Decisions regarding postcraniotomy seizure prophylaxis are complicated, as seizure rates vary with pathology, and available evidence, largely concerning older AEDs, is heterogeneous (Rossetti & Stupp, 2010) with side effect considerations secondary to efficacy. Side effect burden is highly relevant in determining indication for prophylaxis given relatively large numbers needed-to-treat in postcraniotomy prophylactic settings (Foy et al., 1992; Kuijlen et al., 1996; De Santis et al., 2002; Klimek & Dammers, 2010; Vecht & Wilms, 2010). In this study we found both LEV and PHT to be well-tolerated in intravenous preparation perioperatively, and in total intravenous-plus-oral prophylactic regimen.
Two recent studies have directly compared LEV and PHT. A prospective, randomized, single-blinded trail of intravenous LEV versus intravenous fosPHT (loading)/intravenous PHT among 52 (34 LEV, 18 PHT) critical care patients with severe traumatic brain injury (89%) or subarachnoid hemorrhage (SAH) (Szaflarski et al., 2010), compared neurologic outcome, seizure frequency, and serious adverse events (mean duration intravenous AED 7 days). Significantly fewer gastrointestinal side effects (p = 0.04) occurred among patients assigned LEV, with measures of neurologic status (p = 0.02) and long-term outcome also favoring LEV. No dermatologic complications were reported. Outcomes did not include allergic reactions, total adverse events, or discontinuation because of intravenous AED. Differing side effect profile for PHT in our study (few gastrointestinal side effects, salient occurrence of rash/allergy) may relate to our general craniotomy population and lower mean duration of intravenous AED.
A retrospective efficacy and tolerability study for LEV versus PHT monotherapy after supratentorial neurosurgery (105 LEV, 210 PHT) found a significant difference in number of adverse drug reactions requiring change in therapy during hospitalization favoring LEV (LEV 1%, PHT 18%, p < 0.001), with 64% continuation for LEV against 26% for PHT at 12 months (p = 0.03) (Milligan et al., 2008). The PHT group had greater mean age. Our smaller, shorter prospective study with initial parenteral administration and age comparable between groups found consistent continuation rates, but failed to confirm significant differences in continuation or in discontinuation because of side effect.
Other studies concerning tolerability and safety of parenteral and oral PHT and LEV as individual agents or compared with other AEDs/placebo are heterogenous with differing side effect thresholds, and divided between acute seizure (PHT), chronic epilepsy, neurointensive care, and neurosurgical settings.
Discontinuation of PHT because of side effect has been reported at 5% for intravenous use (Martinelli & Muhlebach, 2003), with between 6.5% (Coplin et al., 2002) and 48% (Henkin et al., 1996) requiring infusion rate reduction, and at 12.6% for rapid oral initiation (Ramsay et al., 2010). Total side effect rate is mostly reported around 25–27% for intravenous or oral PHT (Earnest et al., 1983; Appleton & Gill, 2003; Depondt et al., 2011) but has been cited at 9.1% (intravenous) (Coplin et al., 2002) and 55.9% (oral) (Ramsay et al., 2010). The most common reported intravenous side effects are burning pain at the site, 9.1–37% (Earnest et al., 1983; Henkin et al., 1996; Mattson, 1996; DeToledo & Ramsay, 2000; Coplin et al., 2002; Appleton & Gill, 2003); local cutaneous reaction (LCR)/purple glove syndrome (PGS), 1.3% strict PGS to 25.2% mild to moderate LCR (Burneo et al., 2001; O’Brien et al., 2001); hypotension, 1–14%, higher in SE (Earnest et al., 1983; Binder et al., 1996; Henkin et al., 1996; Mattson, 1996; DeToledo & Ramsay, 2000; De Santis et al., 2002; Appleton & Gill, 2003; Martinelli & Muhlebach, 2003); and drug intoxication, approximately 15% (Earnest et al., 1983). Important but less common side effects are allergy, 2% (rapid loading) (Martinelli & Muhlebach, 2003) and cardiac arrhythmia, 1–7% (Earnest et al., 1983; Mattson, 1996; Treiman et al., 1998; DeToledo & Ramsay, 2000; Appleton & Gill, 2003). Severe morbidity and mortality including tissue necrosis (Twardowschy et al., 2009), requirement for limb amputation (Spengler & Arrowsmith, 1988), Stevens-Johnson syndrome (Delattre et al., 1988), and death from cardiovascular complication (DeToledo & Ramsay, 2000) occur rarely.
Discontinuation of 10% for oral PHT to 1 year after craniotomy is reported (Beenen et al., 1999). Side effect profile of oral PHT mostly relates to drug intoxication. In two recent studies side effect rates were somnolence/sedation 5%, 14.2%; unsteadiness/dizziness/vertigo/ataxia 4%, 17.9%; rash 4%, 7.9%; fatigue 8.7%; abnormal vision 7.1%; and gum hypertrophy 5% (Ramsay et al., 2010; Depondt et al., 2011).
We found consistent discontinuation and total side effect rates for PHT. Rash was most common and most commonly associated with discontinuation in keeping with previous report (Foy et al., 1992, postcraniotomy population PHT/carbamazepine). Concomitant medication, particularly antibiotics, might have inflated rash/allergy rate for both study AEDs. The most severe adverse reactions potentially attributable to PHT were systemic allergic reactions in two patients, including one instance of hypotension, both resolving after discontinuation of medications including PHT. No isolated symptomatic hypotension was reported. Operative monitoring and intervention might have reduced the incidence and reporting of perioperative hypotension, common from other causes. Fewer local side effects than expected following intravenous PHT might relate to perioperative setting with anesthetic technique, sedation, and analgesia. Low PHT serum levels during admission might have resulted in fewer early dose-dependent side effects than otherwise.
Our baseline data showed more patients assigned PHT had brain metastases, although total extraaxial malignancy numbers were comparable between LEV and PHT groups (Table 1 and footnotes b, c and i). Of the seven patients who discontinued or had major side effects or both, four (one LEV, three PHT) had metastatic disease, one bilateral subdural hematoma and alcohol-related liver disease, and one SAH, and one (Patient 79 Table 3) meningioma and seizures (the three last all PHT). As a group, the six patients who had postoperative seizures had less baseline comorbidity (one had ischemic heart disease, myelodysplasia, and hyponatremia; one had atrial fibrillation and previous transient ischemic attack), although one died during the study period with glioblastoma multiforme. We cannot discount that more severe disease, particularly metastatic malignancy in the PHT group, might account for some difference in major side effect outcomes, although baseline disease severity is difficult to compare from our data and more side effects in total were seen among patients assigned LEV (Tables S1A,B summarize outcomes against patient characteristics).
Higher BDZ exposure among patients assigned PHT may have related to more extracranial malignancy and death from primary pathology in this group (not statistically significant). (Six of the 12 patients assigned PHT taking BDZ had extracranial malignancy; two of those, and a further patient with glioblastoma multiforme who took BDZ, died during the study period. Two of the five patients taking PHT with major side effects and another two of the six with seizures, had some BDZ exposure by study end).
Eight studies of intravenous LEV monotherapy or add-on therapy involving populations with brain tumors, SE, in critical care, or with need for oral or PHT substitute (total n = 205, 40 children) have reported infusion well-tolerated with no need for discontinuation because of side effects (Knake et al., 2007; Goraya et al., 2008; Ruegg et al., 2008; Berning et al., 2009; Beyenburg et al., 2009; Moddel et al., 2009; Ng et al., 2010; Usery et al., 2010). Side effects were generally mild, with somnolence, fatigue, nausea, and vomiting most common, and total rates of from very few up to around 30%. A critical review in SE (Trinka & Dobesberger, 2009) composited adverse event rate for intravenous LEV to 7.1%, mostly mild transient side effects. A safety and pharmacokinetic study at high doses and/or infusion rates among healthy subjects (Ramael et al., 2006) found no need for discontinuation, but 86% intravenous LEV versus 25% placebo experienced mild to moderate side effects, prominently dizziness (52.8%), somnolence (33.3%), and fatigue (11.1%). Short-term tolerability of intravenous LEV as oral substitute was evaluated (Baulac et al., 2007), with 20% subjects experiencing related adverse events, all mild or moderate. Two studies specifically reported no local injection site side effects for intravenous LEV (n = 48 combined) (Knake et al., 2007; Berning et al., 2009).
Discontinuation rates because of adverse events for oral LEV have been reported as 19% (long term study n = 811, adverse event/ inefficacy) (Depondt et al., 2005), and 14.4% (28 weeks) (Brodie et al., 2007). Retrospective 2-year retention rate of 53.6% in 196 patients is reported (Chung et al., 2007). Side effect rates for oral LEV monotherapy or add-on therapy have been reported from 6.4% (7-day follow-up) (Zachenhofer et al., 2011) to 88.8% (high dose add-on) (Cereghino et al., 2000), mostly between 30% and 70%, although not differing from placebo in large prospective double-blind multicenter trials (Ben-Menachem et al., 2000; Betts et al., 2000; Cereghino et al., 2000; Shorvon et al., 2000; Bird & Joseph, 2003; Newton et al., 2006, 2007).
Most common side effects for oral LEV include somnolence/sedation and asthenia (14.8% vs. 8.4% placebo and 14.7% vs. 9.1% respectively in review of add-on therapy) (Harden, 2001), dizziness, mood and behavior problems, and thrombocytopenia, with nausea, headache, visual blurring, and rash in a small proportion of patients often not more than placebo (Crepeau & Treiman, 2010). One prospective observational study (LEV add-on, n = 200, ≥6 months) (Bird & Joseph, 2003) found minor adverse effects in 27.4% (corresponding with our mild and moderate side effects), with 16% withdrawal because of major adverse effects, inefficacy, or exacerbation of seizure frequency. Most common reported adverse effects were sleepiness 17.7%, aggression 10.3%, dizziness 4.6%, headache 2.3%, and rash 1.1%.
Our findings correspond with previous discontinuation and total side effect rates and relative frequency of mild to moderate side effects, particularly lethargy/tiredness/asthenia, among LEV-treated patients. LEV-emergent mood-related side effects at upper end of reported range (Briggs & French, 2004) were mild to moderate. Number of affected patients did not differ significantly between LEV and PHT (p = 0.25).
Our finding of no postoperative seizures among patients taking LEV versus PHT 6, p = 0.01, contrasts with previous reports of no significant difference in seizure frequency. In direct comparison: 5/34 LEV versus 3/18 PHT by continuous electroencephalography (cEEG) within 72 h postsurgery, p = 1.0 (Szaflarski et al., 2010); 1/105 LEV versus 9/210 PHT ≤7 days postsurgery, p = 0.17 and 11/42 LEV versus 42/117 PHT at 12 months, p = 0.34 (Milligan et al., 2008). Across postneurosurgical studies: reported seizure occurrence was LEV 2.6% (n = 78, 7 days postoperative) (Zachenhofer et al., 2011), 2/12 (to 4 weeks) (Usery et al., 2010); PHT 7/50 (all with subtherapeutic PHT levels, to 1 year) (Beenen et al., 1999); PHT 13/100 versus placebo 11/100 (7 days, mostly add-on) (De Santis et al., 2002); with no significant difference between PHT, carbamazepine, and no treatment n = 276 (to 6 or 24 months, high proportion subtherapeutic levels) (Foy et al., 1992).
Consistent with previous reports (Beenen et al., 1999; De Santis et al., 2002; Milligan et al., 2008), seizures in our PHT group occurred early postcraniotomy. Generally low available PHT serum levels during admission in our study must be considered in interpretation of comparatively high seizure occurrence in the first week postoperatively, and reflect our real-world setting (cf studies reviewed in Kuijlen et al., 1996). Bias in pathology did not seem to account for seizure outcomes (Tables 1 and 3). Low preoperative seizure occurrence (4/74, 5%; Table 1 and footnote h) in our total study population limit the significance of our findings. Nevertheless our results suggest that LEV compares well against PHT for safety in early seizure prophylaxis after craniotomy.
Choice in intravenous AED
Choice in intravenous AED is needed to manage patient specific factors and to minimize multiple AED exposure. In the neurosurgical setting, LEV’s theoretical advantages over PHT include lack of interaction with chemotherapeutic agents (Yap et al., 2008), dexamethasone (Lawson et al., 1981), and antibiotics, avoidance of worsening cutaneous side effects of radiotherapy (Mamon et al., 1999), and potential neuroprotective benefit (Szaflarski et al., 2010). LEV’s milder side effect profile appeals for neurosurgical populations with high baseline morbidity though mood side effects, lethargy (Wen et al., 2006), thrombocytopenia and cost are potential drawbacks. Our safety data lend support to empirical use of intravenous LEV in critical care (Ruegg et al., 2008; Szaflarski et al., 2010) and for prolonged SE (Knake et al., 2007; Berning et al., 2009; Moddel et al., 2009; Trinka & Dobesberger, 2009). Theoretical basis exists for potential advantage in other groups where PHT may be less suitable including those with intracerebral hemorrhage (ICH) (Naidech et al., 2009), SAH (Naidech et al., 2005), the elderly (Beyenburg et al., 2009), women of childbearing potential, those with hepatic impairment or taking hepatically metabolized drugs (Briggs & French, 2004; Crepeau & Treiman, 2010) including other AEDs and warfarin, and with CYP2C9 variant alleles (Depondt et al., 2011).
The PHT pro-drug fosPHT (intravenous or intramuscular) is not available in Australia. Main theoretical advantages of its water soluble formula, especially pertinent to acute seizure settings, are ability for rapid administration and reduction in local and cardiovascular side effects attributed to the propylene glycol carrier of intravenous PHT (Coplin et al., 2002). Rapid administration is necessary to achieve bioequivalence to intravenous PHT, with salient side effect pruritus responsive to infusion rate reduction (DeToledo & Ramsay, 2000; Coplin et al., 2002). Data from our perioperative setting included few acute local (three instances thrombophlebitis) and no acute cardiovascular side effects for intravenous PHT that may have been ameliorated were fosPHT used instead.
Study on a larger sample is required to validate our findings, with power considerations accounting for smaller effect size in the perioperative setting. Necessity to exclude a subset of patients already taking AEDs is likely to have reduced representation of those with low grade and/or highly epileptogenic lesions. Idiosyncratic randomization technique, potentially open to anticipation, introduced greater error vulnerability based on temporal recruitment factors than the planned block randomization. Recruitment from total intake of five different neurosurgical teams was expected to mitigate recruitment and participant outcome reporting bias conferred by the AED allocation method. Blinding was limited as appropriate in our setting.
Compromise of allocation procedure concealment appears not to have introduced significant selection bias (Table 1). Any bias in serious pathology had potential to affect outcomes and censoring analysis. Bias favoring PHT was expected where early discomfort from intravenous AED might have occurred perioperatively or intraoperatively.
We did not direct serum PHT monitoring to optimize therapy in this pragmatic study, meaning seizure and safety results might in part reflect individual pharmacokinetic responses and site-specific management. The low proportion of therapeutic PHT serum levels achieved imply that we did not represent ideal PHT efficacy and capture side effect burden with close titration in the early postoperative period. Perioperative setting and concomitant therapy including analgesia, antibiotics, steroids, chemotherapy, and radiotherapy, were expected to confound side effect reporting. Different pathologies and associated treatment could have confounded side effect profiles and seizure frequency. Conceivably, study AEDs themselves could have modulated patient complaints. We did not undertake independent systematic monitoring for cytopenia or hepatic derangement and did not formally assess cognition, although relevant reports and side effects were included in baseline and side effect data. Monetary cost was not addressed.