Phenobarbital and MK-801, but NotPhenytoin, Improve the Long-Term

Outcome of Status EpilepticusAvinash Prasad, MD, John M. Williamson, BA, and Edward H. Bertram, MD

To examine the effect of therapy on status epilepticus (SE) acutely and on long-term outcome, we compared three drugswith three different mechanisms. Phenobarbital, MK-801, and phenytoin were administered at 1, 2, and 4 hours afterinitiation of limbic status epilepticus by “continuous” hippocampal stimulation in rats. We evaluated the effects of thesedrugs on the course of SE and the subsequent development of chronic epilepsy. Phenobarbital and MK-801 were supe-rior to phenytoin in suppressing SE and in preventing chronic epilepsy. There was no benefit if treatment was given 2hours after the initiation of SE. Phenobarbital was most effective in suppressing electrographic seizure activity, butMK-801 had a slightly wider window for the prevention of chronic epilepsy. Early treatment, rather than electrographicsuppression of SE, correlated with prevention of chronic epilepsy. This study shows that the drugs administered, whichhave different mechanisms of action, have clear differences in altering the outcomes. The findings suggest that studies ofSE treatment should examine the effect of therapy on SE itself, as well as the long-term benefits of each treatment. Theuse of N-methyl-D-aspartate receptor antagonists should be considered early in the treatment of SE.

Ann Neurol 2002;51:175–181DOI 10.1002/ana.10085

Studies of therapy for status epilepticus (SE) shouldevaluate both short- and long-term outcomes. Beyondthe issues of acute survival, improving long-term out-come is perhaps the most important goal of SE treat-ment. Human SE frequently occurs in the context ofan acute brain insult, such as stroke, trauma, or en-cephalitis, and it is therefore difficult to differentiatethe short- and long-term outcomes following pro-longed seizures from those following acute braininjury.1 Experimental SE eliminates multiple indepen-dent variables that can complicate the clinical studies.A model can provide standardized behavioral and elec-trographic seizures and therefore offers many advan-tages for outcome studies of SE.2

Most studies of therapy for experimental SE reporteffects on acute SE suppression3–9 and the preventionof neurological damage.10–15 Far fewer studies have fo-cused on the chronic consequences of SE, one of whichis the delayed development of chronic epilepsy. Pheno-barbital (PB),16,17 valproic acid,16 and MK-80118,19

administered at strategic times have been shown to beeffective in preventing neuronal loss and the develop-ment of chronic epilepsy in kainic acid (KA) and pilo-carpine models of limbic epilepsy. However, none of

these studies defined the optimum time window fortreatment or compared one drug with another.

The principal mechanisms of therapies used to con-trol human SE are GABAergic enhancement andvoltage-gated sodium channel inhibition. N-methyl-D-aspartate (NMDA) antagonists are potentially useful inthe treatment of experimental SE,6,11 but little isknown about their utility in humans. Barbiturates actmainly by �-aminobutyric acid (GABA) receptor en-hancement, but an inhibitory effect on the presynapticrelease of glutamate is also known.20 Benzodiazepinesact through GABA receptor enhancement and PHTinhibits voltage-gated sodium channels. Anecdotal useof the NMDA antagonist MK-801 in terminal humanSE has been reported.21,22

Significant changes occur in the GABAergic and ex-citatory receptor function during early SE.6,10 Drugswith different mechanisms of action administered atdifferent timepoints during this critical period mayvary in efficacy,23,24 and a comparison of efficacy inrelation to the time of administration and the effect onshort- and long-term outcomes may be useful in choos-ing appropriate drugs. We therefore compared threedrugs, each with a different mechanism of action

From the Department of Neurology, University of Virginia, Char-lottesville, VA.

Received Jun 27, 2001, and in revised form Sep 28. Accepted forpublication Sep 28, 2001.

Published online Dec 13, 2001

Dr Prasad is currently at the Department of Neurology, Universityof Alabama Birmingham, Birmingham, AL.

Address correspondence to Dr Bertram, Department of Neurology,University of Virginia, P.O. Box 800394, Charlottesville, VA22908. E-mail: ehb2z@virginia.edu

© 2001 Wiley-Liss, Inc. 175

(GABA agonist, NMDA antagonist, and voltage-gatedsodium channel inhibitor), administered at three differ-ent timepoints after induction of limbic SE in rats, todetermine (1) each drug’s acute effects on SE, (2) theability of each to prevent epilepsy, and (3) the presenceof a time window for each drug to have an effect.

Materials and MethodsAnimal Preparation and Status Epilepticus InductionLimbic SE was induced in adult male Sprague-Dawley ratsby “continuous” electrical midventral hippocampal stimula-tion for 90 minutes (10-second trains of 50Hz; 1-msec bi-phasic square waves were delivered every 12 seconds)through twisted pair bipolar stainless steel electrodes, as de-scribed previously.25 Stimulus intensity was empirically set at400�A (at least 2.5 times above the afterdischarge thresh-old). Once the SE was established, the electrographic seizurepatterns showed standard progress over the next 12 or morehours.25,26 This allowed us to study the effects of the drugson the evolution of SE. Only those rats that developed con-tinuous seizures at 1 hour after the onset of CHS were in-cluded in the study.

Drug TreatmentThere were 10 treatment groups in this study: PB, MK-801,and PHT treatment groups, with each drug given at 3 dif-ferent timepoints, and 1 saline treatment group. PB (80mg/kg), MK-801 (4mg/kg), and PHT (100mg/kg) were injectedintraperitoneally (i.p.) at 1, 2, and 4 hours after initiation of“continuous” hippocampal stimulation (CHS). Control ani-mals (n � 16) received 2ml of isotonic saline 2 hours afterCHS initiation. PB and MK-801 were prepared in isotonicsaline, and PHT was prepared in 30% polyethylene glycoland 70% water. The drug doses were based on preliminarywork in this laboratory, which determined the optimum dosefor consistent SE suppression.27 In earlier studies, we hadfound that these PB and PHT doses produced levels wellabove established human therapeutic ranges 2 hours after in-jection (PB �70.7�g/ml, PHT 24.4 � 1.1�g/ml).27 To en-sure a uniform treatment population, all animals had to dis-play continuous behavioral and electrographic seizure with aminimum electroencephalography (EEG) score of 3 (see the“Short-Term Outcome: Electrographic Monitoring” sectionthat follows) after 60 minutes of CHS initiation.

Short-Term Outcome: Behavioral MonitoringOur model of SE is predominantly nonconvulsive. Rats showoccasional limbic motor seizures in the early stage, but in thelater stages motor manifestations are much less intense andinclude head bobbing, intermittent ambulation, and occa-sional forelimb clonus. Because motor seizure frequency var-ies from animal to animal and over the course of SE, we didnot attempt to classify the effects of therapy on behavioralseizure activity. However, we did evaluate whether the drugswere sedating, because in a previous study we found a closerelationship between successful suppression of electrographicseizure activity and sedation of animals.27 Sedation was de-fined as lying in the test cage with no spontaneous move-ments and reduced motor response to tail pinch.

Short-Term Outcome: Electrographic MonitoringElectrographic seizure activity was monitored with a digitizedelectroencephalography (EEG) system.28 Following CHS, 5minutes of EEG was collected every half-hour for 8 hours.The EEG at 1, 2, 4, 6, and 8 hours post-CHS completionwas classified according to a previously standardized five-point scale:25,26 (1) normal or interictal spikes; (2) intermit-tent discrete seizures; (3) continuous seizure activity with fastspiking; (4) periodic epileptiform discharges (PEDs) with in-termittent superimposed seizures; and (5) PEDs alone. Forthis study, suppression of electrographic SE was defined as areduction of the EEG score to 1 within the first 2 hours ofdrug administration.

Long-Term Outcome: Epilepsy ProphylaxisThe prevention of chronic epilepsy was the primary long-term outcome measure. We have previously shown in ourmodel that a close relationship exists between the develop-ment of chronic epilepsy and the presence of significant hip-pocampal damage;29 however, this relationship was not di-rectly evaluated in this study. Although we could notabsolutely determine that there was no hippocampal neuro-nal loss in animals that did not develop spontaneous seizures,our past experience suggests that such loss was minimal.

Eight weeks after CHS and SE, rats were monitored con-tinuously for 4 weeks with a video-EEG monitor that had acomputerized seizure recognition program (Stellate Systems,Montreal, Quebec, Canada).28,30 Rats were considered epi-leptic if 2 or more seizures were detected.

Mortality OutcomeA final measure of the benefits of therapy was mortality. Thetotal number of rats that died before completion of the studyacross all groups was assessed.

Statistical AnalysisFor the majority of measures, the proportion of animals ineach group was compared with controls for each of the out-come measures using Fisher’s exact two-tailed probabilitytest. Where appropriate, drugs within the treatment groupwere also compared. The effect of treatment on the electro-graphic evolution of SE was evaluated at specified timepointsagainst controls using analysis of variance on ranks. All sta-tistical tests were performed with SigmaStat 2.0 software(SPSS Corporation, Chicago, IL), and � was set at �0.05.

ResultsShort-Term Behavioral OutcomeOverall, PB, MK-801, PHT and saline treatment se-dated 33 of 38 (87%), 37 of 37 (100%), 1 of 37 (3%),and 0 of 16 rats (0%), respectively. Compared withcontrols, PB and MK-801 were superior (p � 0.001),whereas PHT had no effect. PB and MK-801 sedatedrats within 30 minutes of administration and showedequal efficacy in 1-, 2-, and 4-hour treatment groups.Sedation always preceded electrographic SE suppres-sion, although electrographic suppression was not ob-served in all sedated rats.

176 Annals of Neurology Vol 51 No 2 February 2002

Short-Term Electrographic OutcomeThere were three major findings. First, 26 of 38 PB-treated rats (68%), 14 of 37 MK-801–treated rats(38%), 1 of 37 PHT-treated rats (34%), and 0 of 16control rats (0%) had electrographic SE suppressiondefined as a reduction of the EEG score to 1 withinthe first 2 hours of drug administration (Fig 1). Com-pared with controls, PB and MK-801 were superior (allp � 0.001); PHT had little effect on electrographicsuppression. A pairwise comparison showed that PBwas also superior to MK-801 (p � 0.01) in suppress-ing electrographic seizure activity.

Second, although significant electrographic suppres-sion compared with controls was seen in all 3 individ-ual treatment groups that received PB and MK-801,PB showed a trend toward greatest efficacy in the1-hour treatment group (80% at 1 hour vs. 45% at 4hours), whereas MK-801 showed a trend toward great-est efficacy in the 4-hour treatment group (33% at 1hour vs. 50% at 4 hours). These latter findings, how-ever, were not statistically significant (p � 0.4).

Third, PB and MK-801 caused a sustained improve-ment in median EEG scores during the first 8 hoursafter SE. PHT had no significant effect on the evolu-tion of EEG scores. Median EEG scores for the PB,MK-801, and PHT treatment groups at different time-points after initiation of CHS are shown in Figs 2, 3,and 4.

Long-Term Outcome of SE Therapy: EpilepsyProphylaxisRats that survived acute SE were monitored for chronicepilepsy. Overall, PB and MK-801 had a significantbenefit for prevention of chronic epilepsy. Compared with 8 of 10 control rats (80%), 12/31 PB-treated rats

(39%) and 11 of 35 MK-801-treated rats (31%) be-came epileptic (p � 0.002) (Fig 5). Among PB andMK-801 groups, there was a clear benefit to early treat-ment; 1-hour PB and 1- and 2-hour MK-801 treat-ment groups had significantly fewer epileptic rats thanthe control group (p � 0.05). Twenty-four of 30PHT-treated rats (80%) became epileptics, a result nodifferent than that for controls. Although the numberof epileptic and nonepileptic rats with and withoutelectrographic SE suppression were small, nonetheless,suppression of electrographic SE did not correlate withthe prevention of epilepsy (all p � 0.36).

Mortality OutcomeMortality rates for rats treated with PB, MK-801, andPHT were 8 of 38 (21%), 6 of 37 (16%), and 8 of 37(22%), respectively, and did not differ from the ratefor controls, which was 4 of 16 (25%) (all p � 0.47).

Additional PHT DosingBased on clinical experience indicating that high PHTlevel that may exacerbate seizures31 and earlier SE

Fig 1. Electrographic status epilepticus suppression, defined asa return of the electroencephalography (EEG) to score 1 pat-tern, of combined 1, 2, and 4hr treatment groups. PB: pheno-barbital; PHT: phenytoin; *p � 0.01 compared with theMK-801 group: **p � 0.001 compared with the controlgroup.

Fig 2. Median electroencephalography (EEG) scores for 1hrphenobarbital (PB), MK-801, and phenytoin (PHT) treat-ment groups at defined timepoints following “continuous” hip-pocampal stimulation (CHS) and treatment compared to con-trol group. For the PB 1hr treatment group there was asignificant reduction in EEG score at 1, 2, 4, 6, and 8hrs(all p � 0.001), and for the MK-801 1hr treatment groupthere was a significant reduction of score at 4, 6 (all p �0.002), and 8hrs (p � 0.01). In figures 2–4 arrows indicatetime of stimulus onset and time of drug administration.

Prasad et al: Phenobarbital, MK-801, and Phenytoin for Status Epilepticus 177

treatment may have greater efficacy, we administered25mg/kg (a low dose) to 4 rats at the time of CHSinitiation to prevent development of SE. Additionally,PHT 100mg/kg (a standard dose) was administered to6 rats at the time of CHS initiation, primarily to assessthe effect of earlier SE treatment. There was no effectof either treatment on the course of SE or on the out-comes.

DiscussionThere were three major findings in this study: (1) TheGABAergic compound PB and the NMDA antagonistMK-801 have a clear benefit in treating the acute sei-zures of SE and preventing the consequence of chronicepilepsy compared with PHT and controls. (2) Thetime window of epilepsy prophylaxis was narrow, as noagent had a significant benefit beyond 2 hours afterinitiation of SE. MK-801 may have a marginal advan-tage over PB in expanding the time window (2 hoursvs. 1 hour). (3) Earlier administration of these twodrugs, rather than electrographic suppression of SE,correlates best with prevention of chronic epilepsy.

These findings may have significant clinical implica-tions in the choice and timing of administration ofdrugs to treat SE. Standard practice is to treat SE with

a benzodiazepine and PHT at the first sign of SE. Al-though this approach may be appropriate for patientswho present in the earliest stages of SE with severaldiscrete seizures, the findings of this study suggest thata more aggressive approach with other drugs at earlierstages may further improve outcomes. In addition, thisstudy implies that timely administration of appropriatedrugs, rather than the complete electrographic suppres-sion of SE, is the crucial factor in improving long-termoutcomes.

It is interesting to note that the drugs that producedthe best long-term outcomes are also sedating. Thisfinding raises the question of whether sedation can alsopotentially improve long-term outcome, in part be-cause of its role in reducing metabolic requirement.This is possible, but other studies have clearly demon-strated that paralyzed, ventilated animals without sig-nificant metabolic disarray still have SE-induced braindamage.32

In our study, PB and MK-801 (4mg/kg i.p.) wereeffective in suppressing electrographic SE; however, inearly stages PB showed greater efficacy than MK-801.Other investigators, while not directly comparing theefficacy of these drugs, have shown that PB is uni-formly effective in electrographic SE control,9,14,17

Fig 3. Median electroencephalography (EEG) scores for 2hrphenobarbital (PB), MK-801, and phenytoin (PHT) treat-ment groups at defined timepoints following “continuous” hip-pocampal stimulation (CHS) and treatment compared to con-trol group. There was a significant improvement in scores forthe PB 2hr treatment group at 2, 4, 6, and 8hrs (all p �0.001) and for the MK-801 2hr treatment group at 4, 6,and 8hrs (all p � 0.001).

Fig 4. Median electroencephalography (EEG) scores for 4hrphenobarbital (PB), MK-801, and phenytoin (PHT) treat-ment groups at defined timepoints following “continuous” hip-pocampal stimulation (CHS) and treatment compared to con-trol group. There was a significant improvement in medianEEG scores for the PB 4hr treatment group at 6 and 8hrs (allp � 0.01) and for the MK-801 4hr treatment group at 6and 8hrs (all p � 0.001).

178 Annals of Neurology Vol 51 No 2 February 2002

whereas MK-801 efficacy is variable.6,27,33,34 WhenMK-801 (0.5mg/kg) was administered i.p. in the earlystage of SE in the perforant path stimulation (PPS) elec-trogenic model, behavioral and electrographic SE weresuppressed,6 whereas MK-801 (1.0mg/kg), administeredsubcutaneously in a similar model before PPS, reducedbut did not completely suppress electrographic SE.33

Clifford and colleagues administered MK-801 (1.0mg/kg) subcutaneously in the pilocarpine- and kainic acid(KA)–induced SE models. This agent suppressed onlybehavioral and neocortical electrographic seizures; elec-trographic limbic seizures continued.34 These authorsbelieve that an NMDA receptor antagonist is not a KAreceptor antagonist and therefore allows seizure activityto persist in the CA3 region, which has the highest den-sity of KA receptors. In the present study, a higher doseof MK-801 produced significant behavioral suppressionand moderate electrographic suppression of limbic sei-zures, suggesting that the efficacy of the NMDA recep-tor antagonist is probably to some extent dose depen-dent. Model differences may also play a role in thedifferential sensitivity to MK-801.

Overall, PB was most effective in suppressing elec-trographic SE, with a trend toward lessened efficacyover time. MK-801 was much less effective in this as-pect; however, it did show a slight (but nonsignificant)improvement with later treatment. The loss of efficacyof PB in SE is attributed to time-dependent loss ofGABAergic mediated inhibition.24,35,36 Similar find-ings have been demonstrated for human SE. Thelonger the SE lasts, the more difficult it is to controlwith PB and diazepam.37 Interestingly, our studyshows that MK-801 has improved electrographic sup-pression efficacy, an observation perhaps related to the

“use-dependent” phenomenon associated with theNMDA receptor.23,38

In our study, PHT was ineffective at all three time-points in suppressing SE. Standard- and low-dose PHTadministered prior to SE development was similarly in-effective. Walton and colleagues reported that PHT ad-ministered during early discrete seizures could preventsecondary generalization.39 The same group of authorsfailed to achieve control of seizures in an electrogenicSE model and inferred that PHT may not be suitablefor the treatment of generalized convulsive SE models.8

Clifford and colleagues also found PHT ineffective in amodel of SE, whereas PB was effective.40 Crawford andcolleagues also found that human SE resistant to PHTresponded to very high doses of PB.41 A recent studyof SE by the Veterans Affairs Status Epilepticus Coop-erative Study Group42 also supports our findings. Thestudy compared the efficacy of PHT, PB, and diaze-pam and found that PHT was the least effective treat-ment.

An important goal of SE treatment is to improve thelong-term outcome. Our data suggest that, unlike thesuppression of SE, which is possible with appropriatetreatment at many timepoints, the window of oppor-tunity for improving long-term outcome is narrow. Inthis regard, unlike the seizure-suppressing effect, theNMDA receptor antagonist MK-801 may have a slightadvantage compared with PB. PHT does not have anantiepileptogenic effect. The damage in various parts ofthe brain that occurs within 1 hour after SE onset in alithium-pilocarpine rat model43 supports the idea thatthere is a narrow time window for the antiepilepto-genic effect of drugs.

The basis for long-term outcome improvement isnot clear. Prevention of neuronal damage likely plays arole, as early treatment has regularly prevented damagein a number of models of SE. The ability of MK-801to prevent SE-related brain damage and developmentof epilepsy, without significantly suppressing limbicseizure activity in KA and pilocarpine SE models,13,34

suggests that persistent seizure activity can be main-tained by other transmitter systems, and that seizure-related brain damage is in part mediated throughNMDA receptor participation. In our study, suppres-sion of electrographic SE did not correlate with theprevention of epilepsy. MK-801 was less effective insuppressing electrographic SE than PB but had a some-what better antiepileptogenic effect. The finding of apartial dissociation between suppression of electro-graphic SE and epilepsy prophylaxis supports the ideathat suppression of SE is not critical to the preventionof delayed development of epilepsy.

There are questions that this study left unanswered.Are there subtle changes in the anatomies of multipleareas that may affect behavior? Some studies suggestthat there may be such behavioral changes in the ab-

Fig 5. Percentage of rats with documented chronic epilepsy ineach treatment group. *p � 0.05, **p � 0.002 comparedwith the control group.

Prasad et al: Phenobarbital, MK-801, and Phenytoin for Status Epilepticus 179

sence of gross hippocampal pathology.44 Are thereother areas of the brain not involved in the develop-ment of epilepsy that did suffer damage in spite of thetreatments? These important questions need furtherstudy.

The findings of our study may have significant im-plications for the treatment of SE. SE treatment shouldaim to improve long-term outcomes in addition toreaching the short-term goal of stopping SE. AGABAergic drug may be more effective than anNMDA antagonist in suppressing SE in an early stage,but the NMDA antagonist may have a slight advantagein preventing the development of epilepsy. These twotreatments were clearly superior to PHT. However, ourPHT results should be interpreted with caution withregard to the treatment of SE in humans, as there arelikely differences in the severity of human and experi-mental SE. In developing new drugs for SE, two im-portant considerations emerge: (1) treatment shouldnot only suppress electrographic SE but also have an-tiepileptogenic effects, and (2) drugs that do not havepractical use as antiepileptics may have antiepilepto-genic effects and may still be useful adjuncts in thetreatment of SE. Overall, this study suggests that ag-gressive therapy with appropriate compounds at earlystages of SE is essential.

This work was supported by the National Institutes of Health (NS25605 and NS 16102).

We thank John Cornett and Sherry Spradlin for technical assistance.

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