Seizure: European Journal of Epilepsy 75 (2020) 82–86

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Seizure: European Journal of Epilepsy

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The efficacy of perampanel in young children with drug-resistant epilepsy T

a b,c b,c d b,c,e,
Fu-Man Chang , Pi-Chaun Fan , Wen-Chin Weng , Chin-Hao Chang , Wang-Tso Lee *
a
Department of Pediatrics, Taitung MacKay Memorial Hospital, Taitung, Taiwan
b
Department of Pediatric Neurology, National Taiwan University Children’s Hospital, Taipei, Taiwan
c
Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan
d
Center of Statistical Consultation and Research in the Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
e
Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan

ARTICLE INFO ABSTRACT

Keywords: Purpose: Perampanel, a selective, noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

Drug-resistant epilepsy (AMPA) antagonist, has been approved as an effective and safe drug for the treatment of adults and adolescents
Perampanel with epilepsy. However, only a few studies have reported about the efficacy and tolerability of perampanel in
Young children children under 7 years old with refractory epilepsy. In this work, we aimed to describe our clinical experience in
Tuberous sclerosis
this group.
Dravet syndrome
Methods: This single-center retrospective observational study was performed by reviewing the medical records
Epileptic spasms
of children below 7 years old with epilepsy and were treated with perampanel.
Results: A total 38 patients (19 females, 19 males) were enrolled, with a mean age of 4 ± 1.6 years (range, 0–6
years). The response rates (defined as 50 % seizure reduction) were 44 % and 31 % after 6 and 12 months of
treatment, respectively, and the freedom of seizures was reached in 13 % and 10 % after the same treatment
periods. The short- and long-term response rate in patients with tuberous sclerosis (TSC) and Dravet syndrome
was high (67 %). The response rate in refractory spasms was 40 % at 6 months, but dropped to 13 % after 12
months of treatment. The retention rates were 61.1 % and 51.5 % at 6 and 12 months, respectively. Adverse
events were reported in eight patients (22 %), which included emotional change (n = 4), lethargy (n = 2), nasal
bleeding (n = 1), and drug allergy (n = 1).
Conclusions: As a real-world pediatric case series, our study demonstrated the efficacy and tolerability of per-
ampanel in young children with intractable epilepsy. In our experience, lower starting and maintenance dose of
perampanel would be effective in the pediatric group. We also propose the use of perampanel as an effective
therapy for epilepsy in children with TSC and Dravet syndrome.

1. Introduction (AEDs) were approved in the past decade, some patients continue to
have seizures in their daily lives.
Epilepsy is the most common neurological disorder in children. The During the seizure activity, excessive glutamate release leads to the
prevalence of epilepsy ranges from 3 to 5 per 1000 children in devel- activation of neurons and results in neurotoxicity [4]. Therefore, an-
oped countries, and the incidence is about 41–187/100,000 person- tagonists of glutamate receptors may play an essential role in reducing
years [1]. Previous studies have shown the incidence of epilepsy to be seizure-induced neuronal damage. Recently, perampanel (PER), a se-
highest in the first year of life, ranging from 81 to 130/100,000 [1]. Of lective and noncompetitive alpha-amino-3-hydroxy-5-methyl-4-iso-
those with epilepsy, about 10 % of children have drug-resistant epilepsy xazolepropionic acid (AMPA) receptor antagonist, was developed [5].
[2]. The common etiologies of drug-resistant epilepsy can be very di- The AMPA receptor is a primary subtype of ionotropic glutamate re-
verse, including epilepsy syndromes (e.g., West syndrome and Len- ceptor and plays a major role in excitatory postsynaptic potentials [6].
nox–Gastaut syndrome), genetic epilepsy (like tuberous sclerosis, TSC), In September 2018, PER was approved by the US Food and Drug Ad-
structural causes (e.g., cortical dysplasia or mesial temporal sclerosis), ministration as monotherapy and for adjunctive use to treat partial-
and miscellaneous origins (e.g., connective tissue disorders, auto- onset seizures with or without secondarily generalized seizures for
immune epilepsies) [3]. The treatment of drug-resistant epilepsy could people with epilepsy aged 4 years and older. PER can also be used to
be quite challenging [3]. Although several new antiepileptic drugs treat primary generalized tonic-clonic seizures for people with epilepsy

⁎
Corresponding author at: 8, Chung-Shan South Road, Department of Pediatric Neurology, National Taiwan University Children’s Hospital, Taipei, Taiwan.
E-mail address: [email protected] (W.-T. Lee).

https://doi.org/10.1016/j.seizure.2019.12.024
Received 26 June 2019; Received in revised form 21 December 2019; Accepted 22 December 2019
1059-1311/ © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
F.-M. Chang, et al. Seizure: European Journal of Epilepsy 75 (2020) 82–86

aged 12 and older. However, few studies have reported on the efficacy Table 1
and safety of PER in children with drug-resistant epilepsy, especially in Baseline and demographic characteristics of the children.
those younger than 7 years old. Total = 38 n (%)
Birò et al. conducted a multicenter, observational, and retrospective
study among patients with ages ranging from 2 to 17 years. They re- Sex, male/female 19 (50) / 19 (50)
Age at PER initiation, Mean (range) (months) 48 (4–80)
ported a responder rate of 31 % and the achievement of complete sei-
Age at PER initiation, < 3y 11 (29)
zure control in 9 % of the patients after 3 months of treatment [7]. Age at PER initiation, 3-7y 27 (71)
Another Canadian study also reported a 42 % responder rate in children Etiology
between 12 and 18 years; however, 63 % of the patients discontinued Structural 7 (18)
the use of this drug as most of them experienced poor response com- Genetic 17 (45)
Immune 2 (5)
bined with adverse events [8]. Although a few studies focused on the
Unknown 12 (32)
efficacy of PER in children, no previous studies focused on children Treatment
younger than 7 years. Therefore, in the present study, we investigated Ketogenic diet 19 (50)
the efficacy and tolerability of PER in young children. VNS 1 (3)
Mean number of previous AEDs, n (SD) 5.5 (0.7)
Mean number of concomitant AEDs, n (SD) 3.8 (0.7)
2. Methods Mean PER initial dosage, mg (SD) 1.1 (0.8)
Mean PER maximal dosage, mg (SD) 2.2 (1.4)
We reviewed the medical records of children younger than 7 years
with epilepsy and treated with PER in the pediatric department of a PER: Perampanel, VNS: vagus nerve stimulation, AEDs: Antiepileptic drugs.
major University hospital in Taiwan from January 2016 to March 2018.
The following data were collected: gender, age when starting PER, number of those using concomitant antiseizure medications when
seizure type and semiology, epilepsy syndromes, etiologies of epilepsy, starting PER was 3.8 ± 0.7 (range, 2–6). Of these 38 patients, 1 (2.6 %)
the number of previous AEDs taken, the number of concomitant AEDs, had undergone vagus nerve stimulation and 19 (50 %) had previously
other treatments like vagus nerve stimulation and ketogenic diet, initial tried a ketogenic diet or modified Atkins diet. PER was started at a
and maximal daily dose of PER, seizure outcomes at 6 and 12 months of mean daily dose of 1.1 ± 0.8 mg (range, 0.3–4 mg), depending on the
follow-up, adverse events, and reasons for discontinuation. The seizure body weight of each patient (range, 0.03–0.1 mg/kg/day). The titration
frequency was noted based on the reports by patients and their care- rates and dose adjustments were made according to individual clinical
givers. This study was approved by the Institutional Review Board of responses. The mean maximal dose was 2.2 ± 1.4 mg (range, 0.5–6 mg)
the National Taiwan University Hospital. per day, depending on clinical response, and ranged from 0.04 to 0.15
The initial and maximal doses of PER were individualized according mg/kg/day (Table 1). Although a recent study stated that the phar-
to a patient’s clinical condition. We followed the seizure outcome and macokinetics of PER was independent of age and body weight [9], the
tolerability at 6 and 12 months after PER treatment, and a responder total daily dose of PER in our group was adjusted according to each
was defined as having more than 50 % reduction in seizure frequency. patient’s age and bodyweight.
Adverse events and reasons for drug withdrawal were recorded ac-
cording to the observations of the patients’ family members and phy- 3.3. Efficacy
sicians.
The statistical analysis was performed using the statistical software At 6 months, 2 patients were lost to follow-up and four patients
package Statistical Analysis System for Windows. Data were shown as discontinued PER within a month because of adverse events. Of the four
means and standard deviations for quantitative variables. For between- patients, 1 patient had her astatic seizures reduced to 30 %, but her
group comparisons, we used the Chi-square test and Fisher exact test for tonic seizure persisted after PER prescription. The overall response rate
categorical variables. We also used the Kaplan–Meier survival analysis (≥50 % seizure reduction) at 6 months was 44 % (14/32 patients), and
and log-rank test for the differences in retention rates in terms of age, complete seizure control was achieved in 13 % (4/32 patients) of the
sex, and other risk factors. Statistical significance was determined at patients. Increased seizure frequency was noted in 9 (28 %) patients,
p < 0.05. and 9 (28 %) other patients showed no change in seizure frequency.
Another three patients were lost to follow-up at 12 months of
3. Results treatment. The overall response rate at 12 months decreased to 31 %
(9/29 patients), and 10 % (3/29 patients) became seizure-free. No
3.1. Baseline and demographic data significant difference existed in the response rate between genders (p =
0.774), age at PER initiation (< 3 years and 3–7 years, p = 0.393),
A total of 38 patients (19 females, 19 males) using PER were en- epilepsy etiology (genetic or non-genetic, p = 0.486), concomitant use
rolled in the present study (Table 1). They included 11 (29 %) patients of enzyme-inducing AEDs (with or without, p = 0.7041), or seizure
younger than 3 years and 27 (71 %) patients between 3 and 7 years. type (epileptic spasms or not, p = 1.000; Table 2). However, the chil-
The mean age was 4 ± 1.6 years (range, 0–6 years). The etiology of dren with comorbid developmental delay showed better response to
epilepsy was classified according to the International League Against PER treatment (p = 0.050).
Epilepsy classification of epilepsies, including genetic (n = 17), struc- The total retention rate at 6 months was 61.1 % (22/36). Although
tural (n = 7), immune (n = 2), and unknown etiology (n = 12). the retention rate for patients < 3 years of age was 70 % (7/10), that
Among all patients enrolled in the study, six were diagnosed as having for patients aged 3–7 years of age was 57.7 % (15/26). In contrast, the
TSC, five with Rett syndrome or its variant, and two patients with retention rate at 12 months was 51.5 % (17/33). The retention rate for
KCNT1 gene mutation. In addition, 10 patients had specific epilepsy patients < 3 years was 55.6 % (5/9), whereas that for patients 3–7
syndromes, including seven with Lennox–Gastaut syndrome, and three years was 50.0 % (12/24). Although there was no difference in reten-
with Dravet syndrome. tion rate for male and female patients, the retention rate in patients < 3
years was significantly higher than that in patients 3–7 years at 6
3.2. Medication regimen months (p < 0.0003).
There were six patients diagnosed with TSC in our study group, and
To control refractory epilepsy, patients had tried many AEDs before the response rate after 6 and 12 months reached 67 % (4/6 patients;
adding PER; the mean number was 5.5 ± 0.7 (range, 2–11). The mean Table 2). The main seizure types, including focal seizure with impaired

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F.-M. Chang, et al. Seizure: European Journal of Epilepsy 75 (2020) 82–86

*AEDs: Antiepileptic drugs; ASD: autism spectrum disorder; CBZ: Clobazam; CHD: congenital heart disease; DD: developmental delay; FLE: Frontal lobe epilepsy; GTCs: Generalized tonic-clonic seizures; ID: intellectual
disability; LMT: Lamotrigine; LEV: Levetiracetam; NF: neurofibromatosis; OXC: Oxcarbazepine; PER: Perampanel; SCB: sodium channel blocker; TLE: Temporal lobe epilepsy; TPM: Topiramate; TSC: tuberous sclerosis;
Table 2

Present series
Efficacy of perampanel at 6- and 12-month follow-up. Total 32 patients were

Reference
analyzed at 6 months, and 29 patients at 12 months.

[13]
[14]
Responder at 6m n/ Responder at 12m n/
total (%) total (%)

> 50 % reduction in 6 months and seizure free in 1 year

Etiology of epilepsy
Genetic 8/16 (50) 7/16 (44)
Structural 2/5 (40) 1/4 (25)
Immune 0/2 (0) 0/2 (0)
Unknown 4/9 (44) 1/7 (14)

> 50 % reduction in 6 months and 1 year

> 50 % reduction in 6 months and 1 year
> 50 % reduction in 6 months and 1 year
Total 14/32 (44) 9/29 (31)
Specific etiologies

≥50 %seizure reduction in 5 months

Aggravation (increased tonic seizure)

TSC 4/6 (67 %) 4/6 (67 %)
Rett syndrome or Rett 2/4 (50 %) 1/4 (25 %)
variant
KCNT1 mutation 0/2 (0 %) 0/2 (0 %)
Dravet syndrome 2/3 (67 %) 2/3 (67 %)
LGS 3/5 (60 %) 1/4 (25 %)

Treatment response
Epileptic spasms 4/10 (40 %) 1/8 (13 %)
Age at initiation of PER
< 3 years old 4/10 (40 %) 2/9 (22 %)

No benefit

No benefit
3-7 years old 10/22 (45 %) 7/20 (35 %)

PER: Perampanel; TSC: Tuberous sclerosis complex; LGS: Lennox–Gastaut

syndrome.

VGB, VPA, TPM, everolimus

VGB, VPA, LEV, LMT, ZNS
awareness, epileptic spasms, and atonic seizure, improved in our re-

VGB, VPA, CBZ, TPM

VGB, VPA, LEV, ZNS

VGB, LEV, CBZ, VPA
sponders. The comedication in both responders and non-responders

OXC, LEV, sirolimus

Concomitant AEDs
with TSC included multiple AEDs (Table 3), and there was no sig-

OXC, VGB, CBZ

nificant difference in medications. However, these responders all took
VGB and VPA as comedications. The response rate in patients with Rett
SCB, LEV
syndrome (50 %, 2/4 patients) or with KCNT1 mutation (0 %) was not
as good as those with TSC. Furthermore, the response rate in patients
with Dravet syndrome was also high (67 %, 2/3 patients) as in those
Dose (mg)

with Lennox–Gastaut syndrome (60 %, 3/5 patients). The comedica-

tions included LEV, CLB, TPM, and stiripentol in one patient, and LEV,
12

CLB and ZNS in another patient. In our study, we also showed that a
4

2
2
2
4
3
2
total of 11 patients had drug-resistant epileptic spasms, and the re-
ID, cardiac tumor, WPW syndrome

sponse rate at 6 months of treatment was 40 % (4/10 patients) with one

lost to follow-up. When extending the follow-up period to 12 months,
the response rate remained stable in patients of the TSC or Dravet
ASD, ID, cardiac tumor

syndrome groups, but the response rate dropped in the other epilepsy
left hemiparesis, CHD
Other comorbidities

syndrome group.

3.4. Safety
DD

Adverse events were reported in 21 % (8 of 38 patients), including

ID
Demographic characteristics of TSC patients treated with perampanel.

emotional problems (n = 4), fatigue (n = 2), nasal bleeding (n = 1),

Epileptic spasms, tonic

Epileptic spasms, tonic

and skin allergy (n = 1). Four patients discontinued PER in 1 month

due to intolerable adverse events. The patient who reported nasal
Gelastic, atonic

bleeding had been diagnosed with idiopathic thrombocytopenic pur-

Seizure types

TLE, absence
Focal aware

pura during the neonatal period, but there was no more bleeding ten-
Focal tonic

VPA: Valproic acid; VGB: Vigabatrin; ZNS: Zonisamide.

FLE, GTCs

dency when growing up. The initial dosage of PER was higher (4 mg/
day). The symptom improved after we discontinued PER treatment.
Two patients with adverse events were observed in children
younger than 3 years (2/11, 18 %), and both of them had emotional
Not mentioned
Not mentioned

problems. In children between 3–7 years, adverse events were noted in

Mutations

22 % (6/27). All these events happened within 8 weeks after the in-
TSC1
TSC2
TSC2
TSC2
TSC2
TSC2

itiation of PER, and all side effects improved when the dosage of PER
was discontinued or tapered down.
Age (years/Sex)

4. Discussion
14 / F
16 / F
3/M

1/M
3/M
1/F

4/F
6/F

Over the past few years, several studies shared their clinical ex-
periences of PER in adolescents. However, further evidence of PER’s
efficacy in younger children was limited. Our research is a real-world
Patient
Table 3

pediatric case series aiming to demonstrate the efficacy and tolerability

of PER in children under 7 years old with refractory epilepsy. In our
1
2
3
4
5
6
7
8

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study, we found that the responder rates in children with drug-resistant owing to the decreased GABAergic transmission of cortical inter-
epilepsy were 44 % and 31 %, with 13 % and 10 % of seizure freedom neurons, it reduced inhibitory phasic GABA transmission. The promi-
after 6 and 12 months of treatment, respectively. The results were nent cause of this genetic epilepsy can be attributed to the impaired
compatible with previous studies in children over 12 years. According activity of these neurons due to SCN1A mutations affecting the Nav1.1
to previous studies, the responder rates were 31%–68% in children with channel expression [24]. A previous study suggested that Ca(2+)-
refractory epilepsy under 18 years, whereas the rate of seizure freedom permeable AMPA receptors might play a role in epileptogenesis. The Ca
ranged from 9 % to 23 % [7,10,11]. Therefore, the efficacy of PER as (2+)-permeable AMPA receptors are mainly located in GABAergic in-
adjunctive therapy for young children with intractable epilepsy was terneurons. Epilepsy might be related to reduced GABA inhibition
good. arising from the AMPA receptor-mediated excitotoxic death of inter-
In our study, although there was no significant difference in efficacy neurons [25], which may further impair GABA inhibition in Dravet
between children with genetic or non-genetic related epilepsy, the re- syndrome. Therefore, an AMPAR antagonist may attenuate the im-
sponder rate reached 67 % after 6 and 12 months of treatment in pa- paired GABAergic transmission in Dravet syndrome, thus leading to the
tients with TSC and Dravet syndrome. Epilepsy is the most common reduction of seizure frequency. Further investigations on the impact of
neurological manifestation affecting 80%–90% of TSC individuals, with PER in phasic GABA transmission in Dravet syndrome is, therefore,
epilepsy onset during the first year of life affecting 70 % [12]. Previous needed.
studies have shown a variable response of PER in children with TSC In our study, patients presenting with drug-resistant epileptic
(Table 3). One 14-year-old girl with a diagnosis of TSC responded to 4 spasms as the main disabling seizure type also responded well to PER
mg of PER, achieving ≥50 % of seizure reduction in 5 months of treatment. In these patients with epileptic spasms, five were genetic
follow-up [13]. However, another 16-year-old girl had a poor response (including two with TSC), two had structural anomaly, and four had an
to high-dose (12 mg/day) PER treatment [14]. In our current series, unknown etiology. Although they all failed to respond to all treatments,
seizure reduction > 50 % was achieved in four patients, either after 6 including different AEDs, ACTH therapy, and a ketogenic diet, the re-
or 12 months of treatment. All responders took both VGB and VPA as sponder rate remained at 40 % (4/10) at 6 months, and total seizure
comedication. Whether the combination of these AEDs might be more cessation was reported in three patients. There was no significant dif-
effective in seizure control remains to be clarified. In summary, the ference in etiologies between responders and non-responders. All the
total responder rate in children with TSC reached 62.5 % (Table 3), electroencephalography (EEG) results of these responders showed fre-
indicating that PER has good efficacy in terms of controlling seizures in quent generalized and focal epileptiform discha rges before PER use.
TSC. Worth mentioning is the fact that, although patient 3 discontinued Two of them revealed dramatic improvement on EEG within 3 months,
PER because of increased frequency of tonic seizures, his epileptic corresponding to their clinical symptoms. Two of our responders got
spasms ceased after short-term use of PER. Moreover, the main seizure lost to follow-up after 6 months, and it could be the cause of dropped
type of patient 5 was also epileptic spasms, and the frequency decreased responder rate in epileptic spasms at 12 months. The responder rate in
dramatically after using PER. Although we investigated a small number children with refractory epileptic spasms was reported to range from 30
of patients, the efficacy seemed to be generally good in TSC patients % to 60 % [7,21], which agrees with our result. Thus, for poorly con-
with epileptic spasms. Previous animal and human studies have shown trolled epileptic spasms, PER could be the treatment of choice (Table 4).
that the neuron-specific knockout of TSC1 might lead to the activation In past studies, the most common adverse effects of PER were diz-
of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor ziness, somnolence, aggression, decreased appetite, and rhinitis in
(AMPAR) or a significant reduction in the frequency of GABAR-medi- adolescents; among these, dizziness was the leading cause of PER dis-
ated miniature inhibitory postsynaptic currents. This finding indicated continuation [26]. Adverse events were more common in children aged
that the inhibition of the AMPA current by PER might attenuate neu- 12 years or older when compared with those younger than 12 years old
ronal excitability [15,16]. It was also confirmed that the mammalian [27]. In our study, the rate of adverse drug events was lower (22 %)
target of rapamycin (mTOR) inhibitor, such as everolimus, had good than that in the previous study (53 %) [27]. A possible reason was that
efficacy as an add-on antiepileptic drug for TSC patients with epilepsy the patients we enrolled were younger than in the previous study, and
[17,18]. In previous studies, it was mentioned that the stimulation of they might have had difficulty expressing their discomfort. However,
AMPAR could rapidly activate the mTOR signaling pathway through the most common adverse effects were similar to previous studies, in-
the route of extracellular-signal-regulated kinase and the phosphati- cluding aggressive behavior, dizziness, and lethargy. The possible me-
dylinositol 3′ -kinase (PI3K)-Akt signaling pathway. Therefore, PER as chanism of aggressive behavior was discussed in the past, and the
an AMPA receptor antagonist may also attenuate the activation of the fluctuation of glutamate level in the brain, especially the amygdala,
mTOR pathway leading to seizure reduction in TSC patients [19,20]. hypothalamus, and periaqueductal gray matter might play an important
In our series, two of three children with Dravet syndrome also role [28]. The inhibiting effect of PER on glutamatergic transmission
showed good response to PER treatment, and the efficacy of the treat- via the AMPA receptor may lead to this side effect [29].
ment can be maintained for > 1 year. From previous research and our All these adverse events occurred within 2 months of PER initiation,
current series, many children with Dravet syndrome can reach > 50 % and the symptoms improved immediately when the dosage was tapered
seizure reduction using PER, and the responder rate can be as high as 59 or discontinued. One of our cases had epistaxis when using PER at a
% (Table 4) [7,11,13,21,22]. A previous study has shown that many higher dose. In phase 3 of the placebo-controlled adjunctive studies in
different types of seizures might improve in children with Dravet syn- adult patients with partial-onset seizures, five patients reported the
drome under PER treatment, including generalized tonic-clonic sei- same condition when using higher dosages (8 and 12 mg) of PER.
zures, unilateral tonic or clonic, myoclonic, and focal seizures with There were some limitations in our study. First, this was a small case
impaired awareness [22]. Although children with Dravet syndrome series and a retrospective observational study. Second, the evaluation of
comprised only a small number in our study, we also demonstrated that seizure frequency was mainly carried out through patients and their
they had a reduction in the different seizure types. The seizure fre- caregivers, so there might be some recall bias. Finally, the policy of
quency of our responders decreased significantly, including myoclonic, combining different AEDs and titrating the dosage of PER differed
tonic, and clonic seizures. These findings lend support to the hypothesis among clinicians. In conclusion, we demonstrated the efficacy and
that the efficacy of PER in Dravet syndrome might not target a specific tolerability of PER in children younger than 7 years. We propose the use
seizure type but the underlying disease itself [22]. of PER as a possible effective therapy for patients with TSC, Dravet
A recent study suggested that the epileptogenesis of monogenic syndrome, and drug-resistant epileptic spasms. For better control of
epilepsies might be due to NMDA-pathy, tonic gamma-aminobutyric seizures, we can choose PER in children younger than 7 years, based on
acid (GABA)-pathy, or phasic GABA-pathy [23]. In Dravet syndrome, their seizure type and the etiology of their epilepsy.

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F.-M. Chang, et al. Seizure: European Journal of Epilepsy 75 (2020) 82–86

Table 4
Comparison between different studies on treatment response of patients with epileptic spasms and Dravet syndrome.
A. Epileptic spasms

Author Study type Patient response Reference

Biró, et al. Observational, retrospective 3 pediatric patients, 2 responders (60 %), including one seizure free in 3 months [7]
Swiderska, et al. Prospective and retrospective study 3 patients with one responder (33 %) in 6 months [21]
Chang, et al. Observational, retrospective 10 patients with four responders (40 %), including 2 seizure free in 6 months and one seizure free at one Present series
year

B. Dravet syndrome
Shinsaku, et al. Observational, retrospective 10 pediatric patients with 5 responders (50 %) [22]
Lin, et al. Observational, retrospective 5 pediatric and adolescent patients with 4 responders (80 %), including 2 seizure free (follow-up [11]
duration: 19–68 weeks)
Biró, et al. Observational, retrospective 2 pediatric patients with one (50 %) seizure free in 3 months [7]
Swiderska, et al. Prospective and retrospective 1 pediatric patient with early discontinuation of treatment at 3 months due to lack of seizure control [21]
De Liso, et al. Observational retrospective 1 adolescent patient with response to a very low PER dose (2 mg) achieving ≥75 % of seizure reduction [6]
in 10 months.
Chang, et al. Observational, retrospective 3 pediatric patients with 2 responders (67 %) in 6 months and one year follow-up Present series

Declaration of Competing Interest 2016;127:93–100.

[14] Morano A, Fattouch J, Albini M, Casciato S, Fanella M, Basili LM, et al. Perampanel
as adjunctive therapy in highly refractory epilepsies: real-world data from an Italian
None for all authors. tertiary care epilepsy centre. J Neurol Sci 2018;390:67–74.
[15] Zhao JP, Yoshii AA-OX. Hyperexcitability of the local cortical circuit in mouse
Acknowledgements models of tuberous sclerosis complex. (1756-6606 (Electronic)).
[16] Wang Y, Greenwood Js Fau - Calcagnotto ME, Calcagnotto Me Fau - Kirsch HE,
Kirsch He Fau - Barbaro NM, Barbaro Nm Fau - Baraban SC et al. Neocortical hy-
The authors acknowledge statistical assistance provided by the perexcitability in a human case of tuberous sclerosis complex and mice lacking
Center of Statistical Consultation and Research in the Department of neuronal expression of TSC1. (0364-5134 (Print)).
[17] French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Adjunctive
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