This is Aditya Pandey from the University of Michigan presenting on prophylactic anti-epileptic medication use in neurosurgery. I am an associate professor of neurosurgery at the University of Michigan and have clinical interest in cerebrovascular neurosurgery. I am presenting on this topic on behalf of the American Association of Neurological Surgeons Committee on Continuing Medical Education as well as maintenance of certification. I have no disclosures that pertain to this topic. I do have disclosures that include scientific consultant for histosonics as well as obtaining research grant support from Medtronic and I'm a co-investigator on projects that have received an R21 as well as a R03 grant. Seizures are common among the adult population. They affect nearly 1.8% of all adults. This leads to approximately 4.3 million adults being affected by seizures. There is significant effect on the quality of life after one has suffered from a seizure. This is truly exemplified by the fact that that individual is not able to drive unless they have been seizure free for six months. In addition, the loss of quality of life as well as the loss of work hours leads to direct and indirect costs which total more than $15.5 billion a year. The two most common utilized anti-epileptic medications within our medical community are Dilantin and Keppra. I would like to go over the mechanisms as well as the dosing of each of these medications. Using Dilantin or phenytoin first, this preferentially binds to inactive form of the sodium channels, thus leading to a blockade of sodium dependent action potentials. Phenytoin dosage is 10 to 15 milligrams per kilogram and it is not to be given any faster than 50 milligrams per minute. The maintenance dose is usually 100 milligrams PU or IV given at Q8 hour intervals. The dose can then be adjusted after free Dilantin levels within the plasma are obtained. Another commonly utilized anti-epileptic is Levatoracetam or Keppra. The mechanism of action of this medication is that it binds to synaptic vesicle glycoprotein SV2A. This inhibits presynaptic calcium channels and thus the release of neurotransmitters. In all, it prevents conduction of impulses. The most commonly utilized dose is 500 milligrams POVID. Every two weeks, the dose can be increased by one gram per day to a max dose of three grams a day. I would like to present the evidence for anti-epileptic use in several disease processes. I would like to begin with traumatic brain injury as there is great evidence to support the use of anti-epileptics here as well as this being a common disease process. Nearly 275,000 patients are hospitalized yearly with traumatic brain injury. Five to seven percent of these individuals will go on to experience post-traumatic seizures. Level one evidence exists to support prophylaxis of post-traumatic seizures for the first seven days. The most commonly utilized anti-epileptic within this patient population is Dilantin. One of the earliest studies to be performed showing benefit for anti-epileptic prophylaxis in traumatic brain injury patients was from Harborview Hospital. 404 severe TBI patients at Harborview were randomized to either obtaining placebo medication versus Dilantin for 12-month duration. The Dilantin patient population included 208 patients and they were loaded within the first 24 hours of their severe TBI with the medication. The goal Dilantin levels were to be 0.75 to 1.5 micrograms per milliliter. 196 patients went on to be within the placebo group. When evaluating the incidence of seizures within these groups, what was found was that the incidence of seizures within the first week of the traumatic brain injury was much higher within the placebo group as compared to the Dilantin group. Within the Dilantin group, 3.6 percent of the patients had a seizure within the first week. However, within the placebo group, 14.2 percent of the patients had a seizure within the first week. This was a statistically significant difference. However, the incidence of seizures from day 8 to 12 months was not statistically different. Within the Dilantin group, 21.5 percent of the patients suffered from a seizure between day 8 and 12 months and within the placebo group, 15.7 percent suffered a seizure from day 8 to 12 months. This difference was not statistically significant. The previous study which exemplifies that prophylactic use of antiepileptics in severe TBI patients can lead to a reduction in the incidence of seizures within the first week has actually been exemplified by multiple studies. I wanted to exemplify that with the previous study, however, we will not go into detail with each of the other studies. I would like to make a point that Dilantin was previously commonly utilized for antiepileptic prophylaxis in severe TBI patients, however, there seems to be a current trend towards the utilization of levatoracetam. This current study performed in severe TBI patients in Maryland exemplifies this. 109 severe TBI patients in Maryland were studied. What was found was that 98 percent of patients with severe TBI between the years 2000 and 2007 received antiepileptic prophylaxis utilizing Dilantin. This trend changed between 2008 and 2010 as 64 percent receiving antiepileptic prophylaxis utilizing levatoracetam or Keppra. Within this entire patient population, only two patients suffered from post-TBI seizures. This is a small study, however, exemplifies the fact that there is a trend towards utilizing Keppra or levatoracetam within this patient population for seizure prophylaxis. Keppra is thought to have a narrower side effect profile. In addition, dose monitoring does not have to be carried out and thus seems to be better tolerated by patients and easier to utilize. The second disease process that we would like to evaluate with respect to seizure prophylaxis is cerebral subarachnoid hemorrhage. Subarachnoid hemorrhage is caused by the rupture of cerebral aneurysms and affects nearly 30,000 to 35,000 individuals within the United States. Six to 26 percent of these individuals who suffer from subarachnoid hemorrhage will actually go on to have a seizure within the acute time period. Risk factors for early seizures include a higher fissure grade, meaning thick clot within the subarachnoid space. Also presentation with an intracerebral hemorrhage or developing ischemia at the time of subarachnoid hemorrhage. Three to seven percent of all subarachnoid hemorrhage patients will actually go on to develop delayed seizures. Before presenting any particular or specific studies, I would like to review the guidelines published by the American Heart Association and American Stroke Association published in 2012. These guidelines support the utilization of antiepileptic prophylaxis within the subarachnoid hemorrhage patient population within the acute time period. This has been done so as a seizure within the acute time period theoretically would increase the blood pressure and heart rate, thus increasing the probability of a re-rupture if an aneurysm has not been secured. However, once an aneurysm has been secured, the long-term use of antiepileptics within the subarachnoid hemorrhage patient population is not recommended. The second point, which states that long-term utilization of antiepileptics within this patient population is not recommended, is further exemplified by the following study published in the Journal of Cerebrovascular and Endovascular Neurosurgery. This was a retrospective analysis of 84 subarachnoid hemorrhage patients. These individuals had not presented with seizures. However, majority of the patients receiving antiepileptic drugs had microsurgery. There was no difference in seizure frequency or clinical outcome at six months in those individuals who had received prophylactic antiepileptic use versus those that had not. This further exemplifies the fact that long-term utilization of antiepileptics within this patient population is not supported. There continues to be a scarcity of data relating to the utilization of prophylactic antiepileptic use in microsurgery for elective cerebral aneurysms. Thus, we here at the University of Michigan have started a randomized control trial evaluating antiepileptic use in patients undergoing microsurgery for aneurysms. The study known as the SPAR, or the Seizure, Prophylaxis, and Aneurysm Surgery Study, will randomize patients to Keppra for seven days versus no Keppra. This is a non-blinded randomization. And we will evaluate clinical outcomes as well as frequency of postoperative seizures. The third disease process that we will evaluate and study are patients harboring intracerebral hemorrhage. ICH represents 15 to 20 percent of all stroke presentations. Continuous EEG within this patient population has revealed that nearly 30 percent of individuals will be found to have a seizure. Before proceeding with any particular studies, I would like to review the recommendations made by the American Heart Association as well as the American Stroke Association in the guidelines published in 2010. The recommendations are that those ICH patients presenting with seizures should most certainly be treated with antiepileptic drugs. This represents a class one level A recommendation. However, prophylactic antiepileptic drug use is not indicated in patients not presenting with seizures. This represents a class three level B evidence. The fourth disease process that I would like to evaluate with respect to seizure prophylaxis are those patients presenting with brain tumors. In general, the recommendations are those patients with brain tumors presenting with seizures should most certainly be treated with antiepileptic drugs. Those brain tumor patients not presenting with seizures should have no antiepileptic drug use for prophylaxis. In those patients who undergo craniotomy, antiepileptic drugs could be utilized, however, they should be discontinued after one week. Within the brain tumor patient population, a similar theme has occurred as within the traumatic brain injury patient population. While previously patients were being treated with Dilantin for prophylaxis, the recent trend is to utilize Keppra, which actually has been shown to be a benefit. The following study is able to exemplify these points. 146 brain tumor patients were randomized to receive either seven days of levotiracetam or seven days of phenytoin. These were patients who had undergone craniotomy for brain tumors. The incidence of seizures within the levotiracetam group or Keppra group was 1.4%, however, the incidence of seizures within the Dilantin or phenytoin group was 15.1%. This was a statistically significant difference. Within the same patient population, it was noted that those patients who had not presented with seizures and had undergone craniotomy for brain tumor resection, those patients who had received Keppra or levotiracetam for seizure prophylaxis had an incidence of seizures of 1.9%, while those who had received phenytoin, the incidence of seizures was 13.8%. This was, once again, a statistically significant difference. Thus, within the brain tumor patient population, those patients who undergo craniotomy for brain tumor resection, the utilization of Keppra seems to be more effective at preventing seizures than Dilantin. In conclusion, the long-term use of anti-epileptic drugs for the prophylaxis against seizures is not indicated within the TBI patient population or subarachnoid hemorrhage patient population or ICH patient population or the brain tumor patient population. I hope that these slides and the information presented are of use to you in your practice. I thank you for your attention.

prophylactic anti-epileptic medication

neurosurgery

seizures

Dilantin

Keppra