizures is associated with the higher probability of poor outcome. So what do we do with these kinds of ictil-interictal discharges in patients with TBI? So one potential approach, as suggested in this paper by Carolina Maciel et al., rhythmic and or periodic patterns, risk stratify, is this non-convulsive status or unequivocal seizures or just an interictal pattern? If it is an ictil-interictal continuum, any of these periodic discharges, lateralized rhythmic delta activities, so on and so forth, then looking at the frequency, clinically risk stratifying, for example, is there underlying severe traumatic brain injury or are there other markers of neuronal injury? Then consider further EEG monitoring if none of these are present. If some of these features are present, for example, patients with severe TBI, then a treatment trial. And with a treatment trial, is there clinical improvement or not? And what could this treatment trial look like? For example, a benzodiazepine trial or a trial with antiseizure medications and continue treatment with antiseizure medications and then reassess. Also continuing EEG monitoring to assess whether, if there is no clinical improvement, is that improvement on EEG? In patients with moderate to severe TBI, I would suggest consider EEG monitoring early, particularly within the first 72 hours, as a third of these patients will have early seizures and majority of them are going to be non-convulsive or occult. Early post-traumatic seizures are associated with worsened outcomes. Seizure prophylaxis with dilantin or levotiracetine, but don't continue beyond seven days. And status epilepticus is going to occur in about 10% of these patients and manage status epilepticus exactly as you would as per status epilepticus guidelines. Thank you so much for your attention and I look forward to the Q&A session.

occult seizures

severe traumatic brain injury

continuous EEG monitoring

non-convulsive seizures

anti-seizure medications