YEBEH-04213; No of Pages 4 Epilepsy & Behavior xxx (2015) xxx–xxx

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Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus Juliane Redecker 1, Matthias Wittstock 2, Reiner Benecke 3, Johannes Rösche ⁎ Klinik und Poliklinik für Neurologie, Universität Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany

a r t i c l e

i n f o

Article history: Received 6 December 2014 Revised 27 January 2015 Accepted 28 January 2015 Available online xxxx Keywords: Nonconvulsive status epilepticus Perampanel Criteria of efficacy

a b s t r a c t We provide some evidence concerning the efficacy of perampanel (PER) in refractory status epilepticus (SE). We retroactively identified patients with SE treated in our department by searching for the term “status epilepticus” in the electronic archive of medical records. We present and analyze in this paper the subset of data of the patients treated with PER. We analyzed ten episodes of SE in nine patients. At the first administration, PER was given in a dosage of 6 mg to most of our patients (7 of 10). On average, PER was administered as the 6th antiepileptic drug (AED) (range: 2–10). Depending on the criterion for efficacy, PER appears effective for the termination of SE in 2 to 6 (of 10) episodes. Unfortunately, safety data for the administration of PER with loading doses needed for the treatment of SE are lacking. Because of this, PER should be used very carefully in refractory SE and only after first-line treatment options have failed. © 2015 Elsevier Inc. All rights reserved.

1. Introduction Status epilepticus (SE) is a common medical condition with an incidence of at least 20/100,000 annually in the Caucasian population [1]. In generalized convulsive status epilepticus (GCSE), guidelines agree that the treatment of refractory GCSE after the administration of a benzodiazepine and one other antiepileptic drug (AED), such as phenytoin or phenobarbital, requires anesthesia [2]. The recommendations for the treatment of nonconvulsive status epilepticus (NCSE) and simple partial motor status epilepticus or epilepsia partialis continua (EPC) are not that straightforward. Especially in EPC, common recommendations state that any drug effective in chronic epilepsy may be tried [3]. In NCSE, with the exception of subtle SE, it is recommended that by failure of the first-line therapy, further nonanesthetizing i.v. substances such as levetiracetam, phenobarbital, or valproic acid should be tried instead of anesthetics [4]. Studies in animals suggest that alpha-amino-3-hydroxy-5-methyl4-isoxazoleproprionic acid (AMPA) receptor-mediated glutamatergic transmission is strengthened during an established SE [5]. In late kainic acid-induced SE, the noncompetitive AMPA receptor antagonist GYKI 52466 was more effective than diazepam [6]. Perampanel was effective

⁎ Corresponding author. Tel.: +49 381 4944768; fax: +49 381 4944794. E-mail addresses: [email protected] (J. Redecker), [email protected] (M. Wittstock), [email protected] (R. Benecke), [email protected] (J. Rösche). 1 Tel.: +49 381 4944769; fax: +49 381 4944794. 2 Tel.: +49 381 4944791; fax: +49 381 4944792. 3 Tel.: +49 381 4949511; fax: +49 381 4949512.

in the termination of diazepam-resistant SE in a lithium–pilocarpine rat model [7] and had synergistic effects with diazepam in this model [8]. These animal studies suggest that an AMPA-receptor antagonist should have a substantial effect in terminating late stages of SE. Therefore, perampanel (PER), a novel noncompetitive AMPAreceptor antagonist [9,10], should be effective in this condition. In this paper, we present the experience with PER in the treatment of NCSE and EPC at the University Hospital of Rostock, which provides some evidence concerning the efficacy of PER in these conditions. In addition to presenting new data, we also address the conceptual issue of how to determine the efficacy of PER and other AEDs in this setting. This is particularly important in this case, as we observed in a previous database analysis of the treatment of status epilepticus at the University Hospital of Rostock over a 10-year time frame, that mostly a combination therapy of two to four drugs was established at the time of SE termination [11]. A review on topiramate (TPM) in SE [12] describes eight different criteria for possible or certain treatment effect of an AED, which were different from the criteria commonly used in randomized controlled prospective trials in SE (e.g., [13]). Gallentine et al. [14] consider a refractory SE responsive to levetiracetam (LEV) if seizure activity ceased within three days of initiation or dose increase of LEV. Albers et al. [15] considered a SE responsive to lacosamide (LCM) if EEG status resolved within 24 h after start of LCM-i.v. and no further AEDs were added to the treatment protocol during this time period. Hottinger et al. [16] rated the effect of TPM as successful if clinical improvement and electroencephalographical resolution of refractory SE occurred within 24 h after starting treatment with TPM and no further AEDs were required. The effect of TPM was rated as “probably successful”, if

http://dx.doi.org/10.1016/j.yebeh.2015.01.036 1525-5050/© 2015 Elsevier Inc. All rights reserved.

Please cite this article as: Redecker J, et al, Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.01.036

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J. Redecker et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

improvement occurred within 72 h after starting treatment with TPM. In the database analysis mentioned above [11], we defined the last AED administered before SE cessation as the termination drug, regardless of the latency between its first administration and SE cessation. These different approaches show that the scientific community has not yet found a global means to state when and if an AED is successful in ceasing a SE. Therefore, the aim of this study was not only to present our experiences with the use of PER in refractory SE but also to give an impression on how different criteria for the identification of an AED with a possible or certain treatment effect have an influence on the results of retrospective case series. 2. Methods We present a data subset from a large retrospective study. Specifically, we evaluate every status epilepticus treatment at the neurological department of the University of Rostock from January 2010 to June 2013. This study was approved by the local ethics board at University of Rostock under the identifier A-2013-0099. We identify the patients treated by searching the electronic medical records of our clinic for the term “status epilepticus”. We then manually review the medical files of these patients to determine at which time a certain AED was administered, which AED was effective to terminate the epileptic condition, and the time of termination. We classify an antiepileptic drug as effective for the termination of SE using the four different criteria described below. After collecting all the data, we compare and contrast the results of the different efficacy criteria. We chose the four criteria below, as we had found in a previous study [12] that these were the most commonly used criteria in other cases. Comparing the results of the different criteria allows us to study which criterion is a diagnostically conclusive method of determining the AED that actually leads to the cessation of the SE. At least, we will be able to give some advice on how to compare studies using different criteria in reviews concerning treatment effects in SE. As we evaluate every case with all four of these criteria, we show that even with a small number of cases, as in this paper, the criterion by which we decide the AED to be effective or not makes a big difference. The four criteria by which we examine these cases are as follows: 1. the last AED administered before SE termination is defined as effective, regardless of the latency between its first administration and SE cessation; 2. the AED that was the last drug introduced into the antiepileptic therapy within 72 h before the cessation of the SE and without changes in the comedication; 3. the AED that was the last drug introduced into the antiepileptic therapy or increased in dose within 24 h before termination of the SE and without changes in the comedication; 4. the AED that was the last drug introduced into the antiepileptic therapy within 72 h before the cessation of the SE even allowing changes in the comedication. The termination of SE is always defined as the end of convulsion in EPC and the return to baseline of consciousness or the resolution of previously documented electroencephalographic seizure activity in NCSE. Resolution of seizure activity was diagnosed when spikes, sharp waves, or rhythmic waveform showed a frequency below 1 Hz without significant evolution in field, morphology, and frequency [17]. We determine the origin of the SE using different diagnostics, such as the clinical status of the patient, CT, MRI, and, most importantly, EEG. As comedication of the terminating drug, we listed all AEDs given during the 24 h before termination of SE. All subgroups of NCSE were classified according to the system of Shorvon [18]. The end of a generalized tonic–clonic seizure was assumed when convulsions stopped and stertorous breathing started. Episodes in which nonconvulsive seizure activity persisted were classified as NCSE in the postictal phase of

tonic–clonic seizures according to the system of Shorvon [18]. Here, we present the subset of data concerning the patients treated with PER. The first episode of this series was published separately as a case report [19]. 3. Results Ten episodes of SE in nine patients (five female, four male) were treated with PER. Of these cases, there were two cases of EPC (remote symptomatic after stroke) and eight cases of NCSE. Four cases were with new-onset epilepsy. The age of the patients was 73.3 years on average, with a standard deviation of 9.7 years. As PER is not licensed for first-line treatment of SE in Germany, in the University Hospital of Rostock, it has only been given to patients with complicated cases of refractory NCSE or EPC, where first-line treatment has failed. Because of this, the patients in this case study have a higher rate of infirmity and seniority than those in other studies concerning the treatment of SE. For details of etiology and outcome, see Table 1. It has to be acknowledged that the patients in treatment episodes one and three were in a bad condition even prior to the SE. Since a return to baseline cannot be counted as a positive outcome in every case, patients in treatment episodes six and eight had the best outcome. Perampanel was never used as the first AED (the median number of administration being six, with a range of two to ten) and more than 9 h after the onset of the clinical symptoms (median: 137.7 h, range: 9.25–427 h). In the first administration, PER was given in dosage of 6 mg in most of the cases (7 of 10). For details of PER administration, see Table 2. Perampanel was the terminating drug in two cases according to criterion 1, in three cases according to criterion 2, in four cases according to criterion 3, and in six cases according to criterion 4. Treatment episodes five and nine were the only ones in which PER was not a termination drug according to any of our criteria. Since most of our patients were in a state of impaired consciousness, minor neurotoxic adverse events cannot be ruled out, but there were no toxic effects on liver function, renal function, or blood cells. One patient died because of pneumonia. In this patient, PER was not effective, but NCSE was previously terminated with other AEDs. In all other patients, PER was still a part of the medication at the termination of the SE even when not considered as the termination drug to any of our criteria as in treatment episode nine. Taking all AEDs administered in the last 24 h before SE termination into account, a combination therapy of three to five compounds was found in all cases at the time of SE termination (median: four). For details of medication at cessation of SE, see Table 2. 4. Discussion Depending on the different efficacy criteria, PER was the termination drug of NCSE or EPC in 2 to 6 of the 10 episodes in our group of patients. There is a bias in favor of PER, as we only included episodes in which PER was administered and because it is only such a small case study. Of course, the percentage in which PER is the terminating drug differs from one criterion to another. We believe that in this subdivision, criterion 3 is the criterion that holds the most substantiality of the four. Criterion 1 seems to be questionable because an AED, which has been administered several times for days or even weeks, may be identified as the termination drug after many ineffective administrations. Criterion 4 is questionable because an increase in the dosage of other AEDs may be more effective than the mere presence of an additional AED in the last three days before a termination of a SE. Therefore, we think the choice has to be made between criterion 2 and 3. According to these criteria, PER was effective in three or four episodes out of ten. Concerning a drug with pharmacokinetics as PER, further considerations should be taken into account. After oral administration, peak plasma concentrations of PER have been observed within 15 min to 2 h after application [10]. Perampanel distributes into the body tissue, and the remaining

Please cite this article as: Redecker J, et al, Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.01.036

J. Redecker et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

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Table 1 Patients clinical characteristics. Episode

Patient age & gender

Classification of status

Etiology

Outcome

1

81 F 73 F 73 F 59 F 83 F 70 M 77 M 57 M 78 M 82 F

EPC

Remote symptomatic after stroke

Return to baseline

NCSE L

Temporal lobe epilepsy with hippocampal sclerosis

NCSE L

Temporal lobe epilepsy with hippocampal sclerosis

Bedridden, respiration via tracheostomy, artificially fed via parenteral gastric tube Return to baseline after episode two

NCSE PI

Symptomatic epilepsy due to multiple sclerosis

NCSE NL

Remote symptomatic after stroke

NCSE PI

Remote symptomatic after several strokes

Respiration via tracheostomy, artificially fed via parenteral gastric tube Death due to cardiopulmonal decompensation in the course of bronchopneumonia Return to baseline

NCSE NL

Dementia

Disorientation, abnormal behavior

NCSE NL

Cryptogenic epilepsy

Return to baseline

NCSE L

Subcortical arteriosclerotic encephalopathy

Aphasia, bedridden

EPC

Vascular dementia

Single myoclonic seizures in the right arm and the right corner of the mouth

2 3 4 5 6 7 8 9 10

EPC = epilepsia partialis continua, NCSE L = limbic complex partial status epilepticus [18], NCSE NL = nonlimbic complex partial status epilepticus [18], NCSE PI = nonconvulsive status epilepticus in the postictal phase of tonic–clonic seizures [18].

plasma fraction has a terminal half-life of about 105 h. Peak plasma concentrations, as well as trough plasma levels, increase for about 14 days if the initial daily dose is maintained. Because of these effects, if 6-mg PER is administered for the first time in a normal weight patient, there will probably only be a time frame of a few hours in which the plasma concentration is on a therapeutic level. But with repetitive administrations, the plasma concentration will increase considerably. Therefore, the effectiveness of PER to terminate a SE should increase from day to day, and it may have a considerable part in the termination of a refractory SE even more than 72 h after the first administration. To increase the effectiveness of PER to terminate a refractory SE in a shorter period of time, it might be useful to start with loading doses higher than 6 mg or dose intervals shorter than 24 h. Unfortunately, safety data for such dose regimens are lacking. Because of this lacking data, PER should be used very carefully in refractory SE and only after first-line treatment options have failed.

5. Conclusion Depending on the different efficacy criteria, PER was the termination drug of NCSE or EPC in 2 to 6 of the 10 episodes in our group of patients. To increase the effectiveness of PER to terminate a refractory SE, it might be useful to start with loading doses higher than 6 mg or dose intervals shorter than 24 h. Unfortunately, safety data for such dose regimens are lacking. Because of these lacking data, PER should be used very carefully in refractory SE and only after first-line treatment options have failed.

Conflicts of interest Dr. Rösche received speaker's honoraria from Eisai and UCB, served as medical advisor for Eisai, received a travel grant from Eisai, and received financial support for an investigator-initiated trial from Pfizer. The other authors declare that they have nothing to disclose.

Table 2 Details of perampanel (PER) medication and medication at cessation of status epilepticus (SE). Episode

1

Place of PER in the succession of AEDs administered 7

2

10

3

4

4

10

5

Time in hours from onset of symptoms to first PER administration 12.5 210.5

Dosage of first PER administration in mg 2

Time in hours from first PER administration to SE cessation 24.5

Comedication of PER at first dosage

Medication in the last 24 h before cessation of SE

LEV 2250 mg, LCM 100 mg, VPA 1800

PER 4 mg, LEV 3000 mg, LCM 200 mg, VPA 1800 mg, CLN 1 mg

mg, CLN 3 mg, LZP 1.5 mg, AZM 500 mg LCM 400 mg, VPA 1633 mg, MDM 120 mg

6

1

2

47

427

6

57

3

408

6

391

6

5

119.1

6

27

LEV 2000 mg, LZP 2 mg, PHT 187.5 mg

7 8

3 9

80.66 83

6 6

24 12

LZP 1.5 mg, PRM 250 mg VPA 1800 mg, PHT 300 mg, PB 100 mg

9 10

2 7

180.66 156.25

6 4

97 12

LEV 2000 mg CLN 0.5 mg, LEV 1500 mg, VPA 800 mg, LCM 200 mg

9.25

MDM 4 mg, VPA 450 mg, LCM 450 mg, (PER 6 mg) LEV 2000 mg, LCM 200 mg, MDM 26 mg VPA 2400 mg, LEV 1500 mg

PER 6 mg, LCM 500 mg, VPA 1633 mg, MDM 120 mg PER 8 mg, VPA 900 mg, MDM 120 mg, LCM 500 mg PER 12 mg, LEV 2000 mg, LCM 200 mg, MDM 26 mg LEV 2000 mg, VPA 2000 mg, CLN 0.5 mg, LCM 400 mg PER 12 mg, LEV 2000 mg, LZP 2 mg, PHT 187.5 mg PER 6 mg, LZP 1.5 mg, PRM 500 mg PER 12 mg, VPA 1800 mg, PHT 300 mg, PB 100 mg VPA 1600 mg, LEV 3000 mg, PER 8 mg PER 4 mg, LEV 1000 mg, LCM 100 mg, VPA 100 mg

AZM = acetazolamide, CLN = clonazepam, LEV = levetiracetam, LCM = lacosamide, LZP = lorazepam, MDM = midazolam, PB = phenobarbitone, PER = perampanel, PHT = phenytoin, PRM = primidone, VPA = valproate.

Please cite this article as: Redecker J, et al, Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.01.036

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J. Redecker et al. / Epilepsy & Behavior xxx (2015) xxx–xxx

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[10] Steinhoff BJ. Das neue Antiepileptikum perampanel. Psychopharmakotherapie 2012; 19:202–8. [11] Rantsch K, Walter U, Wittstock M, Benecke R, Rösche R. Treatment and course of different subtypes of status epilepticus. Epilepsy Res 2013;107:156–62. [12] Rösche J, Pohley I, Kampf C, Benecke R. Topiramat in der Behandlung des Status epilepticus. Nervenheilkunde 2013;32:225–9. [13] Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 1998;339:792–8. [14] Gallentine WB, Hunnicutt AS, Husain AM. Levetiracetam in children with refractory status epilepticus. Epilepsy Behav 2009;14:215–8. [15] Albers JM, Möddel G, Dittrich R, Steidl C, Suntrup S, Ringelstein EB, et al. Intravenous lacosamide — an effective add-on treatment of refractory status epilepticus. Seizure 2011;20:428–30. [16] Hottinger A, Sutter R, Marsch St, Rüegg St. Topiramate as an adjunctive treatment in patients with refractory status epilepticus. CNS Drugs 2012;26:761–72. [17] Herman ST. The electroencephalogram of nonconvulsive status epilepticus. In: Kaplan PW, Drislane FW, editors. Nonconvulsive status epilepticus. New York: Demos Medical Publishing; 2009. p. 41–61. [18] Shorvon S. What is nonconvulsive status epilepticus, and what are its subtypes? Epilepsia 2007;48(Suppl. 8):35–8. [19] Rösche J, Kampf Ch, Benecke R. Possible effect of perampanel on focal status epilepticus after generalized tonic–clonic status epilepticus. Acta Neurol Belg 2014;114:243–4.

Please cite this article as: Redecker J, et al, Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus, Epilepsy Behav (2015), http://dx.doi.org/10.1016/j.yebeh.2015.01.036

Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus.

We provide some evidence concerning the efficacy of perampanel (PER) in refractory status epilepticus (SE). We retroactively identified patients with ...
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