Add-on perampanel and aggressive behaviour in severe drug-resistant focal epilepsies

Summary

This study aimed to investigate the incidence of aggressiveness in patients with severe drug-refractory focal epilepsy (DRE) who started perampanel (PER) as add-on treatment, and to identify possible predisposing factors.

Data on 49 consecutive patients with severe DRE who initiated PER were retrospectively collected. Twelve of the 49 patients experienced aggressiveness as adverse event related to PER treatment, one third of them on low (2–4 mg/day) PER dosages. PER was discontinued in 10/12 patients because of aggressive behaviors. Aggressiveness could appear after several months or even more than one year of PER treatment. One third of patients with PER-related aggressiveness had intellectual disabilities and 5/12 patients took levetiracetam as a concomitant antiepileptic drug.

Our study suggests that the occurrence of aggressive behaviors in patients with severe DRE is not uncommon during PER treatment and that it may occur after months or even years of treatment with a stable dosage, requiring PER discontinuation in the great majority of patients.

Introduction

Perampanel (PER) is a selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist that is employed as an adjunctive therapy for focal seizures with or without secondarily generalized seizures in patients with epilepsy aged >12 years. The efficacy and tolerability of PER have been assessed in a clinical trial program, which included three randomized, double-blind, placebo-controlled phase III studies in patients suffering from drug-resistant focal seizures (Krauss et al., 2012; French et al., 2012, 2013) and one extension study (Krauss et al., 2014). PER carries a warning about the risk of serious neuropsychiatric adverse events (AEs), including irritability, aggression and anger (European Medicines Agency, 2017; Food and Drug Administration, 2017). Indeed, an analysis of pooled safety data from these three phase III studies suggests that psychiatric AEs are associated with use of PER (Ettinger et al., 2015). In addition, several real-life observational studies have found behavioral disturbances to be a major side effect both in adulthood and pediatric age (Coyle et al., 2014; Biró et al., 2015; Juhl and Rubboli, 2016) reporting higher rates of occurrence than those found in pre-marketing clinical trials. These findings have been challenged by a recent controlled study in adolescents which showed that PER was not associated with clinically relevant behavioral adverse events, but concluded that more data are needed to determine whether PER can be specifically associated with aggressive behavior (Lagae et al., 2016).

In this real-life observational study we retrospectively reviewed our series of patients who started PER as an add-on treatment. Our aims were to investigate the incidence of aggressiveness after PER introduction and possibly to identify any predisposing factors.

Materials and methods

All consecutive patients with severe drug-refractory focal epilepsy (DRE) who started PER as add-on treatment from November 2012 to December 2015 were retrospectively analyzed. The series includes 22 previously reported patients (Juhl and Rubboli, 2016). Epilepsy type was determined by clinical history and by EEG/video-EEG investigations. Seizures were classified as simple partial, complex partial, or secondarily generalized tonic-clonic. Seizure frequency ranged from daily to monthly. The etiology was: mesial temporal sclerosis (7 patients), brain tumor (6), neonatal infarction (4), cortical dysplasia (4), heterotopia (2), stroke (2), meningitis (2), herpes encephalitis (1), meningioma (1), cavernous angioma (1), intrauterine cytomegalovirus infection (1), head trauma (1), unknown (17). Eleven patients had intellectual disabilities (IDs) of varying severity. The mean PER daily dose was 6.6 mg (range: 2–12 mg). PER was initiated at a dose of 2 mg once daily at bedtime and it was uptitrated by 2 mg per week or 2 mg every four weeks, according to medical needs, concomitant medications and the occurrence of side effects. Clinical assessment after PER introduction was performed during outpatient clinical consultations (usually every 3–6 months) and reported in the medical records. Information on worsening of AEs, including neuropsychiatric AEs, after PER initiation was retrieved by reviewing the medical charts and, in most of the cases, by contacting the patients and their relatives. The appearance or worsening of aggressive behavior was defined as the appearance or worsening of verbal or behavioral aggressive manifestations, including physical aggression, as reported by the patient or his/her relatives. In particular, hostile, injurious, angry reactions towards others (including screaming and arguing) were considered to constitute verbal aggression. The patients and their relatives were asked specifically about behaviors (most of the time the relatives reported them spontaneously without being asked) and whether they were first noticed or became more pronounced after PER initiation. Causes of PER discontinuation were specified in the medical records. In the group of patients who presented aggressiveness, we assessed effectiveness by comparing the overall frequency of all seizure types between baseline (the four weeks before PER initiation) and the last three months, as reported at the last outpatient clinic consultation. The minimum follow-up after PER initiation, to assess effectiveness, was six months. Responders were defined as those patients whose seizure frequency was reduced by at least 50%. Aggravation of seizures was defined as an at least 50% increase in seizure frequency.

Results

Forty-nine consecutive patients started PER as an add-on treatment in the period from November 2012 to December 2015. Twelve (M/F=4/8) of the 49 patients experienced aggressiveness as a PER treatment-related AE. Clinical data of the patients are shown in Table I. Their mean age was 44 years (range 25–67 years) and their mean age at epilepsy onset was 12.8 years (range: birth-43 years). The mean duration of epilepsy was 31.3 years; range: 5–57 years. In 11 of the 12 patients the seizure frequency at the baseline varied from daily seizures to 17 seizures per month; only one patient (#8) had monthly seizures. The mean number of antiepileptic drugs (AEDs) per patient at initiation of PER was three (range 1–4); 3 patients also had vagal nerve stimulation. In 5 patients, one concomitant AED was withdrawn during PER treatment (Table I). The mean daily dose of PER was 6 mg (range: 2–8 mg). The titration rate was 2 mg/2 weeks in 2 patients and 2 mg/4 weeks in 9 patients (1 patient took only 2 mg/day as maximum dosage before withdrawal). Four of the 12 patients had IDs. Psychiatric comorbidity was observed in patient #1 (depression) and in patient #4 (obsessive-compulsive disorder and anxiety). No previous history of psychiatric or behavioral disturbances was reported in the other patients.

Table I.

Patient characteristics.

Pts	Pt 1	Pt 2	Pt 3	Pt 4	Pt 5	Pt.6	Pt.7	Pt 8	Pt 9	Pt 10	Pt 11	Pt 12
Gender, age (years)	F, 50	F, 32	M, 32	F, 59	F, 49	F, 43	M, 67	F, 51	F, 48	M, 25	F, 30	M, 42
Age at epilepsy onset (years)	14	1	1	2	9	25	27	20	43	6 months	Since birth	12
Etiology	Unknown	Unknown	Unknown	Left MTS	Unknown	Cortical dysplasia	Brain tumor (glioma)	Cavernous angioma	Unknown	CMV infection	stroke	Unknown
Intellectual disabilities	No	Yes	Yes	No	No	No	No	No	No	Yes	Yes	No
Psychiatric comorbidity	Depression	No	No	Anxiety, obsessive-compulsive disorder	No	No	No	No	No	No	No	No
Seizure types	CPSs	CPSs, sGTCSs	CPSs, sGTCSs	CPSs	CPSs	CPSs	CPSs, sGTCSs	SPSs, sGTCs	SPSs, sGTCs	sGTCs	SPSs, sGTCs	CPSs, sGTCs
Seizure frequency before PER	8–11/mth	5–8/mth	11–17/month	4/month	Daily/weekly seizures	5–8/month	2–3/month	1/month	2–3/month	4/month	1–3/month	Daily/weekly seizures
Concomitant AEDs Maximum	LEV, LTG, PRG, CLB	TPM, SLT, VPA (+VNS)	TPM, VPA, SLT, CLB	LEV, CNZ, CBZ	LTG, LCM, CLB, RTG (+VNS)	LTG, RTG, CLB (+VNS)	LCM, VPA, CLB (+VNS)	LEV, ZNS	LTG	LEV, VPA	VPA, LEV, LCM, TPM	CBZ, CLB, LCM
PER dosage/day	6 mg	2 mg	8 mg	4 mg	8 mg	8 mg	4 mg	4 mg	8 mg	8 mg	6 mg	6 mg
Duration of PER treatment	28 months (ongoing)	2 months	12 months	7 months	26 months (ongoing)	6 months	5 months	24 months	18 months	32 months	10 months	7 months
Concomitant treatment changes during PER treatment	None	None	None	None	Withdrawal of RTG	Withdrawal of RTG	Withdrawal of VPA	Withdrawal of ZNS	None	None	Withdrawal of LCM	None
Seizure frequency during PER treatment	<50% reduction (seizures were milder)	Unchanged	>50% reduction	>50% reduction	<50% reduction (seizures were milder)	Unchanged	Unchanged	Seizure freedom	Unchanged (seizures were milder)	>50% reduction	Unchanged	Unchanged
Side effects	Aggressiveness, “bad” mood tiredness, dizziness, concentration difficulties	Aggressiveness, mood swings, tiredness	Aggressiveness, tiredness	Aggressiveness, “bad” mood, difficulty in finding words	Aggressiveness, mood swings	Aggressiveness, “bad” mood	Aggressiveness	Aggressiveness, “bad mood” concentration difficulties, tiredness	Aggressiveness “bad” mood, concentration difficulties	Aggressiveness	Aggressiveness, irascibility, tiredness	Aggressiveness, headache, tiredness, double vision
Management of aggressiveness	Reduction of PER dosage (to 4 mg/day)	PER withdrawal	PER withdrawal	PER withdrawal	Reduction of PER dosage (to 4 mg/day)	PER withdrawal	PER withdrawal	PER withdrawal	PER reduction then withdrawal	PER reduction then withdrawal	PER withdrawal	PER withdrawal

Abbreviations: F=female; M=male; MTS=mesial temporal sclerosis; CMV= cytomegalovirus; CPSs=complex partial seizures; SPSs=simple partial seizures; sGTCs=secondarily generalized tonic-clonic seizures; LEV=levetiracetam; LTG=lamotrigine; PRG=pregabalin; CLB=clobazam; SLT=sulthiame; TPM=topiramate; VPA=valproic acid; CNZ=clonazepam; CBZ=carbamazepine; LCM=lacosamide; RTG=retigabine; ZNS=zonisamide; PER=perampanel; VNS=vagal nerve stimulator

Aggressiveness referred to a spectrum of manifestations that could range from angry, violent, hostile verbal reactions to overt physical aggressiveness (one patient repeatedly hit his parents for trivial reasons). All the patients and their relatives reported the appearance of these behaviors after the introduction or up-titration of PER. Other behavioral or psychiatric AEs were a “bad” mood (5 patients), mood swings (two patients), and irascibility (1 patient). In 10 patients (10/12 of the subgroup of patients with aggressiveness, 10/49 of the whole analyzed cohort), the aggressive manifestations were considered intolerable either by the patient or by his/her family and led to discontinuation of PER, even in subjects showing a remarkable reduction of seizure frequency. In fact, one third of patients achieved a >50% seizure reduction, including 1 patient (#8) who became seizure free. Four of the 12 aggressive patients exhibited aggressiveness at low PER dosages (2 mg in one, 4 mg in three). PER tapering was performed, reducing the dosage by 2 mg every one-three weeks. After PER withdrawal, behavior greatly improved or normalized in all the patients, as reported by the patients themselves and their relatives. In 2 patients (#1 and #5) aggressiveness improved by reducing the dosage by 2 and 4 mg, respectively, therefore PER was not discontinued. These 2 patients have now been taking PER for 28 and 26 months respectively; in both, the seizure reduction is <50%, but seizures are reported as milder.

The duration of PER treatment ranged from 2 to 32 months (mean: 14.7 months). Interestingly, appearance of aggressive behaviors could occur after several months of stable and well tolerated PER treatment. In fact, 4 out of 10 patients (#3, #8, #9, #10) had taken the drug for at least 12 months. Patient #8 had achieved seizure freedom with a low dose (4 mg) of PER; she developed aggressive behaviors about 20 months after PER initiation, which led to PER discontinuation after 24 months of treatment. On the contrary, in 2 patients (#2 and #7), intolerable aggressiveness appeared shortly after PER initiation, resulting in PER discontinuation after two and five months of treatment, respectively.

The AEDs most frequently associated with PER were: clobazam in 6/12 patients, levetiracetam in 5/12, valproic acid in 5/12, lacosamide in 4/12, and topiramate in 3/12, in various combinations.

Discussion

The most common AEs of PER reported in pre-marketing clinical trials were dizziness, somnolence and headache (Steinhoff et al., 2013). Psychiatric AEs were described in only a small proportion of patients, and the rate of occurrence increased at higher PER dosages. In particular aggression was reported in only 3.1% of patients on PER 12 mg/day as compared to 0.5% of patients taking placebo (Steinhoff et al., 2013). With regard to adolescent patients, further analysis of the phase III PER studies and a recent randomized study have shown that aggressive behavior occurred in about 8% of cases (Rosenfeld et al., 2015).

Our observational study in a cohort of patients with severe DRE revealed PER-related aggressiveness in about a quarter (12/49) of patients, a higher incidence than those reported in pre-marketing studies. Our findings are similar to those published by Coyle et al. (2014) in adults, and by Biró et al. (2015) in children and adolescents, who reported psychiatric AEs, including mood swings, irritability and aggression, in 25 and 24% of patients, respectively. On the other hand, the present findings are discordant with other real-life observational studies which reported the appearance of irritability and aggression in only about 2% of patients (Steinhoff et al., 2014). This discrepancy might depend on the characteristics of our study group, which was a highly selected cohort of patients with severe DRE, and on our longer observation period after PER initiation, which allowed us to detect the appearance of aggressiveness after several months or even after more than one year of stable PER treatment, at variance with previous preclinical and observational studies that included more heterogeneous groups of epilepsy patients and had shorter follow-ups. The interpretation that longer follow-ups might be associated with an increased rate of aggressive behaviors is further supported by the observation that in adolescents who continued PER in the extension study, aggression occurred in up to 18% of patients (Rosenfeld et al., 2015).

In our study we could not confirm that the occurrence of aggressive behavior was related to high PER dosages, as suggested by pre-marketing clinical trials; indeed the maximum dosage of PER was 2–4 mg/day in 4 of our patients and 6 mg/day in a further three. Other observational studies also failed to detect a correlation between occurrence of side effects and PER dosage (Steinhoff et al., 2014; Coyle et al., 2014). In addition, we did not find any correlation between occurrence of aggressiveness and titration rate, since in most of our patients, PER was increased at the slowest rate of 2 mg every four weeks. Our results further document the effectiveness of PER in reducing seizure frequency in patients with severe DRE, since a seizure reduction >50% at six months of follow-up was observed in one third of the patients (including one seizure-free patient), and two additional patients reported a reduction of seizure frequency (albeit < 50%) and seizure intensity. However, in spite of the seizure improvement, the intensity of the aggressive manifestations, in particular when associated with mood changes, were considered, by 10/12 patients and their relatives, sufficiently intolerable and worrisome to warrant PER discontinuation. PER withdrawal was followed by resolution of or a remarkable decrease in aggressiveness. In the remaining patients, reduction of the PER dosage was effective in improving the aggressive behavior, and allowed the PER treatment to be continued.

More than one third of the patients in our series affected by ID developed PER-related aggressive behavior, which required discontinuation of the treatment in all of them. This finding is in agreement with the findings of recent studies by Snoeijen-Schouwenaars et al. (2017) and Huber and Schmid (2017) in patients with epilepsy and IDs who reported behavioral AEs, including, aggression, irritability mood changes, in about 40 and 50% of subjects, respectively. These observations should alert us to the possibility that PER may be not tolerated in a non-negligible proportion of epilepsy patients with IDs. On the contrary, psychiatric comorbidity was observed only in 2 of our patients with PER-related aggressiveness, suggesting that it may not play a role in the development of behavioral AEs.

With regard to the possibility that aggressiveness could result from the combination of PER with other drugs, the limited number and the heterogeneity of the polytherapies in our cohort prevent us from drawing clear-cut conclusions. In previous studies (Glauser et al., 2016; Snoijen-Schouwenaars et al., 2017), polypharmacy did not predict an increased probability of occurrence of side effects, including psychiatric AEs. In our study, 5/12 patients who developed aggressiveness took levetiracetam, a drug which has been reported to be associated with aggressive behavior (Dinkelacher et al., 2003; Wieshmann and Baker, 2013). In addition, pharmacodynamic interactions between levetiracetam and PER have been suggested (Patsalos et al., 2015). Therefore, we cannot exclude that the combination of these two drugs may reduce the tolerability of PER, increasing the risks of behavioral and psychiatric AEs. Finally, the possibility that in our patients the occurrence of aggressiveness might be related to modifications of treatments with concomitant AEDs seems unlikely since only a minority of patients changed their AED regimen (withdrawing one drug) during PER treatment.

Previous studies have shown that some patients may develop psychiatric AEs during treatment with different drugs with distinct mechanisms of action, suggesting that these patients might be prone to develop psychiatric AEs when taking any AED (Mula et al., 2007). However, this possibility does not seem to apply to our patients since only 2 of them had a psychiatric comorbidity and none of the others had ever reported psychiatric disorders during previous AED regimens. In addition, they returned to their baseline behavior as soon as PER was reduced or interrupted.

We are aware that the retrospective design of our study inevitably means that we may have missed or misinterpreted some data, or neglected some confounding factors. However, the data collection was based not only on retrieval of information from medical charts, but also on questioning, specifically for this study, of the majority of the patients and their relatives about the occurrence and type of aggressive manifestations, and their relationships with the initiation of PER. In addition, we acknowledge that the size of our cohort is limited and that it is composed of a highly selected group of patients with severe DRE referred to a tertiary center, and this has to be taken into consideration before extending our findings to the general population of patients with epilepsy.

In conclusion, our study suggests that in patients with severe DRE the occurrence of aggressive behaviors may be not uncommon during PER treatment, and that these may appear after months or even years of stable dosage, requiring PER discontinuation in the great majority of patients, even in the presence of a remarkable reduction in seizure frequency. In addition, coexistence of IDs and association of PER with levetiracetam might increase the probability of developing aggressiveness, however, further studies are warranted to confirm these latter findings. Finally, our data indicate that patients and their relatives should be counselled on the risk of psychiatric AEs, including aggressiveness, when PER is initiated.