Seizure 18 (2009) 676–679

Utility of levetiracetam in patients with subarachnoid hemorrhage

Dharmen Shah a, Aatif M. Husain a,b,*a Department of Medicine (Neurology), Duke University Medical Center, Durham, NC, United Statesb Neurodiagnostic Center, Veterans Affairs Medical Center, Durham, NC, United States

A R T I C L E I N F O

Article history:

Received 20 October 2008

Received in revised form 11 September 2009

Accepted 17 September 2009

Keywords:

Subarachnoid hemorrhage

Phenytoin

Levetiracetam

Seizures

Antiepileptic drugs

Adverse events

A B S T R A C T

Purpose: To determine the utility and tolerability of levetiracetam (LEV) compared to phenytoin (PHT) in

preventing clinical seizures in patients with subarachnoid hemorrhage (SAH).

Methods: Utility and tolerability of PHT and LEV in patients with SAH were determined by the

occurrence of breakthrough clinical seizures or adverse events necessitating a change of medication.

Comparisons were performed with Chi-square tests.

Results: All 176 patients were initially treated with PHT. No breakthrough clinical seizures occurred. In

70 (39.8%) patients, PHT was replaced with LEV due to adverse events including elevation of

transaminases, thrombocytopenia, unexplained fever, rash, gastrointestinal disturbance, and worsening

mental status. After switching to LEV, all adverse effects resolved except gastrointestinal disturbance

and worsening mental status in 4 patients. Adverse events occurred more often in patients taking PHT.

Conclusions: In patients with SAH, LEV appears to have superior tolerability compared to PHT.

Published by Elsevier Ltd on behalf of British Epilepsy Association.

Contents lists available at ScienceDirect

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journal homepage: www.e lsev ier .com/ locate /yse iz

Subarachnoid hemorrhage (SAH) is a neurological emergencywith high mortality and morbidity. The incidence of SAH rangesfrom 8 to 10.5 per 100,000 per year.1,2 Over the last few decades,SAH mortality has decreased, mostly due to improvements in theneurologic intensive care units (NICU). Despite this improved care,the mortality remains high, with as many as 36% of patients dying.3

The markers for poor outcome are the patient’s level ofconsciousness upon admission, age, amount of blood seen onthe initial computed tomography (CT) scan, cerebral vasospasm,re-bleeding, surgical complications, and seizures.4–8

Seizures can occur at presentation of SAH or later in the diseasecourse. The re-bleeding rate and severe disability is higher in SAHpatients who have seizures. Seizures can also cause destabilizationof critically ill patients. The presence of seizures is recognized as anindependent predictor of poor outcome in patients with SAH.4 TheAmerican Heart Association (AHA) guidelines suggest thatprophylactic antiepileptic drugs (AED) may be considered in theimmediate posthemorrhagic period.9

The use of PHT in critically ill patients is complicated by itscomplex pharmacokinetics and adverse events. Levetiracetam(LEV) is a chemically unrelated AED that has linear pharmacoki-netics and is not hepatically metabolized. Its efficacy has beendemonstrated in a wide variety of seizure types and status

* Corresponding author at: 202 Bell Building, Box 3678, Duke University Medical

Center, Durham, NC 27710, United States. Tel.: +1 919 684 8485;

fax: +1 919 684 8955.

E-mail address: Aatif.husain@duke.edu (A.M. Husain).

1059-1311/$ – see front matter . Published by Elsevier Ltd on behalf of British Epilepsy

doi:10.1016/j.seizure.2009.09.003

epilepticus.10 In an intensive care unit or other inpatient setting,therapy can be initiated at a therapeutic dose without risk of AEDhypersensitivity syndrome. These favorable properties of LEVsuggest that it may have a unique role in patients with SAH toprevent seizures and minimize adverse events. The purpose of thisstudy was to determine the utility and tolerability of LEV inpatients with SAH, and see how it compares to PHT.

1. Methods

All patients admitted to Duke University Medical Center withnon-traumatic SAH between January 1, 2002 and June 30, 2006were considered for enrollment in this study. Charts of patientswho were treated with either PHT or LEV were reviewed in detail.This study was approved by the local Institutional Review Board(IRB).

Chart review included review of admission history and physicalexamination. Presence of clinical seizures was noted. Routine andprolonged electroencephalograms (EEG) were also reviewed whenavailable to document frequency of seizures. Utility of the AED wasdetermined by noting whether breakthrough clinical seizuresoccurred.

Adverse events and whether the AED was switched due to theseadverse events were noted. In particular the adverse eventsevaluated in detail included elevation of transaminase levels,thrombocytopenia, unexplained fever, rash, and worsening mentalstatus. Any elevation of transaminase levels was identified, butelevations that were twice the upper limit of normal werespecifically noted. Platelet count of less than 100,000 mm3 and a

Association.

Table 2Number of patients experiencing adverse events.

Side effect PHT

(n = 176) (%)

LEV

(n = 70) (%)

P value

Breakthrough clinical seizures 0 0 NS

Elevated transaminases 53a (30.1) 0 <0.001

Thrombocytopenia 21 (11.5) 0 <0.001

Unexplained fever 10 (5.7) 0 <0.05

Rash 3 (1.7) 0 NS

GI disturbance 4 (2.3) 1 (1.4) NS

Worsening mental status 9 (5.1) 3 (4.3) NS

a Of these only 23 (43.4%) patients were switched to LEV. PHT = phenytoin,

LEV = levetiracetam, NS = not significant, and GI = gastrointestinal.

D. Shah, A.M. Husain / Seizure 18 (2009) 676–679 677

fever of greater than 38 8C were also noted. Worsening confusionor level of alertness was considered worsening mental status.Complaints of nausea, vomiting, or diarrhea were noted asgastrointestinal disturbance.

The AED dose and plasma concentration and renal functiontests results were also noted when available. Discharge summariesand first follow-up neurology or neurosurgery clinic evaluationswere reviewed to determine whether AED adverse events hadresolved. Only patients that had at least one follow-up visit wereincluded. The frequency with which the AED needed to be changedand occurrence of adverse events were compared between the PHTand LEV groups using Chi-square tests.

2. Results

A total of 176 patients, 113 women, with SAH were enrolled inthis study. The mean age of the patients was 58.2 (�15.6) years. Inall patients the SAH was secondary to rupture of an intracranialaneurysm. The site of the aneurysms is presented in Table 1.Aneurysms of the anterior communicating artery were the mostcommon, occurring in 59 (33.5%) of patients. The Hunt and Hess gradewas 3 or less in 111 (63%) patients, grade 4 in 51 (29%) patients, andgrade 5 in 14 (8%) patients. PHT and LEV were the only AED used inthis series of patients. All patients received PHT first, and LEV wasused only if PHT resulted in adverse events. The PHT loading dose was20 mg/kg and maintenance dose was 5–7 mg/kg/day. The meanplasma concentration of PHT was 16 (�6.1) mcg/mL. LEV was startingwithout a loading dose at 1500 mg twice a day. Plasma concentra-tions for LEV were not available.

All patients were initially treated with PHT within 24 h ofsymptom onset. Five (2.8%) patients had one or more clinicalseizures at presentation before administration of PHT. Clinicalseizures did not occur in any patient after initiation of AED therapyuntil at least their first follow-up. Either routine or prolonged EEGwas obtained in only 8 (4.5%) patients. Prolonged EEGs were 24 h inlength. Five of these EEGs were performed on patients who hadclinical seizures at presentation; these patients were on PHT. Twoadditional patients being treated with PHT and one being treatedwith LEV had an EEG because of worsening mental status. None ofthe EEGs showed electrographic seizures or interictal epileptiformactivity.

Seventy (39.8%) of the PHT-treated patients were subsequentlyswitched to LEV. The switch occurred after a mean of 3.8 days afterstart of treatment with PHT, with all patients having been switchedby day 10. Of these patients, 57 (81.4%) patients were switchedbecause of suspected PHT induced adverse events. These includedelevated transaminase levels, thrombocytopenia (platelet count ofless than 100,000 per mm3), unexplained fever (temperaturegreater than 38 8C), and rash (Table 2). All patients withthrombocytopenia, unexplained fever, and rash were switchedto LEV, however only 23 of the 53 (43.4%) patients with elevatedtransaminase levels were switched. These 23 patients hadtransaminase elevation greater than twice normal. Another 13(18.6%) patients experienced gastrointestinal disturbance orworsening mental status and were switched to LEV. The

Table 1Aneurysms associated with diagnosis of SAH.

Location of aneurysm Number (%) of patients

Anterior communicating artery 59 (33.5)

Posterior communicating artery 33 (18.8)

Internal carotid artery 23 (13.1)

Middle cerebral artery 22 (12.5)

Basilar tip 15 (8.5)

All other 24 (13.6)

association of these adverse events with PHT was considereduncertain; however a change in AED occurred regardless.

While on LEV, none of the 70 patients had clinical seizures. All56 patients who were switched to LEV because of elevatedtransaminase levels, thrombocytopenia, unexplained fevers, orrash had resolution of these adverse events by the time they weredischarged from the hospital or by the first follow-up clinic visit(14–41 days after discharge). The frequency of the first threeadverse events was significantly higher in the PHT group comparedto the LEV groups (Table 2). Of the 4 patients with gastrointestinaldisturbance prompting the change in AED to LEV, 3 (75%)improved. Worsening mental status prompted a change in theAED in 9 patients; 6 (66.7%) patients improved after beingswitched to LEV. One patient continued to have GI disturbance and3 continued to have worsened mental status. It is possible that LEVmay have caused these adverse effects in 4 (5.7%) patients. Allpatients continued to take PHT or LEV at least until first follow-up.

3. Discussion

In this retrospective study, patients with non-traumatic SAHdid not have breakthrough clinical seizures after treatment withPHT or LEV. However, patients treated with PHT had more frequentadverse events consisting of elevated transaminase levels,thrombocytopenia, and unexplained fevers. In 39.8% of patients,PHT had to be discontinued because of adverse events; in thesepatients LEV was used instead. Serious adverse events leading todiscontinuation of LEV were not seen.

Seizures are a complication of SAH. Variables that increase theincidence of seizures after SAH include high grade, age less than 50years, rupture of a middle cerebral artery aneurysm, intracerebralhematoma, blood in the quadrigeminal cistern, persistent neuro-logical deficit, and re-bleeding.11 In older studies, seizures werereported to occur in up to 26% of patients with aneurismal SAH.12

However, more recent studies noted that between 5 and 11% ofpatients develop seizures around the time of the hemorrhage.5,13,14

The declining incidence of seizures has been attributed toimproved NICU care and the routine use of prophylactic AED. Inthe present series, only 2.8% of patients had seizures. All theseoccurred at onset of the SAH and prior to institution of AEDtherapy. The relatively low incidence of seizures may be due to theroutine use of prophylactic AED.

Whether AED should be used prophylactically in all patientspresenting with SAH is debated. Since the incidence of seizures inthis patient population has diminished considerably in the last 20years, some investigators have suggested that routine use ofprophylactic AED is not justified.14 However, others havesuggested that the incidence of nonconvulsive seizures detectedwith continuous EEG monitoring is as high as 19% in patients withSAH.15 Moreover, the prognosis is worse in patients who haveseizures.4,5,16,17 The Stroke Council of the American HeartAssociation notes that seizures may result in neuronal injury

D. Shah, A.M. Husain / Seizure 18 (2009) 676–679678

and further destabilization of critically ill patients and must betreated aggressively.18 Moreover, they and others suggest thatprophylactic AED therapy with PHT should be considered.2,18 Allpatients presenting to the NICU at Duke University Medical Centerwith SAH are prophylactically treated with PHT initially. AED use istypically continued for at least 6 months. During the time period inwhich this study was conducted, continuous EEG monitoring wasnot routinely used to monitor SAH patients, thus potentiallyunderestimating the frequency of seizures.

Several recent studies have raised doubts about whether PHT isthe best AED to use for prevention of seizures in critically illpatients with SAH. Higher PHT dose was found to result in worseneurologic and cognitive outcomes in SAH survivors.19 PHT mayalso interfere with the metabolism of nimodipine, which iscommonly used to minimize vasospasm. Nimodipine is metabo-lized by the cytochrome P-450 isozyme of the hepatic microsomalenzyme system. This system is induced by PHT, thus increasing themetabolism of nimodipine.20 This may leave patients moresusceptible to vasospasm from lower nimodipine concentra-tion.21,22 Since evaluation of vasospasm was not a focus of thisstudy, it is not certain whether patients treated with PHT in thisstudy had this complication more often. Unexplained fever mayoccur with PHT, which may worsen prognosis.23 Finally, the use ofPHT in the NICU is challenging due to frequent adverse events, anarrow therapeutic range, nonlinear pharmacokinetics, andfrequent monitoring of total and free levels, especially duringvasospasm.13,24

Many of the issues complicating the use of PHT in critically illpatients were noted in this study as well. Elevation of transaminaselevels, thrombocytopenia, unexplained fevers, and rash occurredcommonly in patients treated with PHT. Though not a focus of thestudy, it was noted that the dose of PHT was frequently changed tomaintain an appropriate plasma concentration. Nimodipineplasma concentration was not available in this study, so whetherPHT resulted in increased clearance of this medication is unclear.

LEV is a novel AED whose exact mechanism of action isunknown. Recent evidence shows that it binds to the synapticvesicle protein 2A (SV2A), which is involved with neurotransmitterrelease from nerve cells.25,26 Additionally, LEV also has indirecteffects on gamma amino butyric acid (GABAergic) neurotransmis-sion, modulates potassium and high voltage calcium currents, andinfluences expression of genes associated with kindling.27 It haslinear pharmacokinetics with low intra- and inter-subject varia-bility. The bioavailability of LEV is not affected by food, it notprotein-bound and does not affect the protein binding of otherdrugs, and its volume of distribution is close to the volume of intraand extra-cellular water.28,29 LEV has also been shown to beneuroprotective in the animal models of SAH, closed head injury,and self-sustaining status epilepticus.30,31 The efficacy of LEV hasbeen demonstrated in partial and generalized seizures as well asstatus epilepticus.10,32 Many of the patients in this study receivedthe oral formulation of LEV, which is difficult to administer incritically ill patients. In the last few years, intravenous LEV hasbecome available, and its administration has become much easierand quicker in the NICU.

LEV has been used instead of PHT with favorable results incritically ill patients.33–36 Patients with acute brain injury and aftersupratentorial neurosurgery were noted to have problems similarto those discussed above when treated with PHT.33,35 Switchingthese patients to LEV resulted in fewer complications.

The main limitation of this study is that it was retrospective andrelatively small in size with unequal groups. When comparing twoAED, a prospective, randomized trial would provide the mostrobust data. Such a trial is difficult to perform because of theurgency of treatment of SAH patients and issues surroundinginformed consent in patients with worsening mental status. A

retrospective analysis, such as this one, provides preliminary datasuggesting the utility of LEV in this patient population and maylead to further studies. Details of PHT and LEV serum levels werenot analyzed in this study. This was because the focus of the studywas whether PHT was discontinued or not, not how difficult it wasto maintain consistent levels. This study also does not address theincidence of seizures in SAH acutely and long term and whetherprophylactic AED therapy should be used in every patient. Drugsother than PHT and LEV were also not evaluated. Though valproicacid (VPA) has been reported to be useful in SAH, it was not used inany patient in this series.21,22 How VPA would compare to LEVcannot be answered by this study.

Seizures are a complication of SAH. PHT is used commonly toprevent seizures in the acute phase of management. Thecomplicated pharmacokinetics, interactions with other commonlyused drugs, and adverse effects of PHT often necessitate changingtherapy. LEV appears to be well tolerated in patients with SAH, haslinear pharmacokinetics, no significant drug–drug interactions,lacks many of the side effects of PHT, and is available in anintravenous formulation. It may be reasonable to consider LEV forprophylactic treatment of seizures in patients presenting withSAH.

Acknowledgements

This study was supported in part by a grant support from UCBPharma and was presented in abstract form at the AmericanEpilepsy Society annual meeting, December, 2007.

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