Perampanel reduces seizure frequency in patients with developmental and epileptic encephalopathy for a long term

doi:10.21203/rs.3.rs-5286706/v1

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Perampanel reduces seizure frequency in patients with developmental and epileptic encephalopathy for a long term

https://doi.org/10.21203/rs.3.rs-5286706/v1

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Seizures in patients with developmental and epileptic encephalopathies (DEEs) are often highly resistant to various antiseizure medications. Perampanel (PER) is a novel antiseizure medication that non-competitively inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and is expected to reduce seizure frequency not only for focal seizures and generalized tonic-clonic seizures (GTCS) but also for other seizure types. This study aimed to clarify the long-term therapeutic efficacy and tolerability of PER in patients with DEEs. We analyzed data regarding patients’ background characteristics, medication retention, trends in seizure frequency, and adverse events obtained from 16 patients with DEEs who had been on PER treatment for 60 months. The retention rates were 56.3% and 43.8% at 12 and 60 months, respectively. At 60 months after PER initiation, the rate of patients with > 50% seizure reduction was 38.5%, 38.5%, 36.4%, 60.0%, 40%, and 66.7% among patients with focal seizures, atypical absence seizures, tonic seizures, GTCS, atonic seizures, and myoclonic seizures, respectively. The frequency of adverse events was 75.0%. PER showed long-term efficacy in various seizure types. PER is a promising treatment option for patients with DEEs.

Health sciences/Health care/Therapeutics/Drug therapy

Health sciences/Neurology/Neurological disorders/Epilepsy

perampanel

Lennox-Gastaut syndrome

epilepsy with myoclonic atonic seizures

long-term

efficacy & safety

Developmental and epileptic encephalopathies (DEEs) are a group of disorders characterized by epileptic seizures, electroencephalography (EEG) abnormalities, and developmental delays or regressions; further, they were proposed in the 2017 revision of the International League Against Epilepsy classification [1, 2].

DEEs, being highly heterogeneous, can include various syndromes, such as Lennox-Gastaut syndrome (LGS), Dravet syndrome, West syndrome, and epilepsy with myoclonic atonic seizures (EMAtS) [2–5].

Patients with DEEs usually present various seizure types, including focal seizures, atypical absence seizures, tonic seizures, generalized tonic-clonic seizures (GTCS), atonic seizures, and myoclonic seizures [5, 6]. Antiseizure medications (ASMs) often have limited efficacy, with some cases requiring multidrug therapy as well as ketogenic diets [7] or surgical procedures, including vagus nerve stimulation and/or corpus callosotomy [8, 9]. Despite the various treatments, the risk of fatal outcomes due to epileptic seizures remains high [10].

Perampanel (PER) is an ASM with a unique mechanism of action that non-competitively inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor [11]. In Japan, PER was approved for marketing in 2016 for epilepsy patients ≥ 12 years of age with focal seizures and/or GTCS. From 2020, it has been used for focal seizures in patients ≥ 4 years of age [12]. Further, its efficacy and tolerability have been investigated in randomized clinical trials for patients ≥ 12 years of age with epilepsy, refractory focal seizures, or GTCS with 1–3 concomitant ASM at the start of the study [13, 14] and numerous real-life clinical studies for patients with refractory epilepsy of various age groups and treatment histories [15–20]. Additionally, long-term outcomes within 3–5 years have been reported regarding patients who were investigated in randomized clinical trials [21–25].

Several reports have evaluated the therapeutic efficacy of PER for DEEs, including LGS [5, 26–33]. However, the only long-term studies on PER treatment for patients with DEEs have been a 3-year study on patients with LGS [34], a 5-year follow-up case report on patients with Dravet syndrome [35], and a 3-year follow-up case report on a patient with GRIN-1 mutation [36]. The long-term outcomes of PER treatment of other DEEs, including EMAtS, remain unclear.

This study aimed to examine the long-term efficacy and tolerability of PER for DEEs over a 60-month period.

2 − 1. Characteristics of patients

During the study period, twenty-six patients with DEEs were started on PER. Among them, we excluded two patients who were transferred, five patients who received additional ASMs after PER initiation, and three patients who restarted PER after discontinuation within the 60-month study period. Accordingly, we included sixteen patients, among them eleven patients with LGS, two with EMAtS, and one each with Dravet syndrome, SZT2 mutation, and tuberous sclerosis complex (TSC) (Table 1, Suppl. table 1)

Table 1

Characteristics of patients PER, perampanel; MRI, magnetic resonance imaging; DEE, developmental and epileptic encephalopathy; LGS, Lennox-Gastaut syndrome; EMAtS, epilepsy with myoclonic atonic seizures; TSC, Tuberous sclerosis complex; ASM, antiseizure medication; VNS, vagus nerve stimulation; GTCS, generalized tonic-clonic seizure
		n = 16	(%)
Age at PER initiation	< 12 years old	7	(43.8)
	12–18 years old	6	(37.5)
	> 18years old	3	(18.8)
Sex	Male	9	(56.3)
Age at seizure onset	< 2 years old	9	(56.3)
Structural abnormality on brain MRI		7	(43.8)
Background disease	Post cerebral infarction	2	(12.5)
	Gene mutation	2	(12.5)
	Cerebral palsy	1	(6.3)
	Cortical dysplasia	1	(6.3)
	Post anti-NMDA receptor encephalitis	1	(6.3)
	Post-acute encephalopathy	1	(6.3)
	Unknown	8	(50.0)
DEE type	LGS	11	(68.8)
	EMAtS	2	(12.5)
	Dravet syndrome	1	(6.3)
	SZT2 mutation	1	(6.3)
	TSC	1	(6.3)
Intellectual ability	Borderline to mild intellectual disability	4	(25.0)
	Moderate to severe intellectual disability	12	(75.0)
	Severely retarded	5	(31.3)
	Autism spectrum syndrome	10	(62.5)
Number of previous ASMs before PER initiation	< 10 drugs	9	(56.3)
Post-operation	VNS	1	(6.3)
	Corpus callosotomy	1	(6.3)
Number of concomitant ASMs	< 4 drugs	3	(18.8)
With enzyme-induced ASM		8	(50.0)
Seizure type at PER initiation	Focal seizure	13	(81.3)
	Atypical absence seizure	13	(81.3)
	Tonic seizure	11	(68.8)
	Primary or secondary GTCS	10	(62.5)
	Atonic seizure	10	(62.5)
	Myoclonic seizure	9	(56.3)
Titration schedule	Every 2 weeks	6	(37.5)
	Every 4 weeks	9	(56.3)

The case of SZT2 mutation was identified at 2 months of age with epilepsy. She had visual contact until onset, but it gradually disappeared, and at the initiation of PER, she was severely retarded and had an intellectual disability. Brain magnetic resonance imaging (MRI) showed a shortened and thickened corpus callosum. Whole exome analysis revealed a compound heterozygous mutation in SZT2 with the paternal allele c.3700_3716del:p.Asn1234Alafs*35 and maternal allele c.5482del:p.Gly1829Valfs*52 [37]. The case of TSC occurred at 7 months of age with West syndrome, and brain MRI showed subependymal nodules and multiple cortical nodules. Although genetic testing was not performed, the diagnostic criteria of TSC were satisfied [38]. At the start of PER, the patient had severe retarded and intellectual disability. Angiofibromas are clustered around the nose. There are multiple 1–3 cm angiomyolipomas on both kidneys.

The median (range) age at initiation of PER was 9 years 8 months (4 years, 2 months to 35 years, 2 months); the age at onset was 2 years 1 month (0 months to 11 years, 1 month); the duration from DEE onset to PER initiation was 7 years and 8 months (2 years, 2 months to 24 years, 3 months); the number of ASMs used before PER initiation was 8 (5–13); and number of concomitant ASMs at PER initiation was 4 (2–8).

The most common concomitant drugs were lamotrigine (n = 12, 75.0%), valproate (n = 11, 68.8%), and clonazepam (n = 10, 62.5%) (Suppl. table 2).

2–2. Retention rate

During the 60-month study period, nine patients (56.3%) discontinued PER, including six (37.5%) patients due to inefficiency, one (6.3%) due to inefficiency and adverse events, one (6.3%) due to adverse events, and one (6.3%) due to seizure aggravation. Seven (43.8%) patients discontinued PER within the first 12 months. The retention rate at 60 months was 43.8% (Fig. 1).

The patient who discontinued PER due to seizure aggravation was a 13-year-old boy with LGS due to cortical dysplasia, whose focal seizures and tonic seizure frequency increased immediately after PER initiation. Accordingly, PER was stopped 2 weeks after initiation, with the seizure frequency returning to baseline after PER was stopped.

There was no relationship between the discontinuation of PER and the background factors of each case; it was due to poor efficacy of PER or adverse events (Suppl. table 3).

2–3. Efficiency

At 60 months after PER initiation, the responder group comprised five (38.5%) patients with focal seizures, five (38.5%) with atypical absence seizures, four (36.4%) with tonic seizures, six (60.0%) with GTCS, four (40.0%) with atonic seizures, and eight (66.7%) with myoclonic seizures (Table 2).

Table 2

Efficiency of perampanel on seizure types
		12 months		24 months		36 months		48 months		60 months
		n	(%)	n	(%)	n	(%)	n	(%)	n	(%)
Focal seizure,	Discontinued	5	(38.5)	6	(46.2)	6	(46.2)	6	(46.2)	7	(53.9)
n = 13	No response	4	(30.8)	1	(7.7)	3	(23.1)	3	(23.1)	1	(7.7)
	50% responder	2	(15.4)	4	(30.8)	2	(15.4)	2	(15.4)	3	(23.1)
	75% responder	2	(15.4)	2	(15.4)	2	(15.4)	1	(7.7)	1	(7.7)
	Seizure free	0	(0.0)	0	(0.0)	0	(0.0)	1	(7.7)	1	(7.7)
	Responder group	4	(30.8)	6	(46.2)	4	(30.8)	4	(30.8)	5	(38.5)
Atypical absence seizure,	Discontinued	6	(46.2)	6	(46.2)	6	(46.2)	6	(46.2)	6	(46.2)
n = 13	No response	2	(15.4)	1	(7.7)	2	(15.4)	2	(15.4)	2	(15.4)
	50% responder	2	(15.4)	3	(23.1)	2	(15.4)	2	(15.4)	2	(15.4)
	75% responder	3	(23.1)	3	(23.1)	3	(23.1)	0	(0.0)	0	(0.0)
	Seizure free	0	(0.0)	0	(0.0)	0	(0.0)	3	(23.1)	3	(23.1)
	Responder group	5	(38.5)	6	(46.2)	5	(38.5)	5	(38.5)	5	(38.5)
Tonic seizure,	Discontinued	6	(54.5)	6	(54.5)	6	(54.5)	6	(54.5)	6	(54.5)
n = 11	No response	2	(18.2)	0	(0.0)	2	(18.2)	2	(18.2)	1	(9.1)
	50% responder	2	(18.2)	4	(36.4)	2	(18.2)	2	(18.2)	3	(27.3)
	75% responder	1	(9.1)	1	(9.1)	0	(0.0)	1	(9.1)	0	(0.0)
	Seizure free	0	(0.0)	0	(0.0)	1	(9.1)	0	(0.0)	1	(9.1)
	Responder group	3	(27.3)	5	(45.5)	3	(27.3)	3	(27.3)	4	(36.4)
Primary or secondary GTCS,	Discontinued	3	(30.0)	3	(30.0)	3	(30.0)	3	(30.0)	4	(40.0)
Primary or secondary GTCS,	No response	1	(10.0)	2	(20.0)	1	(10.0)	1	(10.0)	0	(0.0)
n = 10	50% responder	2	(20.0)	1	(10.0)	2	(20.0)	2	(20.0)	2	(20.0)
	75% responder	2	(20.0)	3	(30.0)	1	(10.0)	1	(10.0)	1	(10.0)
	Seizure free	2	(20.0)	1	(10.0)	3	(30.0)	3	(30.0)	3	(30.0)
	Responder group	6	(60.0)	5	(50.0)	6	(60.0)	6	(60.0)	6	(60.0)
Atonic seizure,	Discontinued	3	(30.0)	3	(30.0)	3	(30.0)	3	(30.0)	3	(30.0)
n = 10	No response	0	(0.0)	2	(20.0)	2	(20.0)	3	(30.0)	3	(30.0)
	50% responder	3	(30.0)	3	(30.0)	2	(20.0)	1	(10.0)	1	(10.0)
	75% responder	2	(20.0)	2	(20.0)	2	(20.0)	1	(10.0)	1	(10.0)
	Seizure free	2	(20.0)	0	(0.0)	1	(10.0)	2	(20.0)	2	(20.0)
	Responder group	7	(70.0)	5	(50.0)	5	(50.0)	4	(40.0)	4	(40.0)
Myoclonic seizure,	Discontinued	2	(22.2)	3	(33.3)	3	(33.3)	3	(33.3)	3	(33.3)
n = 9	No response	1	(11.1)	1	(11.1)	0	(0.0)	0	(0.0)	0	(0.0)
	50% responder	2	(22.2)	1	(11.1)	2	(22.2)	2	(22.2)	2	(22.2)
	75% responder	3	(33.3)	3	(33.3)	2	(22.2)	3	(33.3)	1	(11.1)
	Seizure free	1	(11.1)	1	(11.1)	2	(22.2)	1	(11.1)	3	(33.3)
	Responder group	6	(66.7)	5	(55.6)	6	(66.7)	6	(66.7)	6	(66.7)
GTCS: generalized tonic-clonic seizure, Responder group: total of 50% responder, 75% responder and seizure free

The median (range) PER dose among patients who could continue PER treatment was 6 mg/day (8–3 mg) at 12 months, 7 mg/day (3–8 mg) at 24 months, and 8 mg/day (3–10 mg) at 36, 48, and 60 months. The number of patients in the responder group with any seizure type was seven (43.8%) between 12 and 60 months. In addition, the number of patients in the responder group for all seizure types was four (25.0%) at 12 months, five (31.3%) at 24 months, four (25.0%) at 36 months, and three (18.8%) at 48 and 60 months (Suppl. table 4).

Regarding the relationship between the profile of each patient and the proportion of the responder group at 60 months, there was a significantly higher proportion of responders among patients with tonic seizures when the seizure frequency group was higher before PER initiation (Table 3).

Table 3

Relationship between the profile of each patient and the responder group at 60 months
		Focal seizure, n = 13		Atypical absence seizure, n = 13		Tonic seizure, n = 11		Primary or secondary GTCS, n = 10		Atonic seizure, n = 10		Myoclonic seizure, n = 9
		Responder, n = 5	p-value	Responder, n = 5	p-value	Responder, n = 4	p-value	Responder, n = 6	p-value	Responder, n = 4	p-value	Responder, n = 6	p-value
Sex	Male	3	> 0.999	2	0.592	3	0.546	3	0.571	3	> 0.999	4	> 0.999
Age at seizure onset	< 2 years old	2	0.592	1	0.266	2	> 0.999	2	0.076	1	0.524	2	0.167
Structural abnormality on brain MRI		2	0.592	1	0.266	2	> 0.999	2	> 0.999	1	0.191	2	0.500
DEE type	LGS	3	0.511	3	0.511	4	> 0.999	4	0.524	2	0.500	4	> 0.999
	EMAtS	2	0.128	2	0.128	0	> 0.999	2	0.467	2	0.500	2	0.500
	Dravet syndrome	0	> 0.999	0	0.110	0	> 0.999	0	0.400	0	> 0.999	0	0.333
	SZT2 mutation	0	> 0.999	0	> 0.999	0	> 0.999	0	0.400	0	> 0.999	0	> 0.999
	TSC	0	> 0.999	0	> 0.999	0	> 0.999	0	0.400	0	> 0.999	0	> 0.999
Intellectual ability	Borderline to mild intellectual disability	1	> 0.999	2	> 0.999	0	0.236	2	0.467	1	> 0.999	1	> 0.999
	Severely retarded	2	> 0.999	1	> 0.999	2	0.491	1	0.500	0	0.200	2	> 0.999
	Autism spectrum disorder	2	0.592	3	> 0.999	2	0.491	4	> 0.999	3	> 0.999	3	> 0.999
Number of concomitant ASMs	< 4 drugs	0	0.487	0	0.487	0	0.491	0	0.133	0	> 0.999	0	0.333
With enzyme-induced ASM		2	0.293	2	> 0.999	1	> 0.999	3	0.571	2	> 0.999	2	> 0.999
Median seizure frequency (/month)		45	0.304	40	0.087	60	0.028*	7	0.235	12	0.665	30	0.692
Titration schedule	Every 2 weeks	1	0.266	2	> 0.999	0	0.194	2	> 0.999	1	0.524	1	> 0.999
MRI, magnetic resonance imaging; DEE, developmental and epileptic encephalopathy; LGS, Lennox-Gastaut syndrome; EMAtS, epilepsy with myoclonic atonic seizures; TSC, Tuberous sclerosis complex; ASM, antiseizure medication
*: p-value < 0.05

2–4. Safety

During the study period, twelve (75.0%) patients experienced adverse events, including six (37.5%) patients with somnolence, five (31.3%) with emotional changes such as irritability or agitation (three with irritability, and two with agitation), two (12.5%) with dizziness, and one (6.3%) with athetosis. One (6.3%) patient experienced a combination of somnolence with emotional changes and dizziness with emotional changes.

Except for two patients who discontinued PER due to adverse events (one with athetosis and one with dizziness and emotional changes), the others had mild symptoms. Almost all adverse events occurred gradually within two weeks after PER initiation or dose escalation; moreover, the adverse symptoms improved following adjustment of the PER dose or reduction of concomitant medications. Additionally, no patient complained of adverse reactions at 60 months after PER initiation.

Regarding the relationship between adverse events and background characteristics, somnolence and dizziness were significantly more frequent among patients with severe retardation and borderline-to-mild intellectual disability, respectively (Table 4).

Table 4

Relationship between adverse events and patients’ background characteristics
Adverse events		Somnolence, n = 6		Emotional change, n = 5		Dizziness, n = 2		Athetosis, n = 1		Total, n = 12
		n	p-value	n	p-value	n	p-value	n	p-value	n	p-value
Sex	Male	4	0.633	2	0.596	0	0.175	1	> 0.999	7	> 0.999
Age at seizure onset	< 2 years old	4	0.633	2	0.596	1	> 0.999	0	0.438	6	0.585
Structural abnormality on brain MRI		3	> 0.999	1	0.301	2	0.175	1	0.438	6	0.585
DEE type	LGS	4	> 0.999	5	0.119	2	> 0.999	1	> 0.999	10	0.063
	EMAtS	1	> 0.999	0	> 0.999	0	> 0.999	0	> 0.999	1	0.450
	Dravet syndrome	0	> 0.999	0	> 0.999	0	> 0.999	0	> 0.999	0	0.250
	SZT2 mutation	0	> 0.999	0	> 0.999	0	> 0.999	0	> 0.999	0	0.250
	TSC	1	0.438	0	> 0.999	0	> 0.999	0	> 0.999	1	> 0.999
Intellectual ability	Borderline to mild intellectual disability	0	0.234	1	> 0.999	2	0.049*	1	0.25	3	> 0.999
	Severely retarded	4	0.036*	1	> 0.999	0	> 0.999	0	> 0.999	4	> 0.999
	Autism spectrum disorder	4	> 0.999	3	> 0.999	1	> 0.999	1	> 0.999	8	0.604
Number of concomitant ASMs	< 4 drugs	0	0.250	1	> 0.999	1	0.350	0	> 0.999	1	0.136
With enzyme-induced ASMs		2	0.608	1	0.282	1	> 0.999	1	> 0.999	5	0.569
Titration schedule	Every 2 weeks	2	> 0.999	1	0.588	2	0.125	1	0.375	5	> 0.999
MRI, magnetic resonance imaging; DEE, developmental and epileptic encephalopathy; LGS, Lennox-Gastaut syndrome; EMAtS, epilepsy with myoclonic atonic seizures; TSC, Tuberous sclerosis complex; ASM, antiseizure medication
*: p-value < 0.05

This study investigates the efficacy and tolerability of PER treatment for DEEs over 60 months.

A five-year study of clobazam in patients with LGS reported 82%, 75%, and 85% seizure reduction from baseline at 3, 4, and 5 years, respectively [39]. High-purity cannabidiol reduced seizure frequency in patients with LGS by 53% from baseline at 145–156 weeks after initiation [40]. Valproate is recommended as the first-line drug for the treatment of EMAtS [41]. Recent studies on the treatment of epilepsy in patients with EMAtS have investigated the efficacy of felbamate [42] and cannabidiol [43]. However, there have been no reports of outcomes with long-term use of a specific drug. Regarding the treatment of Dravet syndrome with ASMs, 3-year outcomes have been reported for stiripentol (long-term outcomes for patients with > 50% seizure reduction; efficacy rates of 48% and 55% for GTCS and focal seizures, respectively) [44], fenfluramine (70% of patients remained seizure-free for a mean duration of 6 years and 7 months) [45], and cannabidiol (43% efficacy rate at 145–156 weeks after initiation) [46]. In this study, the 3-year efficacy rates of PER were 30.8% for focal seizure, 38.5% for atypical absence seizure, 27.3% for tonic seizure, 60.0% for primary or secondary GTCS, 50.0% for atonic seizure, and 66.7% for myoclonic seizure (Table 2). It is difficult to compare PER with other drugs due to differences in the evaluation methods across previous studies [39–41, 44–47]. However, although PER is less effective than clobazam for LGS [39], it is likely to have similar long-term efficacy as cannabidiol for LGS and Dravet syndrome [40, 41]. Although PER, like cannabidiol, does not have very high efficacy because DEEs are comorbid with very refractory epilepsy, it shows good potential to suppress seizures. Cannabidiol has yet to be approved in Japan as of March 2024; further, in Europe, it is only approved for patients with Dravet syndrome, LGS, and TSC [49]. PER has the advantage that it can be used in all patients with DEEs since it can be used regardless of the epilepsy syndrome (i.e., it is not limited to patients with Dravet syndrome, LGS, or TSC).

Regarding PER, the short-term (3–12 months) efficacy rates for refractory epilepsy, including DEEs such as LGS and Dravet syndrome, range from 30–69% [26, 27, 29–33], which is consistent with our findings. Additionally, we confirmed that the efficacy rates at 12–24 months after PER initiation were maintained for up to 60 months for all seizure types.

Regarding the efficacy against each syndrome, PER was highly effective for every seizure type in patients with EMAtS, without significant differences according to seizure type. To our knowledge, there have been no studies on the use of PER for EMAtS. EMAtS is an age-dependent syndrome in which seizures often disappear within 3 years of onset; however, it shows high drug resistance during the early stages of the onset [47, 48]. In our study, one of the patients with EMAtS was 2 years 2 months from onset (the other patient was 6 years 4 months from onset), and the natural history of EMAtS may have affected the efficacy rate. In other words, the possibility cannot be ruled out that the decrease in seizures was not due to the effect of PER treatment but because the patient reached 3 years old during treatment. The responder rate of PER for myoclonic seizures in patients with idiopathic generalized epilepsy and juvenile myoclonic epilepsy is reported to be 85–89% [50]. Gamma-aminobutyric acid (GABA) receptor dysfunction has been associated with the onset of myoclonic seizures [51]. AMPA receptors are present in developing GABAergic terminals, and their activation inhibits GABAergic activity [52, 53]. Inhibition of the AMPA receptor by PER may activate GABAergic function. Although the relationship between AMPA receptors and myoclonic seizures is unknown, the responder rate for myoclonic seizures in this study was high, especially in EMAtS cases, where myoclonic seizures were suppressed in 2 out of 2 cases (100%). PER is not targeted to a specific seizure type. However, when effective, it is often effective for all seizure types in an “all or nothing” manner [35], and the high sensitivity for myoclonic seizures may have influenced the high responder rate for EMAtS cases in this study.

A variety of genetic mutations can cause DEEs. However, only three of the cases included in this study had genetic analysis, including one LGS case with tetrasomy 15q, one case with SCN1A mutation (Dravet syndrome), and one case with SZT2 mutation. The case with tetrasomy 15q was in the responder group, but the other cases had no efficacy for PER and discontinued it. It is reported that the efficacy of PER is high for cases with SCN1A, GNAO1, PIGA, SYNGAP1, CDKL5, NEU1, PCDH19, POLG1, and POLG2 mutations [54]. In addition, there are case reports of PER’s effectiveness, including epsilon sarcoglycan gene mutation [55] and GRIN1 mutation [36]. Tetrasomy 15q is known as a chromosomal abnormality that can cause LGS [56], and its epileptogenesis is said to be due to a rearrangement of the α5 and β3 GABA receptor subunit gene [57]. Although there are no reports of the use of PER for patients with Tetrasomy 15q, PER may be effective in epilepsy, a genetically abnormal disorder that results in the inhibition of GABAergic function [54]. Regarding Dravet syndrome, effectiveness for PER in cases with SCN1A c.2588 T > C, p.Leu863Ser or c.4547C > A, p.Ser1516* has been reported [35, 58]. The mutation site of the SCN1A in the patient with Drave syndrome in this study was c.664C > T, p.Arg222*. PER for patients with SCN1A mutation is highly effective in suppressing epileptic seizures, but in 33–5% of cases, it has been reported to be less effective [31, 54]. The reason may lie in the difference in amino acid mutation sites. Regarding EMAtS, genetic mutations such as SLC2A1, SLC6A1, CHD2, SCN1A, and GABRG2 are known to cause it [59], but the genetic analysis was not performed in our patients with EMAtS. Therefore, we do not know whether the cases with EMAtS in this study were genetically highly effective for PER. If the genetic factors of the effective cases and their relationship to the AMPA receptor are found, the genetic information for each patient could help select PER as the ASM for the patient. On the other hand, in real-world clinical practice, genetic analysis is not performed in all cases of refractory epilepsy, including DEEs. We believe that the purpose and result of this report would not change even if the genetic variants of all the cases included in this study were revealed.

The reported incidence of adverse events among patients with DEEs ranged from 22–70%, with 9–18%, 5–50%, 10–22%, and 32% for dizziness, somnolence, emotional changes, and behavioral disturbances, respectively [5, 26, 27, 29–33]. The relationship between adverse events of PER and background characteristics in patients with DEEs remains unclear. Our findings indicated that somnolence and dizziness were significantly more frequent among patients with severe retardation and those with borderline-to-mild intellectual disability, respectively. However, most adverse events were mild, and we do not believe that PER should be excluded as a treatment option for patients with severe retardation or borderline-to-mild intellectual disability.

This study has several limitations. First, this study had a small sample size. It was difficult to increase the sample size because this study focused on rare diseases. Due to the small number of cases, it is difficult to draw conclusions regarding the efficacy of PER based on the results of this study alone. Second, we could not perform long-term EEG monitoring or evaluate subclinical seizures. Third, since we could not perform routine monitoring of the blood concentration of PER, we could not evaluate the relationship between the blood concentration and efficacy or safety. Fourth, emotional changes in patients with severe retardation may have been overlooked in the absence of behavioral disorders such as violence. In addition, regarding somnolence, there is an objective indicator that even patients with severe retardation sleep longer; however, dizziness might have been underestimated since it is a subjective symptom. Moreover, in case of severe intellectual disability, the patient may not complain of dizziness, even if it was present. Conversely, the possibility cannot be ruled out that adverse events may have been overlooked due to the intellectual and motor abilities of each case.

4 − 1. Study design and patients

This retrospective study included patients who visited the Department of Pediatrics, Tochigi Children’s Medical Center at Jichi Medical University. The inclusion criteria were as follows: (i) developmental delay or regression after onset, (ii) seizures not controlled after treatment with two or more drugs, (iii) multidrug treatment for ≥ 2 years after onset [60], and (iv) patients who started PER treatment between June 2016 and May 2018. The exclusion criteria were as follows: (i) patients who were transferred to a different hospital during the study period and could not be followed up, (ii) patients who received additional ASMs and/or underwent surgery for epilepsy after PER initiation, and (iii) patients who restarted PER after discontinuation. Patients who discontinued PER were also considered excluded cases if they had episodes that fit (i) or (ii) during the 60-month period after starting PER.

The diagnostic criteria for LGS are as follows: (i) various types of seizures, including tonic seizures, atonic seizures, atypical absence seizures, and GTCS, and (ii) > 3 Hz slow spike and waves during awake state and rapid rhythms of 10–20 Hz during the sleep state on EEG [26, 27]. The diagnostic criteria for EMAtS are as follows: (1) normal development and cognition before the onset of epilepsy; (2) onset of epilepsy between the ages of 6 months and 6 years (peak: 2–4 years); (3) mandatory presentation of myoclonic-atonic seizures; (4) presence of generalized spike-wave discharges at 2–3 Hz without persistent focal spike discharges [59]. The diagnostic criteria for Dravet syndrome are as follows: (i) onset of prolonged febrile or afebrile focal seizures or GTCS at ≥ 1 year of age, (ii) onset of myoclonic or atypical absence seizures at ≥ 1 year of age, (iii) status epilepticus induced by fever or bathing, and (iv) cognitive and behavioral disorders after onset [61].

4 − 2. Data collection

The following data were collected from electronic medical records: age at PER initiation, sex, age at onset, structural abnormalities on brain MRI, background disease, genetic abnormalities, DEE type, severity of intellectual disability, number of ASMs used prior to PER initiation, history of surgical therapy and/or ketone diet, ASMs used concomitantly upon PER initiation, seizure type, and PER titration schedule. The mean seizure frequencies of each seizure type within 3 months before PER initiation were compared with those at 12, 24, 36, 48, and 60 months after PER initiation. Patients with < 50%, 50–74%, 75–99%, and 100% seizure reduction were classified as no response, 50% responders, 75% responders, and seizure-free, respectively. Patients who discontinued PER and had no response were included in the non-responder group; moreover, 50% responders, 75% responders, and seizure-free patients were included in the responder group.

4 − 3. Statistical analysis

All statistical analyses were performed using the R software program version 4.3.2 (https://crane.r-project.org, accessed on 29 Dec 2023) (R Foundation for Statistical Computing, Vienna, Austria). The Fisher’s exact test was used to evaluate background factors related to the retention of PER. These factors included sex, age at onset (< 2 years vs. ≥2 years), structural abnormalities on MRI, DEE type, intellectual ability (borderline-to-mild vs. moderate-to-most severe intellectual disability), number of ASMs used before PER initiation (< 10 vs. ≥10), number of concomitant ASMs at PER initiation (< 4 vs. ≥4), use of enzyme-induced ASMs (carbamazepine, phenytoin, and phenobarbital), and the titration schedule. Similarly, the Fisher’s test was used to evaluate background factors related to the responder group and cases with adverse events regarding sex, age at onset (< 2 years vs. ≥2 years), structural abnormalities on MRI, DEE type, intellectual ability (borderline-to-mild vs. moderate-to-most severe intellectual disability), number of ASMs used before PER initiation (< 10 vs. ≥10), number of concomitant ASMs at PER initiation (< 4 vs. ≥4), use of enzyme-induced ASMs (carbamazepine, phenytoin, and phenobarbital), and the titration schedule. The Mann-Whitney U test was used to evaluate the relationship between age at PER initiation and PER discontinuation. Similarly, the Mann-Whitney U test was used to evaluate the relationship between age at PER initiation and the responder group, age at initiation and the cases with adverse events, and seizure frequency and the responder group.

4–4. Ethics

This study was approved by the ethics committee of Jichi Medical University (Jichi Medical University 17–118). This study had been performed according to the Declaration of Helsinki. Upon PER initiation, informed consent was obtained from the patients and their parents. If patients had difficulty expressing their intention due to their intellectual ability or age, we only obtained informed consent from their parents. PER prescriptions for patients aged < 12 years were for off-label use at the time of the study initiation [12], which was explained to the patients or their parents.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Author contribution

H.Y. wrote the manuscript; H.O. and T.T. contributed to the conceptualization and design of this study; H.Y., H.O., K.M., K.K., Y.M., T.M., Y.A., K.W., and K.N. collected and analyzed data; H.O., K.M., and T.T. critically reviewed the manuscript and supervised the entire study process. All authors have read and approved the final manuscript.

Data availability statement

All data generated in this study are provided in the manuscript and Supplementary Information.

Funding

None.

Acknowledgments

Ms. Makiko Mieno, Associate Professor in the Department of Medical Informatics at the Center for Information, Jichi Medical University, supervised the statistical analysis. We express our gratitude to all the patients and their parents for their cooperation and participation in this study. We would also like to thank the medical colleagues of the Jichi Medical University Tochigi Children’s Medical Center, who are devoted to the treatment of patients with refractory epilepsy.

Scheffer, I. E. et al. Classification of the epilepsies: New concepts for discussion and debate-Special report of the ILAE classification task force of the commission for classification and terminology. Epilepsia Open1, 37–44 (2016).
Scheffer, I. E. et al. ILAE classification of the epilepsies: Position paper of the ILAE commission for classification and terminology. Epilepsia58, 512–521 (2017)
Wirrell E, Tinuper P, Perucca E, Moshé SL. Introduction to the epilepsy syndrome papers. Epilepsia63, 1330–1332 (2022).
Trivisano. M. et al. CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures. Epilepsy Behav.51, 53–56 (2015).
Alonso-Singer, P. et al. Perampanel as adjuvant treatment in epileptic encephalopathies: a multicenter study in routine clinical practice. Epilepsy Behav. 134, 108836 (2022).
Gallop, K., Wild, D., Nixon, A., Verdian, L. & Cramer, J.A. Impact of Lennox-Gastaut syndrome (LGS) on health-related quality of life (HRQL) of patients and caregivers: literature review. Seizure 18, 554–558 (2009).
Lemmon, M. E. et al. Efficacy of the ketogenic diet in Lennox-Gastaut syndrome: a retrospective review of one institution’s experience and summary of the literature. Dev Med Child Neurol. 54, 464–468 (2012).
Lancman, G. et al. Vagus nerve stimulation vs. corpus callosotomy in the treatment of Lennox- Gastaut syndrome: a meta-analysis. Seizure22, 3–8(2013).
Douglass, L.M. & Salpekar, J. Surgical options for patients with Lennox-Gastaut syndrome. Epilepsia55, 21–28 (2014).
Autry, A.R., Trevathan, E., Van Naarden Braun, K. & Yeargin-Allsopp, M. Increased risk of death among children with Lennox-Gastaut syndrome and infantile spasms. J Child Neurol.25, 441–447 (2010).
Zaccara, G., Giovannelli, F., Cincotta, M., & Iudice, A. AMPA receptor inhibitors for the treatment of epilepsy: the role of perampanel. Expert Rev Neurother.13, 647–655 (2013).
Ikemoto, S., Hamano, S. I., Hirata, Y., Matsuura, R. & Koichihara, R. Perampanel in lissencephaly-associated epilepsy. Epilepsy Behav Case Rep.11, 67–69 (2019).
Steinhoff, B. J., et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia54, 1481–1489 (2013).
French, J.A. et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial. Neurology85, 950–957 (2015).
Biro, A. et al. Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies: first experiences. Neuropediatrics46, 110–116(2015).
Villanueva. V. et al. Safety, efficacy and outcome-related factors of perampanel over 12 months in a real-world setting: The FYDATA study. Epilepsy Res.126, 201–210 (2016).
Huber. B., & Schmid, G. A two-year retrospective evaluation of perampanel in patients with highly drug-resistant epilepsy and cognitive impairment. EpilepsyBehav. 66, 74–79 (2017).
Villanueva, V. et al. Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12-month general study. Epilepsia59, 1740–1752 (2018).
Ikemoto, S., Hamano, S. I., Hirata, Y., Matsuura, R. & Koichihara, R. Efficacy and serum concentrations of perampanel for treatment of drug-resistant epilepsy in children, adolescents, and young adults: comparison of patients younger and older than 12 years. Seizure73, 75–78 (2019).
Villanueva, V. et al. PERMIT study: a global pooled analysis study of the effectiveness and tolerability of perampanel in routine clinical practice. J Neurol.269, 1957–1977 (2022).
French, J. A. et al. Long-term open-label perampanel: Generalized tonic-clonic seizures in idiopathic generalized epilepsy. Epilepsia Open7, 393–405 (2022).
Im K, et al. Long-term efficacy and safety of perampanel as a first add-on therapy in patients with focal epilepsy: Three-year extension study. Epilepsy Behav. 125, 108407 (2021).
Piña-Garza, J. E. et al. Assessment of the long-term efficacy and safety of adjunctive perampanel in adolescent patients with epilepsy: post hoc analysis of open-label extension studies. Epilepsy Behav.135, 108901 (2022).
Rektor, I. et al. Assessment of the long-term efficacy and safety of adjunctive perampanel in tonic-clonic seizures: analysis of four open-label extension studies. Epilepsia61, 1491–1502 (2020).
Krauss, G. L. et al. Final safety, tolerability, and seizure outcomes in patients with focal epilepsy treated with adjunctive perampanel for up to 4 years in an open-label extension of phase III randomized trials: Study 307. Epilepsia59, 866–876 (2018).
Auvin, S., Dozieres, B., Ilea, A. & Delanoë, C. Use of perampanel in children and adolescents with Lennox-Gastaut syndrome. Epilepsy Behav.74, 59–63 (2017).
Crespel, A., Tang, N. P. L., Macorig, G., Gelisse, P. & Genton P. Open-label, uncontrolled retrospective study of perampanel in adults with Lennox-Gastaut syndrome. Seizure75, 66–69 (2020).
Maeda, A. et al. Exacerbation of repetitive falls due to atonic seizures following perampanel administration. Cureus15, e40818 (2023).
Steinhoff, B. J. et al. First clinical experiences with perampanel--the Kork experience in 74 patients. Epilepsia55, 16–18 (2014).
Qu, R. et al. Use of perampanel in children with refractory epilepsy of genetic aetiology. Epileptic Disord. 24, 687–695 (2022).
Chang, F. M., Fan, P. C., Weng, W. C., Chang, C. H. & Lee, W. T. The efficacy of perampanel in young children with drug-resistant epilepsy. Seizure75, 82–86 (2020).
Lin, K. L. et al. Efficacy and tolerability of perampanel in children and adolescents with pharmacoresistant epilepsy: the first real-world evaluation in Asian pediatric neurology clinics. Epilepsy Behav.85, 188–194 (2018).
Yoshitomi, S. et al. Efficacy and tolerability of perampanel in pediatric patients with Dravet syndrome. Epilepsy Res. 154, 34–38 (2019).
Matricardi, S. et al. Long-term effectiveness of add-on perampanel in patients with Lennox-Gastaut syndrome: a multicenter retrospective study. Epilepsia (2023) 64, e98–e104.
Turón-Viñas, E. et al. Long-term efficacy of perampanel in a child with Dravet syndrome. Child Neurol Open8, 2329048X211050711 (2021).
Dicanio, D., Nicotera, A. G, Cucinotta, F. & Di Rosa, G. Perampanel treatment in early-onset epileptic encephalopathy with infantile movement disorders associated with a de novo GRIN1 gene mutation: a 3-year follow-up. Neurol Sci.42, 1627–1629 (2021).
Tsuchida, N. et al. Novel biallelic SZT2 mutations in 3 cases of early-onset epileptic encephalopathy. Clin Genet.93, 266–274 (2018).
Northrup, H. & Krueger, D. A. International tuberous sclerosis complex consensus group. tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International tuberous sclerosis complex consensus conference. Pediatr Neurol. 49, 243–254 (2013).
Conry, J. A. et al. Stable dosages of clobazam for Lennox- Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years. Epilepsia55, 558–567 (2014).
Patel, A. D. et al. Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: results of a long-term open-label extension trial. Epilepsia62, 2228–2239 (2021).
Nickels, K. et al. How do we diagnose and treat epilepsy with myoclonic-atonic seizures (Doose syndrome)? Results of the pediatric epilepsy research consortium survey. Epilepsy Res. 144, 14–19 (2018).
Reed, L. al. Efficacy of felbamate in a cohort of patients with epilepsy with myoclonic atonic seizures (EMAtS). Epilepsy Res. 201, 107314 (2024).
Caraballo, R. H. et al. Cannabidiol in children with treatment-resistant epilepsy with myoclonic-atonic seizures. Epilepsy Behav.143, 109245 (2023).
Myers, K. A., Lightfoot, P., Patil, S. G., Cross J. H. & Scheffer, I. E. Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study. Dev Med Child Neurol. 60:574–578 (2018).
Ceulemans, B. et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia53, 1131–1139 (2012).
Scheffer, I. E. et al. Add-on cannabidiol in patients with Dravet syndrome: results of a long-term open-label extension trial. Epilepsia62, 2505–2517 (2021).
Oguni, H. et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics33, 122–132 (2002).
Trivisano, M. et al. Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution. Epilepsy Res. 97, 133–141 (2011).
Sills, G. J. Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies. Ther Adv Neurol Disord. 16, 17562864231191000 (2023).
D’Souza, W. et al. Perampanel for the treatment of patients with myoclonic seizures in clinical practice: evidence from the PERMIT study. Seizure100, 56–66 (2022)
Hirose, S. Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Prog Brain Res. 213, 55–85 (2014).
Satake, S., Saitow, F., Yamada, J. & Konishi, S. Synaptic activation of AMPA receptors inhibits GABA release from cerebellar interneurons. Nat Neurosci.3, 551–558 (2000).
Fiszman, M. L., Erdélyi, F., Szabó, G. & Vicini, S. Presynaptic AMPA and kainate receptors increase the size of GABAergic terminals and enhance GABA release. Neuropharmacology52, 1631–1640 (2007).
Nissenkorn A, Kluger G, Schubert-Bast S, Bayat A, Bobylova M, Bonanni P, et al. Perampanel as precision therapy in rare genetic epilepsies. Epilepsia (2023) 64:866-874.
Belli, E. et al. Perampanel as a novel treatment for subcortical myoclonus in myoclonus-dystonia syndrome. Neurol Sci. 44, 2943–2945 (2023).
Battaglia, A. et al. The inv dup(15) syndrome: a clinically recognizable syndrome with altered behaviour, mental retardation and epilepsy. Neurology48, 1081–1086 (1997).
Battaglia, A. The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet J Rare Dis. 3, 30 (2008).
Ishikawa, N. et al. Successful treatment of intractable life-threatening seizures with perampanel in the first case of early myoclonic encephalopathy with a novel de novo SCN1A mutation. Seizure71, 20–23 (2019).
Oguni, H. Epilepsy with myoclonic-atonic seizures, also known as Doose syndrome: Modification of the diagnostic criteria. Eur J Paediatr Neurol. 36, 37–50 (2022).
Kwan, P. et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE commission on therapeutic strategies. Epilepsia 51:1069–1077 (2010).
Dravet C. Severe myoclonic epilepsy in infants and its related syndromes. Epilepsia41, 7 (2000).

No competing interests reported.

SFigure1.tif
Supplementary Figure 1. The retention rate of perampanel. The retention rate was 62.5% at 6 months, 56.3% at 12 months, 50.0% at 24–48 months, and 43.8% at 60 months.
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Perampanel reduces seizure frequency in patients with developmental and epileptic encephalopathy for a long term

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Abstract

1. Introduction

2. Results

2 − 1. Characteristics of patients

2–2. Retention rate

2–3. Efficiency

2–4. Safety

3. Discussion

4. Methods

4 − 1. Study design and patients

4 − 2. Data collection

4 − 3. Statistical analysis

4–4. Ethics

Declarations

References

Additional Declarations

Supplementary Files

Status:

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