Highlights
- •Open-label, uncontrolled retrospective study of adjunctive perampanel.
- •Adult patients with Lennox-Gastaut syndrome or Lennox-Gastaut-like encephalopathy.
- •Seventy-one adults received perampanel by 2 mg steps at 2- to 4-week intervals until 6 mg/day.
- •About 2/3 of the patients were responders.
- •Its use may be limited in some patients with mostly behavioral side-effects.
Abstract
Purpose
Perampanel (PER) was added to the anticonvulsant regimen of 71 patients with Lennox-Gastaut Syndrome (LGS) to evaluate its efficacy against seizures and its tolerability.
Method
We evaluated at 3-month intervals 62 with pure LGS and 9 with LGS-like epileptic encephalopathy (28 females, 43 males, mean age 40.1 ± 11.5 yrs, median 38, range 20–71) in whom PER was introduced by 2 mg steps at 2- to 4-week intervals up to 6 mg/day, with possible dose reduction or increases after that. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed.
Results
Mean PER exposure was 538.9 days ± 425 (median 429), with 44 patients (62 %) on PER at last follow-up. About 2/3 of patients were responders, including 35.2 % that had a ≥75 % decrease in their seizures. Among these 16.9 % had a ≥90 % decrease. No improvement was seen in 14 patients; 5 had a less than 50 % response, and 6 had seizure aggravation. Therefore, 25 (35.2 %) were considered non-responders. Half of the patients developed at least one side-effect. Significant negative changes in behavior were noted in 1/3 of the cases, including irritability (8.5 %) and aggressivity (7 %). Contrastingly, 4 patients reported positive behavioral and psychological well-being side-effects.
Conclusions
This retrospective, open-label study provides evidence that PER may significantly help in LGS. PER should be tried in LGS patients who are not satisfactorily controlled. Its use may be limited in some patients due to behavioral side-effects occurring, particularly at doses ≥ 6 mg/d.
Keywords
1. Introduction
The Lennox-Gastaut syndrome (LGS) is a recognizable form of epileptic encephalopathy characterized by multiple etiologies, multiple seizure types, cognitive deterioration, extensive electroencephalographic (EEG) changes awake and asleep, and resistance to antiepileptic drug (AED) treatment [
1
, 2
, 3
]. The long-term evolution of LGS is characterized by the possible abatement of EEG changes, especially awake, and by the persistence of invalidating seizures [[4]
]. Traditional pharmacological options include valproate (VPA) and a combination of VPA and lamotrigine (LTG) [[2]
]. There are multiple other options including clobazam (CLB) [[2]
], levetiracetam (LEV) [[5]
], cannabidiol [[6]
,[7]
], orphan drugs like felbamate (FBM) [[8]
] rufinamide (RUF) [[9]
,[10]
], vagal nerve stimulation (VNS) [[2]
], transcranial stimulation [[11]
], the ketogenic or modified Atkins diets [[12]
,[13]
], resective or palliative surgery in selected cases [[14]
] and deep brain stimulation [[15]
]. In short, the large number of therapeutic proposals only underlines the extreme resistance of LGS to therapy. In the words of Hancock and Cross, “the optimum treatment for LGS remains uncertain and no study to date has shown any one drug to be highly efficacious” [[16]
].Perampanel (PER) is a novel AED that selectively inhibits postsynaptic AMPA receptors, and its efficacy has been demonstrated in drug-resistant focal epilepsies, more recently in primary generalized tonic-clonic seizures [
[17]
]. There is little evidence of the possible efficacy of PER in specific conditions with epilepsy, as in Lafora disease [[18]
,[19]
] or Unverricht-Lundborg disease [[20]
]. There were some preliminary reports on the potential efficacy of PER in LGS [[21]
,[22]
], including a recent report of a short series of 13 children and adolescents [[23]
]. Therefore, we decided to retrospectively evaluate the effect of add-on PER in patients with LGS who had persisting severe, and disabling seizures. A large number of adult patients were found. Although the use of PER is off-label in LGS, we felt that it was our responsibility to try this promising agent in patients who were poorly controlled.2. Patients and methods
Among 150 patients with a diagnosis of LGS or LGS-like epileptic encephalopathy that had been seen for many years in our clinics (Montpellier and Marseille), 71 with persisting invalidating seizures received add-on PER since May 2014, when PER was first marketed in France, to May 2018. We considered that seizures were invalidating whenever they significantly impaired the patients’ autonomy and quality of life, as reported by the patients or their caregivers, and confirmed during clinical and EEG monitoring. All had been submitted to an extensive video-EEG evaluation and diagnostic procedures, including magnetic resonance imaging (MRI) or a computed tomography (CT) scan in older patients, who were reluctant to undergo MRI with general anesthesia. The diagnosis of LGS is based on commonly accepted criteria: (i) multiple seizure types including tonic, atonic, atypical absence seizures and tonic seizures predominantly occurring at night, (ii) abnormal EEG, consisting of an interictal pattern of diffuse, slow spike-wave complexes at <3 Hz, occurring during wakefulness, and of paroxysmal fast rhythms (10–20 Hz) and polyspikes during sleep [
[1]
,[2]
]. As supportive diagnostic criteria, we included progressive intellectual disability and behavioral problems.The diagnosis was reviewed and confirmed in 62 cases. In 9 cases, all with severe epileptic encephalopathy, cognitive impairment, and resistant epilepsy, the phenotype of LGS was incomplete (for example, due to the absence of sleep-related tonic seizures), and these patients were categorized as “LGS-like”. None had a specific syndromic diagnosis other than LGS, for example, Dravet syndrome or Doose syndrome.
We retrospectively collected the data. EEG monitoring was not systematic, and the effect on the EEG was not specifically studied. Indeed, recordings for a minimum of 24 h are recommended to evaluate the efficacy of a drug on the EEG in LGS. Patients and caregivers were seen at 3-month intervals and encouraged to notify any problems by phone between visits. They kept seizure logs to report major seizures, mostly falls, although there was no precise documentation of atypical absences, which are not possible to quantify without long-term video-EEG, and of sleep-related tonic-seizures, which can be quantified only during full-night sleep video-EEG. At each visit, a complete clinical examination, with a screening of side-effects, occupational status and overall well-being, were recorded. The up- and down titration of PER, and the changes in associated AED were performed in a clinical setting and followed our usual practice. The effect of PER was assessed at the latest follow-up or when the drug was discontinued, considering the frequency of seizures reported over at least 3 months at the baseline visit. The efficacy against seizures was noted as: aggravation (increased seizures reported), no response (less than 50 % decrease), 50 % decrease (50–74%), 75 % decrease (75–89 %), and 90 % for patients with no witnessed seizures. Indeed, as no systematic long-term awake or sleep EEG recordings were performed, it is impossible to be sure that infrequent atypical absences or tonic seizures during sleep had not been overlooked. Therefore, we chose not to quantify the absence of visible and reported seizures as a 100 % result.
2.1 Data availability
Anonymous data presented in this study will be shared on request to the corresponding authors.
3. Results
3.1 Demographic data
There were 28 females and 43 males, aged between 20 and 71 years old (mean 40.1 ± 11.5 years, median 38). Epilepsy began at 2.76 ± 3.3 years old (median 2). The epilepsy duration was 37.4 ± 11.6 years (median 35). There were 38 patients (53.5 %) with epilepsy of an unknown etiology and 33 patients (46.5 %) with epilepsy of structural, genetic, infectious, or metabolic etiology. In the second group, there were 8 patients with cortical malformations (4 with band heterotopia, 2 with micropolygyria, 2 with pachygyria), 7 patients with a genetic disorder (5 with tuberous sclerosis, one with 21 trisomy, one with an SCN2A deletion), 6 patients with a polymalformative encephalopathy. Other significant history included sequellae of the neonatal anoxia (5), encephalitis (3), craniostenosis (1), hydrocephalus (1), severe head trauma (1), and cranial radiotherapy (1). Demographic data are reported in Table 1.
Table 1Demographic data of the study population.
| Demographic data | ||
|---|---|---|
| Sex | Males | 43 patients |
| Females | 28 patients | |
| Age | 20–71 y Mean 40.1 ± 11.5 y Median 38 y | |
| Epilepsy start | Mean 2.76 ± 3.3 y Median 2 y | |
| Epilepsy duration | Mean 37.4 ± 11.6 y Median 35 y | |
| Epilepsy etiology | Unknown | 38 patients (53.5 %) |
| Structural/genetic/infectious/metabolic | 33 patients (46.5 %) | |
| Cortical malformation | 8 patients | |
| 4 patients | |
| 2 patients | |
| 2 patients | |
| Genetic disorder | 7 patients | |
| 5 patients | |
| 1 patient | |
| 1 patient | |
| Polymalformative encephalopathy | 6 patients | |
| Sequellae of neonatal anoxia | 5 patients | |
| Sequellae of encephalitis | 3 patients | |
| Craniostenosis | 1 patient | |
| Hydrocephalus | 1 patient | |
| Severe head trauma | 1 patient | |
| Cranial radiotherapy | 1 patient | |
y = years.
3.2 Treatment
The duration of PER exposition was 538.9 days ± 425 (median 429), i. e. 18 ± 14.2 months (median 14.3). Patients were receiving 3.4 ± 0.96 (median 3, range 1–6) antiepileptic agents at the moment of PER introduction: VPA (80.3 %), LTG (67.6 %), VPA + LTG combined (64.8 %), benzodiazepines (59.2 %), topiramate (TPM) (23.9 %), zonisamide (ZNS) (23.9 %), RUF (21.1 %), carbamazepine (16.9 %), LEV (11 %), phenobarbital (10 %), FBM (7 %), and lacosamide (LCM) (4.2 %). VNS was present in 19 (26.8 %). The maintenance PER dosage was 5.45 ± and 2.23 mg (median 6). The maximal dose prescribed was 5.79 mg ± 2.34 mg (median 6). Within the follow-up period, twenty-two patients (31 %) decreased the number of antiepileptic drugs they were using.
Twenty-seven patients stopped PER (38 %). This was due to side effects in 17 (24 %), including seizure aggravation in 6 (8.5 %), inefficacy in 10 (14 %), including 3 patients who had responded initially and one who stopped without a precise reason. Therefore, 44 patients (62 %) were still on PER at last follow-up, including patients who were in the process of up titrating PER. Among these, 3 experienced a partial loss of efficacy after 12–24 months but chose to remain on PER.
3.3 Efficacy
Forty-six patients (64.8 %) were responders with a decrease of seizure frequency ≥50 %, including 25 patients (35.2 %) with a ≥75 % decrease in seizures. Among these 12 (16.9 %) had a ≥90 % decrease. PER gave no improvement in 14 patients; 5 had less than a 50 % response, and 6 had seizure aggravation. Therefore, 25 (35.2 %) were considered non-responders.
3.4 Side effects
Thirty-seven patients (52.1 %) developed one or several side effects, including seven patients with two and two patients with three side effects. Side-effects appeared at a daily dose of 6 mg in the majority of cases. Significant negative changes in behavior were noted in 23 patients (32 %), which were well characterized for 13 patients (18 %) with irritability (6, 8.5 %), aggressivity (5, 7 %), and agitation (2, 2.8 %). For the other 10 patients, the changes were less well characterized, such as having bad contact, bad mood and opposition resulting in additional daily management difficulties. It must also be noted that positive side effects were seen in four patients (5.6 %), with patients and caregivers reporting a feeling of wellness, calm and better contact. In decreasing order of prevalence, we also found seizure aggravation (6, 8.5 %), somnolence (4, 5.6 %), dizziness (3), weight gain (2), falls, ataxia, sadness, insomnia, and asthenia (1 each).
4. Discussion
In spite of all the proposed therapies, LGS remains a therapeutic challenge, and any new treatment possibility is welcome. Given the major part played by bilateral synchrony in the genesis of the various seizure types associated with LGS [
[24]
], new AEDs with proven efficacy against focal seizures are potentially beneficial anticonvulsants in LGS. However, some AEDs may aggravate seizures in LGS, as shown for LCM [[25]
]. When trying a new AED in LGS, particular attention should be paid to the possibility of paradoxical aggravation of seizures. In patients with LGS, especially adults, there is a high prevalence of psychiatric and behavioral co-pathologies [[24]
]. As PER may provoke or increase such co-pathologies [[26]
], particular attention must also be paid to the tolerability of this drug. Patients with LGS very often receive multiple drugs, and drug-drug interactions may create problems. However, PER can be considered safe in that respect, with minimal or no interactions with other AEDs [[27]
].The patients reported in this study represent a broad spectrum of the adult population with LGS or a related form of epileptic encephalopathy, with a variety of etiologies. In this population, the incidence of PER-related side-effects appears to be higher than among patients treated with PER for resistant focal epilepsy. According to Steinhoff et al. (2013) [
[28]
], whom pooled regulatory studies of PER in drug-resistant focal epilepsies, the rate of treatment discontinuation due to adverse effects increased from 6.7%–19.2% when the daily dosage increased from 2 to 12 mg. Among our patients, 24 % stopped PER because of adverse effects, such as abnormal behavior, seizure aggravation, and aggression.Controlled studies of several anticonvulsants led to specific indications in the treatment of LGS. However, none of these controlled trials yielded spectacular results. For FEB, a 19 % decrease in seizure frequency (4 % were aggravated) was reported [
[29]
], vs 32 % for LTG (9 % on placebo) [[30]
], 26 % for TPM (5 % were aggravated) [[31]
], and 33 % (vs 12 % on placebo) for RUF [[32]
]. For clobazam, there were up to 83.3 % responders during a short-term, 10-week trial [[33]
], but tolerance is a well-known limitation for this drug, as with other benzodiazepines. Open studies have examined ZNS with 22.6 % experiencing a >75 %, and 24.6 % a > 50 % reduction of seizure frequency for up to a year [[34]
]. There is only anecdotal evidence, in very small samples, of LGS patients who responded to LEV or vigabatrin. A recent randomized, double-blind, placebo-controlled trial evaluating cannabidiol as an adjunctive therapy in these patients showed a median seizure reduction of 43.9 % in the cannabidiol group vs. 21.8 % in the placebo group. In spite of these reports, experts recommend valproate initially, with lamotrigine, CLB, or TPM prescribed as second-line medications. Additionally, the early use of non-pharmacological approaches is advised [[2]
,[3]
].The results of this open-label, uncontrolled retrospective study compare favorably with those collected during controlled studies. Our large sample size and the mean duration of follow-up in our study point to robust findings. PER can and should be used in adults with LGS and active epilepsy. Our study has several limitations. It is a retrospective, open-label, and uncontrolled study, and our results need to be confirmed with a prospective, placebo-controlled study. In this study, the efficacy of PER was not directly related to co-medication, duration of treatment, age of the patients, duration and etiology of epilepsy, true LGS or LGS-like encephalopathy, or the occurrence of status epilepticus during the evolution and baseline period before the introduction of PER. This study is a global evaluation of PER in adults but using precise criteria for diagnosing LGS following the Marseille school. This is why we separate true LGS and LGS-like encephalopathy. Further studies are needed with a larger number of patients to analyze specific points like etiology, comedication and history of status epilepticus.
5. Conclusion
In this large series of adult patients with longstanding, invalidating LGS, or a closely related form of epilepsy, we used PER without major difficulties. There were significant side-effects, mostly behavioral and psychiatric, which occurred during titration, leading to withdrawal in 24 %. However, 16.9 % reached a total control of all seizure types. Although the persistence of minor atypical absences, or tonic seizures during sleep, could not be excluded. Additionally, 64.8 % experienced an improvement with a ≥50 % reduction of reported seizures. There was only marginal, very late tolerance with a partial loss of efficacy in a few patients.
We conclude that PER is a highly useful, effective, and safe drug in adult patients with LGS. The first weeks or months, covering the up-titration period, should be closely monitored, with proper information given to patients and caregivers, because a significant proportion of patients will experience side-effects that may lead them to discontinue PER. In our opinion and experience, PER is a promising drug for treating LGS, compared to other drug studies that have an orphan drug label, like FBM and RUF.
Declaration of Competing Interest
Dr. Crespel received support for teaching programs from Sanofi-Aventis, UCB, GSK, and is an advisory board member for Eisai-France.
Dr. Gelisse received support for teaching programs from Sanofi-Aventis, UCB, and Psicofarma. He received a research grant from Janssen-Cilag. He worked as a consultant for Eisai-France in 2011.
Dr. Tang reports no conflicts of interest.
Dr. Macorig reports no conflicts of interest.
Dr. Genton received speaker invitations and honoraria from Sanofi-Aventis, Novartis, GSK, Pfizer, Janssen-Cilag, UCB, Eisai, and Actelion. He received support for teaching programs from Sanofi-Aventis and UCB.
All co-authors have been substantially involved in the study and preparation of the manuscript. No undisclosed persons have had a primary role in the study or manuscript preparation. All co-authors have approved the submitted version of the paper and accept responsibility for its content.
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Article info
Publication history
Published online: December 17, 2019
Accepted:
December 15,
2019
Received in revised form:
December 12,
2019
Received:
July 15,
2019
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© 2019 British Epilepsy Association. Published by Elsevier Ltd.
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