By: Anthony Vecchione, PharmD Candidate c/o 2016
Seizures are a well-described complication of acute brain injury and neurosurgery. Antiepileptic drugs (AEDs) are frequently utilized for seizure prophylaxis in neurocritical care patients, but this practice is controversial because of the possible adverse effects of these drugs (which can affect patient outcomes). Practitioners have prescribed AEDs for seizure prophylaxis in a variety of disease states, including intracerebral tumors, traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), ischemic stroke, and for patients undergoing craniotomy.1 The incidence of seizures and the type of AEDs used in these disease states varies greatly with the extent of neurologic injury, lesion location, and interventions performed. There has been growing interest in newer AEDs for seizure prophylaxis in the intensive care setting because of safety and monitoring issues associated with conventional AEDs (e.g. phenytoin).1 The purpose of this article is to review the primary literature and current guidelines, in order to outline the appropriate use of AEDs for seizure prophylaxis in the neurosurgical care setting.
Current treatment guidelines and literature do not support the use of routine seizure prophylaxis in patients with primary brain tumors or metastatic lesions. The use of AEDs is complicated in these patients because of the potential for significant drug interactions with commonly administered chemotherapeutic agents (e.g. erlotinib, gefitinib, irinotecan, temsirolimus). Enzyme-inducing AEDs (e.g. carbamazepine, phenytoin, oxcarbazepine) should be avoided in patients receiving regimens that include these chemotherapeutic agents. There is also the potential for serious and possibly life-threatening cutaneous adverse events (e.g. Steven Johnson Syndrome [SJS], toxic epidermal necrolysis [TEN]) in patients undergoing cranial radiation therapy. It remains unclear if newer AEDs (which do not require therapeutic drug monitoring, have fewer drug-drug interactions, and have a superior adverse effect profile) have a role in managing this patient population.2,3 The brain metastases guidelines state that the need for AEDs is clear in patients who have experienced a seizure by the time their brain tumor is diagnosed. However, the evidence does not support primary prophylaxis with AEDs in patients with brain tumors who have not experienced a prior seizure, even with metastases (Class I).4
Posttraumatic seizures (PTS) in TBI patients are classified as either early PTS (i.e. within the first 7 days of injury) or late PTS (i.e. more than 7 days after injury). The incidence of early PTS in TBI patients has been correlated with the severity of the injury. Penetrating injuries have the highest incidence of PTS in about 50% of patients, while other high risk patients (e.g. those with depressed skull fractures, subdural hematomas, intracerebral hematomas, a cortical contusion) have a PTS incidence of 20% to 25%.5 Current guidelines from the Brain Trauma Foundation state that most studies do not support AEDs evaluated thus far for the prevention of late PTS. Therefore, initiating seizure prophylaxis more than one week following TBI is not recommended.
For the prophylaxis of early PTS, phenytoin has been shown to reduce the incidence of seizures.6 The American Academy of Neurology (AAN) guidelines had an analysis using pooled evidence from two “class I” studies that evaluated phenytoin. The analysis demonstrated a significantly lower rate of early PTS in patients given AED prophylaxis compared to controls. It was concluded that prophylaxis with phenytoin in patients with severe TBI was effective in decreasing the risk of early PTS.7
The AAN and brain trauma guidelines were published before recent trials that evaluated levetiracetam for seizure prophylaxis in TBI patients. Levetiracetam offers some advantages over other AEDs as it does not require serum concentration monitoring, has favorable pharmacokinetic properties (e.g. excellent bioavailability), and has no known drug interactions.8 A study published in Neurosurgical Focus compared levetiracetam and phenytoin for seizure prophylaxis in severe TBI. There were 15 of 32 patients (46.9%) in the levetiracetam group compared to 12 of 41 patients (29.3%) in the phenytoin group, who warranted electroencephalogram (EEG) monitoring for seizure activity. In 7 of 15 (46.7%) levetiracetam cases, the results were normal (and in 8 cases, the results were abnormal); 1 patient had seizure activity, whereas 7 had seizure tendency. All the EEG results in the phenytoin group were normal. The higher incidence of abnormal EEG findings in the levetiracetam group was statistically significant (p = 0.03). However, despite this finding, patients treated with levetiracetam and phenytoin had no statistical difference in seizure activity incidence (p = 0.556). The conclusion of this study was that levetiracetam was as effective as phenytoin in preventing early PTS, but levetiracetam is associated with an increased seizure tendency on an EEG analysis.8 Based on this study, levetiracetam may be effective for early PTS prophylaxis, but we need more studies to make a solid judgment.
The incidence of seizures after subarachnoid hemorrhage (SAH) may be as high as 20% due to the occurrence of seizures and seizure-like phenomena at the time of aneurysm rupture and their association with early complications (e.g. re-bleeding). Following aneurysm treatment and discharge, seizure incidence appears low and may be related to the method used to secure the aneurysm, thickness of the subarachnoid clot, location of the aneurysm, and presence of a subdural hematoma. The use of prophylactic AEDs in the perioperative setting is common but controversial. The incidence of seizures appears low, the influence of seizures on outcomes is unclear, and various risk factors for seizures have been identified with little consistency. Randomized controlled trials demonstrating the safety and efficacy of prophylactic AEDs in patients with SAH are also lacking.
Additionally, some studies have demonstrated worse neurologic outcomes with the use of prophylactic AEDs. Studies (comparing phenytoin to placebo and phenytoin to levetiracetam) have associated poor outcome scores with patients receiving phenytoin prophylaxis. In these studies, levetiracetam was given for a short duration and some patients experienced seizures after medication discountinuation.9-14 The American Heart Association / American Stroke Association (AHA/ASA) guidelines state that the administration of prophylactic AEDs may be considered in the immediate post-hemorrhagic period or the first 7 days after aneurysm rupture (Class IIb, Level of Evidence B).15 However, they do not recommend specific AEDs that can be used for prophylaxis. Neurocritical Care guidelines state that routine use of AED prophylaxis with phenytoin is not recommended after SAH (strong recommendation), but routine use of other AEDs for prophylaxis may be considered (very low quality evidence; weak recommendation). If AED prophylaxis is used, a short course (3 to 7 days) is recommended (low quality evidence; weak recommendation).16 The Neurocritical Care guidelines also do not recommend specific AEDs for prophylaxis. Further studies are warranted to determine AEDs to use for SAH seizure prophylaxis.
The reported incidence of seizures following arterial ischemic stroke (AIS) ranges from 4% to 23%. Early or acute-onset seizures occur between 24 hours and 4 weeks after AIS, while and late-onset seizures occur greater than 4 weeks after AIS. Although the exact underlying pathophysiology of post-AIS seizures is unclear, it is thought that edema and cytotoxicity induced by an ischemic insult are responsible for early-onset seizures, whereas scar tissue formed after anoxia and deformation of dendrites is responsible for late-onset seizures. Due to a lack of data on the prophylactic administration of AEDs in this patient population, the AHA/ASA guidelines for the early management of adults with ischemic stroke do not recommend prophylactic AEDs. Recurrent seizures should be treated in accordance with the previously mentioned standard. There is also poor data on the newer, less toxic AEDs in patients with post-AIS seizures.17
Intracerebral hemorrhage (ICH) is a frequent cause for admission to the neurocritical care unit. Patients with ICH are at the greatest risk of seizure within the first few days after ictus, with over half of the seizures occurring in the first 24 hours. The incidence of early seizures has been reported in 7.4% to 17% of patients with ICH, while late seizures are reported in 2.6% to 10.2% of these patients. Seizure prophylaxis in patients with ICH is controversial. There are currently no randomized placebo-controlled trials evaluating the efficacy and safety of prophylactic AED therapy in patients with ICH. The current available evidence is observational, and it represents a heterogeneous group of patient comorbidities and severity of illness. It is critical to investigate the use of newer AEDs for seizure prophylaxis in ICH patients.18-19 The AHA / ASA guidelines recommend that prophylactic AEDs not be used (Class III; Level of Evidence: B).20
In conclusion, after reviewing the primary literature and current guidelines on the major disease states seen in the Neurosurgical Care Unit, further studies are needed to assess the utility of newer AEDs (e.g. levetiracetam, lamotrigine, lacosamide) for these patients. Conventional AEDs are associated with poorer outcomes because of drug interactions, need for drug level monitoring, and adverse drug reactions. With further studies of newer AEDs for seizure prophylaxis, we can potentially improve patient outcomes in the Neurosurgical Care Unit.
- Rowe AS, Goodwin H, Brophy GM, et al. Seizure prophylaxis in neurocritical care: a review of evidence-based support. Pharmacotherapy. 2;34(4):396-409. doi: 10.1002/phar.1374.
- Zachenhofer I, Donat M, Oberndorfer S, Roessler K. Perioperative levetiracetam for prevention of seizures in supratentorial brain tumor surgery. Journal of Neurooncology. 2011;1:101–6.
- Kern K, Schebesch KM, Schlaier J, et al. Levetiracetam compared to phenytoin for the prevention of postoperative seizures after craniotomy for intracranial tumours in patients without epilepsy. Journal Clinical Neuroscience. 2012;1:99–100.
- Mikkelsen T, Paleologos NA, Robinson PD, et al. The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. Journal of Neurooncology. 2010;1:97–102.
- Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med. 1990;8:497–502.
- Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of severe traumatic brain injury. XIII. Antiseizure prophylaxis. J Neurotrauma. 2007;24:S83–6.
- Chang BS, Lowenstein DH. Practice parameter: antiepileptic drug prophylaxis in severe traumatic brain injury: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003;1:10–6.
- Kruer RM, Harris LH, Goodwin H, et al. Changing trends in the use of seizure prophylaxis after traumatic brain injury: a shift from phenytoin to levetiracetam. J Crit Care. 2013;28:e9–13.
- Baker CJ, Prestigiacomo CJ, Solomon RA. Short-term perioperative anticonvulsant prophylaxis for the surgical treatment of low-risk patients with intracranial aneurysms. Neurosurgery. 1995;5:863–70; discussion 870–1.
- Rosengart AJ, Huo JD, Tolentino J, et al. Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. J Neurosurg. 2007;2:253–60.
- Rhoney DH, Tipps LB, Murry KR, Basham MC, Michael DB, Coplin WM. Anticonvulsant prophylaxis and timing of seizures after aneurysmal subarachnoid hemorrhage. Neurology. 2000;2:258–65.
- Naidech AM, Kreiter KT, Janjua N, et al. Phenytoin exposure is associated with functional and cognitive disability after subarachnoid hemorrhage. Stroke. 2005;3:583–7.
- Chumnanvej S, Dunn IF, Kim DH. Three-day phenytoin prophylaxis is adequate after subarachnoid hemorrhage. Neurosurgery. 2007;1:99–102; discussion 102–3.
- Murphy-Human T, Welch E, Zipfel G, Diringer MN, Dhar R. Comparison of short-duration levetiracetam with extended-course phenytoin for seizure prophylaxis after subarachnoid hemorrhage. World Neurosurg. 2011;2:269–74.
- Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;6:1711–37.
- Diringer MN, Bleck TP, Claude Hemphill J III, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care. 2011;2:211–40.
- Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;3:870–947.
- Messe SR, Sansing LH, Cucchiara BL, Herman ST, Lyden PD, Kasner SE. Prophylactic antiepileptic drug use is associated with poor outcome following ICH. Neurocrit Care. 2009;1:38–44.
- Naidech AM, Garg RK, Liebling S, et al. Anticonvulsant use and outcomes after intracerebral hemorrhage. Stroke. 2009;12:3810–5.
- Morgenstern LB, Hemphill JC III, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;9:2108–29.