2017 January-March; 2(1): 43–48. ISSN: 2499-1783
Published online 2018 April 9. doi: 10.11138/ccre/2017.2.1.043.

First clinical experiences with perampanel in adult patients with drug-resistant epilepsy and cognitive impairment

Bianca Orlando,corresponding author Tommaso Martino, Silvia G. Quitadamo, Maria T. Di Claudio, Alessandra Lalla, Carlo Avolio, and Giuseppe d’Orsi

Epilepsy Centre - Clinic of Nervous System Diseases, Riuniti Hospital, Foggia, Italy

corresponding authorCorresponding author.

Corresponding author: Bianca Orlando, Clinic of Nervous System Diseases, Riuniti Hospital of Foggia, Viale Luigi Pinto 1, 71100 Foggia, Italy, E-mail: bianca89orlando@gmail.com

Abstract

The aim of the present study was to evaluate the efficacy and safety of perampanel (PER) in adult patients with drug-resistant epilepsy and cognitive impairment in clinical setting. We retrospectively analyzed treatment response, seizure outcome and adverse effects of PER in thirty-three adult patients (mean age 31.6 years, range 19–55) with drug-resistant epilepsy and cognitive impairment. PER was started with 2 mg/day at bedtime and was up-titrated by 2 mg/day every 2–4 weeks. Evaluation was carried out after 6, 9, 12 and 18 months of PER treatment. Patients were affected by focal epilepsy (of structural, metabolic or unknown etiology) (n=19), Lennox-Gastaut syndrome (n=8), Lafora disease (n=4), generalized genetic epilepsy (n=1), Dravet syndrome (n=1). Retention rate was 93.9% at 3 months, 81.8% at 6 months, 66.7% at 12 months. The mean PER dosage was 6.4 mg (range 2–12) at the end of follow-up. An overall improvement of seizure frequency was obtained in 48.5% of patients after 12 months, with 9 patients (21%) experiencing a greater than 50% seizure reduction. Adverse events were experienced by 51.5% patients, leading to PER discontinuation in 42% of subjects. The most common adverse events were behavioral changes (primarily aggressiveness, 24%) and dizziness (9%). Behavioral changes were not influenced by concomitant use of other drugs, but was observed in 7 out of 11 patients with a history of behavioral problems. PER may achieve clinically improvement for a small minority of patients with adult drug-resistant heterogeneous epilepsies and intellectual disability, although few patients achieved complete seizure control. Monitoring for psychiatric adverse effects is recommended. Further studies in larger cohort with a long-term follow-up are warranting.

Keywords: perampanel, drug-resistant epilepsy, intellectual disability, efficacy, tolerability

Introduction

Perampanel (PER), a novel orally antiepileptic drug (AED), is the main of a new class of focal epilepsy drugs. It is a selective, noncompetitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors on post-synaptic neurons (1). PER is approved in more than 45 countries for adjunctive treatment of partial seizures with or without secondary generalization in patients with epilepsy aged ≥12 years. Three phase III studies demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg, when added to 1 to 3 approved AEDs, improved seizure control in patients with uncontrolled partial-onset seizures (24). It is also indicated as adjunctive therapy for primary generalized tonic-clonic seizures. The most common adverse drug reactions in patients receiving PER were irritability, headache, weight increase, vestibule-cerebellar adverse effects (dizziness, ataxia), sedative effects (somnolence). Of particular concern are psychiatric effects (aggression, hostility, irritability, anger, and homicidal ideation) and cognitive side effects. Preliminary studies demonstrated efficacy of PER in patients affected by epilepsy and cognitive impairment, with seizure reduction achieved in 20 to 53.2% (59).

We present here a single center’s first clinical experience with PER in adults patients with drug-resistant epilepsy and cognitive impairment to evaluate the efficacy and safety of PER.

Material and methods

In this retrospective observational single-center study, patients affected by drug-resistant epilepsy and cognitive impairment, whose therapy with PER was initiated between September 2015 and November 2015 in the Epilepsy Center of the Clinic of Nervous System Diseases of Foggia, Italy, were analyzed. Data were extracted from the institutions’ ongoing paper and electronic records. Evaluation was carried at baseline and after 3, 6, 9, 12, 18 months of PER treatment. Patients were monitored with clinical follow-up, laboratory and neurophysiological (Video-EEG during wakefulness and sleep) assessment. Changes in seizure frequency were measured as the number of seizures on the preceding three months, compared to the baseline seizure frequency. Patients were classified as seizure-free, responders (≥50% reduction in number of seizures) or non-responders (<50% reduction). Adverse events, global clinical impression (7-point scale) and retention rate were analyzed at each visit. Data were expressed as mean ± SD, unless otherwise indicated, and analyzed using R version 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria). Crude differences across groups were evaluated by means of the Pearson’s Chi-squared test and t-test as appropriate.

Results

We enrolled 33 patients, 18 males (mean age 29.56 ± 10.89) and 15 women (mean age 35.53 ± 10.37) affected by drug-resistant epilepsy and cognitive impairment (Tab. 1). Three patients underwent unsuccessful resective surgery, six patients were treated with vagus nervus stimulation without significant response. Brain MRI was normal or documented nonspecific abnormalities in 17 patients, while in the remaining patients it was suggestive for the presence of hypothalamic hamartoma (n=1), malformations of cortical development (n=6), cerebral malformations (n=1), mesial temporal sclerosis (n=2), tuberous Sclerosis (n=1), bilateral occipital calcifications associated with celiac disease (n=1), Sturge-Weber syndrome (n=1), hypoxic-ischemic encephalopathy (n=3).

Table 1Table 1
Demographic and clinical features of the study population.

Initial dose of PER was 2 mg daily at night time sleep, with an increase of 2 mg daily every 4 weeks. The median number of medications taken before PER was 9 (range 3–15), and the median number of concomitant medications was 2 (range 1–4). PER was administered as add-on therapy in patients assuming sodium channel blocker (24 patients, 73%), enzyme-inducing drugs (10 patients, 30%), levetiracetam (8 patients, 24%). The average dosage at the end of follow-up of PER was 6.4 mg ± 2.26 mg (Fig. 1). PER was discontinued after an average of 7.3 months. In detail, it was discontinued at 3 months (n=2), 6 months (n=6), 9 months (n=9), 12 months (n=11) and 18 months (n=12) with a retention rate, respectively, of 93.9, 81.8, 72.7, 66.7, 63.6% (Fig. 2). The number of patients treated was 29/33 (87.9%) at 3 months, 27/33 (81.8%) at 6 months, 23/33 (69.7%) at 9 months, 19/33 (57.6%) at 12 months, 3/33 (9.1%) at 18 months. Seizures free or reduction of seizure frequency ≥50% was obtained in 7/33 patients (21%).

Figure 1Figure 1
PER dosage at the end of follow-up.
Figure 2Figure 2
Patient flow chart from baseline to 18 months of PER treatment.

A 24-year-old woman with Lennox-Gastaut syndrome was seizure free from the third month after introduction of PER at dosage of 2 mg/day until the end of follow-up (18 months); she was taking 1500 mg/day valproic acid, 2000 mg/day rufinamide, 3000 mg/day levetiracetam. The patient was born at 39 weeks of gestation without neonatal asphyxia and developmental milestones were severely delayed. From the age of 4 years, she developed tonic (Fig. 3), clonic, atonic seizures, and atypical absences refractory to multiple anti-epileptic drugs (phenobarbital, valproic acid, clobazam, topiramate, levetiracetam, lamotrigine, rufinamide, carbamazepine). EEGs showed bursts of diffuse slow spike-waves at 2–2.5 cycles/sec. when the patient is awake, and burst of fast rhythmic waves and slow polyspikes and diffuse fast rhythms at about 8–10 cycles/s during sleep.

Figure 3Figure 3
Global clinical impression at the end of follow-up.

A reduction in seizure frequency <50% was observed in 9/33 patients (27%), while in 52% there was no response (Tab. 2). Global Clinical Impression was 2 or greater in 17 patients (Fig. 4). Adverse events (Tab. 3) occurred in 17/33 patients (51.5%), causing treatment discontinuation in 14/17 patients (82%) after an average duration of 7 months. The mean PER dosage at which adverse events were seen was 4 mg. The most common adverse events were: irritability (24%, n=8), seizures worsening (12%, n=4), dizziness (9%, n=3), fatigue (3%, n=1). Behavioral disorders were present in 19 patients (57.6%); after addition of PER, there was a worsening of pre-existing behavioral disorders in 9 out of 19 patients (47%), and their appearance in 3 out of 14 patients (21%) without pre-existing behavioral disorders for dosage of 4 mg or higher.

Table 2Table 2
Number of responder, responder with seizure frequency reduction ≥50% and seizure free patients.
Figure 4Figure 4
Ictal polygraphy of a tonic seizure during sleep in a 24-year-old woman with Lennox-Gastaut syndrome. She was seizures free from the third month after introduction of PER at dosage of 2 mg/day until the end of follow-up (18 months).
Table 3Table 3
Adverse events during treatment with perampanel.

Only two patients out of 33 patients achieved the highest dosage of PER (12 mg/day) within 18 months of follow-up. The first patient was affected by structural (cortical malformations) focal epilepsy with a seizure frequency of 2–3 episodes daily and behavioral disorder (he was taking 3000 mg/day levetiracetam and 400 mg/day lamotrigine; he was also treated with vagus nervus stimulation without significant response). After the introduction of PER, seizure frequency improved to 1–2 episodes monthly (≥50% reduction in number of seizures). The first improvement was achieved after 3 months of treatment with a PER dosage of 4 mg/day, and a further improvement was achieved after 12 months with a PER dosage of 10 mg/day. Despite the therapeutic benefit, it was necessary to withdraw PER after 16 months of treatment for worsening of preexisting behavioral disorder, with restlessness and aggressiveness. The second patient who achieved the PER dosage of 12 mg/day was affected by Lafora disease, with a seizure frequency of 3–4 tonic-clonic seizures weekly; he was also taking 1500 mg/day valproic acid, 100 mg/day phenobarbital, 400 mg/day zonisamide and 30 mg/day clobazam. There was no improvement in the seizure frequency after introduction of PER, despite the full dosage.

Discussion

Previous case reports and case series demonstrated the PER efficacy in seizure control and improvement of neurological dysfunction in Lafora disease (1012) with a reduction in tonic-clonic seizures and myoclonus seen in 4/10 and 7/10 patients respectively (12). Its efficacy was also demonstrated in children and adolescents with Lennox-Gastaut syndrome (13) with a responder rate of 69.2% regarding both generalized tonic-clonic seizures and drop seizures. A patient affected by Dravet syndrome responded to a very low PER dose (2 mg) achieving ≥75% of seizure reduction (14). PER may show efficacy even in Unverricht-Lundborg disease, particularly against myoclonus, but also against generalized tonic-clonic seizures with an efficacy of 50% (15). Finally in patients affected by epilepsy and cognitive impairment seizure reduction was achieved in 20 to 53.2% (59). In our first clinical experiences with PER in adult patients with drug-resistant epilepsy and cognitive impairment, the primary efficacy endpoints was the proportion of patients who were seizure-free at 18 months and the proportion of responders (patients with ≥50% seizure reduction from baseline) at 18 months. Overall some improvement of seizure frequency was obtained in 48% of patients after 12 months of treatment with PER, with reduction in seizure frequency <50 in 27%, while 21% of patients were seizures free or had a reduction of seizure frequency ≥50%. Psychiatric and behavioral changes are well known adverse events of PER (16). It has been reported a frequency of adverse effects in the psychiatric field of 50% in patients with highly drug-resistant epilepsy and cognitive impairment (7), in 40.3% of patients with intellectual disability and epilepsy (6) and in 55% of patients with intellectual disability treated with perampanel (5). In our small cohort we found a similar frequency of behavioral changes (the most common adverse event was aggressiveness), experienced by 21% patients and enhanced in 47% patients with prior psychiatric comorbidity. The concomitant assumption of levetiracetam did not modify the frequency of behavioral disorders (chi-squared, p=0.46). Finally, it was previously observed PER efficacy and safety with concomitant enzyme (CYP3A4)-inducer antiepileptic drugs (17). In our series, we found no significant differences between concomitant use of enzyme-inducing and non-inducing antiepileptic drugs, regarding efficacy, adverse effects and withdrawals.

In conclusion, in our first clinical experiences PER may achieve significant clinical improvement for a minority (21%) of adult patients with drug-resistant epilepsy and cognitive impairment. Monitoring for psychiatric adverse effects, experienced by 21% patients and enhanced in 47% patients with prior psychiatric comorbidity, is recommended. Further studies in larger cohort with a long-term follow-up are warranting.

Footnotes

Conflicts of Interest

We declare that there are no conflicts of interest.

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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