The Cognitive and Behavioural Effects of Perampanel in Children with Neurodevelopmental Disorders: A Systematic Review
Abstract
:1. Introduction
2. Materials and Methods
2.1. Searching Strategy and Review Organization
2.2. Searching Strategy and Review Organization
3. Results
3.1. Literature Search
3.2. Effect of PER on Cognitive Function with Single Domains Analysis
3.3. Effect of PER on Behaviour and Psychiatric Status
3.4. Cognitive and Behavioural Effects of PER in Children with Neurodevelopmental Disorders
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
References
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N | Authors, Year | Type of Study | Population and Neurodevelopmental Disorder Examined | Age Group | Treatment | Cognitive and Behavioural Effects | Main Findings |
---|---|---|---|---|---|---|---|
1 | Meador et al., 2016 [11] | Randomized, double-blind, placebo-controlled, parallel-group phase II study 19-week follow-up | 123 adolescents (12 to <18 years) with an IQ ≥ 70 and a diagnosis of focal-onset seizures | Adolescents aged 12 to 18 years | 79 patients treated with PER, 44 with placebo PER: 8–12 mg/day 1–2 other ASMs | CDR System Global Cognition Score (overall p > 0.05): Power of attention (p > 0.05) Working memory (p > 0.05) Quality of episodic memory ↑ (p = 0.012) Continuity of attention ↓ (p = 0.013) Speed of memory ↓ (p = 0.032) Letter fluency (p > 0.05) Category fluency (p > 0.05) LGPT (p > 0.05) | Worse performance under PER in continuity of attention and speed of memory. Better performance in quality of episodic memory. Favourable cognitive profile for PER |
2 | Villanueva et al., 2016 [13] | Multicentre, retrospective, 1-year observational study aiming at characterizing the PK profile of PER and the relationship between PER plasma concentration and cognitive function | 110 adolescents with the same characteristics as in Meador et al., 2016 [11] | Adolescents aged 12 to 18 years | Same as in Meador et al., 2016 [11] | CDR System Global Cognition Score (overall p > 0.05): Power of attention (p > 0.05) Working memory (p > 0.05) NS Quality of episodic memory ↑ (p < 0.05) Continuity of attention ↓ (p < 0.05) Speed of memory (p > 0.05) NS | No significant relationship between PER exposure and overall cognitive function |
3 | Auvin et al., 2017 [14] | Prospective cohort study Mean follow-up duration: 10.8 months (range, 1–24 months) | 13 patients with LGS. Mean age 12.8 years (median 13, range 6–18.5) Patients had received prior treatment with 6–9 different ASMs | Patients aged 6 to 18.5 years | PER was initiated at 2 mg/day and titrated to a median maximum dose of 6 mg/day (range 4–8) | Parents and physicians reported improvement in cognitive function and/or behaviour for 7 patients (53.8%) parallel to seizure reduction | No formal conclusions on cognitive function and behaviour, as they were not formally assessed but relied on anecdotal observations |
4 | Piña-Garza et al., 2018 [3] | Open-label extension phase of the trial by Meador et al., 2016 [11] | Patients who completed all scheduled visits in the double-blind phase in the study by Meador et al., 2016 [11] were eligible (114 adolescents) | Adolescents aged 12 to 18 years | Same as Meador et al., 2016 [11]; those assigned to placebo switched to PER 2 mg/day, which was up- titrated weekly in 2 mg increments, up to a maximum of 12 mg/day | CDR System Global Cognition Score (overall p > 0.05): Power of attention ↓ (p = 0.03) Working memory (p > 0.05) NS Quality of episodic memory (p > 0.05) NS Continuity of attention (p > 0.05) Speed of memory p > 0.05) Letter fluency (p > 0.05) Category fluency (p > 0.05) Lafayette Grooved Pegboard test (p > 0.05) | PER did not significantly affect cognitive parameters, except for the power of attention. No clinically meaningful effects on growth and development |
5 | Rohracher et al., 2018 [15] | Observational cohort study, 12 months | 2396 adolescents from 45 centres in Europe (95% focal-onset seizures), using PER as add-on | Adolescents aged 12 to 18 years | PER as add-on: 2 mg/day, which was up- titrated weekly in 2-mg increments, up to a maximum of 12 mg/day | No significant relationship between PER exposure and overall cognitive function. Depressed mood and mood disorders (4.8%), Mental confusion/slowing/psychomotor retardation (2.3%), Psychosis/hallucination/delusion (1.8%), Anxiety (1.6%), Sleep disturbance (1.5%), Memory problems (1.3%), Other psychiatric TEAEs, Suicidal thoughts/ideation (0.8%), Speech problems/slurred speech (0.9%) | 1-year retention rate of 48%, seizure free in 9%; TEAEs were in line with previous reports (68%) |
6 | Lin et al., 2018 [16] | Cohort study, 12 months | 66 children and adolescents (age 14.9 ± 2.3 years) with refractory epilepsy, using PER as add-on | Patients aged 14.9 ± 2.3 years | The targeted doses varied depending on clinical response and tolerability. The mean maximal dosage of add-on PER was 4.9 ± 2.9 mg (median 4 mg, range: 2–8 mg). | No significant relationship between PER exposure and overall cognitive function. The appearance of irritability and aggression were only founded in seven patients (10.6%) | TEAEs in 35.7%, leading to discontinuation of PER in 12.1%. Irritability (10.6%) was the most common |
7 | Fogarasi et al., 2020 [17] | Global, multicentre, open-label, single-arm study To evaluate the effects of PER on cognitive function, secondary safety endpoints included changes from base line in ABNAS at week 23 | 180 patients from 4 to 12 years of age | Patients aged 4 to 12 years | Mean PER dose 7.0 mg/day (range 2–16 mg/day) PER used as oral suspension (0.5 mg/mL) | No significant changes in clinics at week 23 from baseline as assessed by ABNAS in total score and each of the domains | PER did not produce any clinically significant effects on cognitive function, secondary function at week 23 safety endpoints compared with baseline |
8 | Majid et al., 2016 [18] | Report aiming at exploring the PER exposure–response relationships for cognition and safety with data from Fogarasi et al., 2020 [17] | 156 PER-treated subjects aged 4 to <12 years with partial-onset seizures or primary generalized tonic–clonic seizures | Patients aged 4 to 12 years | Same as in Fogarasi et al., 2020 [17] | No discernible relationship between PER and changes from baseline for ABNAS, CBCL, or LGPT | Cognitive function is not clinically impaired by PER administration |
9 | Santamarina et al., 2020 [19] | Cohort study, 12 months | 149 adolescents with epilepsy, using PER as add-on | Adolescents aged 12 to 18 years | The mean dose of PER among patients receiving PER at 12 months was 6.2 mg/day (median 6 mg/day) | Concomitant ASMs did not affect the tolerability of PER in the current study and adding PER did not seem to have significant effects on psychiatric comorbidities. Irritability was the most common AE leading to discontinuation | TEAEs in 48.3%, leading to PER discontinuation in 10.1%. Dizziness (15.4%), irritability (14.1%), and drowsiness (14.1%), were the most common |
10 | Kanemura et al., 2020 [20] | Cohort study, 12 months | 14 adolescents (mean age 13.3 years, age range 12.1–14.3 years) with LEV-resistant epilepsy and behavioural problems, using PER in polytherapy | Adolescents aged 12.1 to 14.3 years | Mean dose of PER was 9.43 mg/day (range, 4–12 mg/day) | Hyperactivity and impulsivity improved in 6 patients. PER does not confer any significant short- or long-term effects on the global cognition score in adolescent patients | PER treatment may be effective in decreasing behavioural problems in association with improved EEG findings |
11 | Moraes et al., 2020 [21] | Nested cohort study, 12 months | 160 adolescents with refractory focal epilepsy using PER as monotherapy or add-on | Adolescents aged 12 to 18 years | Titration was in 2 mg increments to reach a target dose (4–12 mg) and occurred weekly to monthly depending on specialist preference and patient tolerability | Improved QOL, mood, and irritability following introduction and maintenance for at least six months on PER | In the retrospective cohort, mood changes (7.6%), depression (4.3%), and irritability (6.5%) were the most common |
12 | Operto et al., 2020 [22] | Cohort study, 12 months | 37 adolescents (age 13.78 ± 1.60 years) with focal refractory epilepsy | Adolescents aged 13.78 ± 1.60 years | The mean dose of PER at T1 and T2 follow up was 3.13 ± 0.83 mg/d and 3.50 ± 0.86 mg/d, respectively | PER therapy did not significantly influence attention and executive functions; on contrary, it was possible to highlight a slight improvement in cognitive performance. Even the emotional and behavioural profile has not changed after PER, and no significant adverse effects on behaviour have been reported | No negative effect on executive function, emotion, or behaviour with PER, but 5 patients (13.5%) discontinued PER due to dizziness and headache |
13 | Operto et al., 2021 [23] | Prospective observational study, 12 months | 46 adolescents aged 12–18 years with focal and generalized refractory epilepsy already in therapy with one or two ASMs | Adolescents aged 12 to 18 years | Patients received a variable dose of PER ranging from 2 to 8 mg (mean dose = 3.40 ± 1.17) | Visuospatial memory and perception were not significantly affected by PER therapy. These results, therefore, suggest that PER has a good tolerability contour in adolescence even in the medium/long term | No significant TEAEs were reported, with the exception of transient irritability (n = 3) and dizziness (n = 2), which did not require drug withdrawal |
14 | Liguori et al., 2021 [24] | Prospective observational study | 10 children treated with PER as first add-on treatment | Children aged 11.20 ± 5.70 years | The initial titration of PER was 2 mg daily for 2 weeks, then followed by the increment to 4 to 8 mg daily until the first follow-up visit at 3 months | A significant increase in beta1 and total beta bands were found in children suggesting a beneficial effect of this drug on cognition and alertness, although the sample size was small | Positive effect of PER on attention and cognition in patients with epilepsy. PER does not worsen daytime sleepiness at 3 months |
15 | Matricardi et al., 2023 [25] | Retrospective observational cohort study | 87 patients with LGS who received PER as adjunctive treatment | Patients aged < 18 years | The titration of PER was ≤2 mg every week in 20 (23.0%) patients, 2 mg every 2 weeks in 52 (59.7%), and 2 mg every 3–4 weeks in 15 (17.3%) patients. The maxi-mum dose given was 6 (IQR = 4–8) mg/day | 20% of the patients experienced irritability and aggression, particularly in association with rapid titration, duration of epilepsy, and numerous previous treatments. | In approximately three quarters of patients who experienced TEAEs, PER was withdrawn, whereas TEAEs were no longer detectable following down-titration in the remaining cases. The inverse association between the occurrence of TEAEs and the time to seizure relapse among responders may be due to the reactive reduction in PER dosage to improve treatment tolerability. PER appears to be effective in patients with LGS and generally well tolerated, with a possible partial loss of efficacy in a few patients over time |
16 | Kanemura et al., 2021 [20] | Observational Study, 24 months | 19 patients (10 males, 9 females) between 12 and 18 years old treated with PER in monotherapy or as add-on therapy Neurodevelopmental disorder: ASD | Patients aged 12 to 18 years | After a 3 month baseline period, PER was initiated once daily, starting at a dose of 2 mg/day for the first 2 weeks, and with dosage increasing in increments of 2 mg/day every 2 weeks. PER dosage was adjusted up to a maximum of 12 mg/day, based on the judgment of the clinicians | Utility of PER in improving neuropsychiatric impairments including behavioural disturbances in ASD related to improvement in clinical seizures/frontal IEDs, and unrelated to seizure/EEG improvement in at least some ASD patients. PER may be well tolerated as a therapy even for ASD patients with intractable epilepsy. | Utility of PER in behavioural improvements for some, but not all, ASD patients. Treatment with PER appears well tolerated |
17 | Snoeijen-Schouwenaars et al., 2017 [26] | Retrospective study, 24 months | 20 children treated with PER in monotherapy or as add-on therapy Neurodevelopmental disorder: ID | Patients aged < 18 years | The initial PER dose ranged from 0.5 mg to 2 mg once a day. The titration rate was guided individually by the treating neurologist. The mean maximum daily dosage PMP was 5.6 mg (range 1–12 mg) | Behavioural adverse effects were encountered in 40.3% of patients. The most common behavioural adverse effects were aggression, agitated behaviour, disruptive behaviour, and mood symptoms. There was a trend indicating that a lower number of concomitant ASMs was associated with more behavioural adverse effects. Pre-existing behavioural problems or polypharmacy did not predict the occurrence of additional behavioural adverse effects | Side effects were encountered in nearly 60% of our patients which is in line with both the previous studies that did not focus on patients with ID. |
18 | Lagae et al., 2016 [13] | Multicenter, randomized, double-blind, placebo-controlled, parallel-group study | 85 adolescents between 12 and 17 years of age, with an intelligence quotient (IQ) score ≥ 70, and refractory focal-onset seizures, treated with PER as add-on therapy | Adolescents aged 12 to 17 years | PER as add-on therapy: 2 mg/day uptitrated weekly in 2-mg increments to a target dose range of 8–12 mg/day. | Cognitive Drug Research (CDR) System has been shown not to be significantly different from that of placebo. PER did not have a detrimental effect on “competence” or “problem” scores compared with placebo. Lack of any clinically significant impact of PER on any behavioural measures. | The most frequently reported AEs (≥10%) being dizziness, somnolence, and headache, with an overall safety profile similar to previous studies |
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Scorrano, G.; Lattanzi, S.; Salpietro, V.; Giannini, C.; Chiarelli, F.; Matricardi, S. The Cognitive and Behavioural Effects of Perampanel in Children with Neurodevelopmental Disorders: A Systematic Review. J. Clin. Med. 2024, 13, 372. https://doi.org/10.3390/jcm13020372
Scorrano G, Lattanzi S, Salpietro V, Giannini C, Chiarelli F, Matricardi S. The Cognitive and Behavioural Effects of Perampanel in Children with Neurodevelopmental Disorders: A Systematic Review. Journal of Clinical Medicine. 2024; 13(2):372. https://doi.org/10.3390/jcm13020372
Chicago/Turabian StyleScorrano, Giovanna, Simona Lattanzi, Vincenzo Salpietro, Cosimo Giannini, Francesco Chiarelli, and Sara Matricardi. 2024. "The Cognitive and Behavioural Effects of Perampanel in Children with Neurodevelopmental Disorders: A Systematic Review" Journal of Clinical Medicine 13, no. 2: 372. https://doi.org/10.3390/jcm13020372