Evaluating concerns for perampanel in the treatment of pediatric Dravet syndrome

With sincere appreciation for the efforts the writers have made, we address the article “Efficacy and tolerability of perampanel in pediatric patients with Dravet syndrome” by Muthaffar et al. (1). Upon examining the article, we felt the need to add a few comments. Dravet syndrome (DS) an uncommon type of epilepsy is associated with unprovoked seizures that may progress to develop neurological disturbances and psychomotor problems, reported to occur within a year of life commonly. Study shows that factors resulting in DS could be a family history of seizures and another major factor suggested is gene analysis involving de novo mutation most commonly in SCN1A, which like in many other types of infantile epileptic encephalopathies has been found but the pathophysiology of this seizure (2) and DS needs to be understood precisely and further studies are being carried out to understand it for much efficient treatment, as intractable seizures in DS are found to be resistant to usually prescribed anti-epileptics eight placebo regime. Seizures in DS show pleomorphism consisting of firstly focal seizures with or without secondary generalization in early years of life and other common types may be convulsive generalized clonic seizures (GCS), or alternating unilateral clonic, myoclonic, atypical absences with or without secondary generalization and rarely, tonic seizures (3). Thus, in the article types of seizures occurring in patients with DS need to be understood in depth to understand the perampanel (PER) mechanism of action and its efficacy concerning different types, as it has been generally considered in the study effective treatment for all types of seizures if it is effective for one type.

The methods section is well defined although detailing the inclusion and exclusion criteria is needed a little more. They have not taken into account whether any other comorbidity in the patients should be taken into account or removed. In the study, only one patient was found to have 100% efficacy and that with the maximum drug dose (8 mg) used. Therefore, it was concluded that a positive correlation is shared between max dose and PER efficacy, but it was not significant as for the study, saying increasing dosage being a definite treatment is not conclusive. Thus, to increase the efficacy of PER which is used as an adjunctive treatment preferably rather than a standalone first line, it has to be closely monitored which anti-seizures medications (ASMs) (most commonly used were valproic acid and clobazam), ketogenic diet (in well-complained patients) or surgical interventions vagal nerve stimulation, corpus callosotomy or temporal lobectomy) may be made and help work better along with PER to decrease the incidence of intractable seizures and help control the progression of neurodevelopmental delays, behavioral disturbances and also to decrease the mortality rate. The average age used in the study is 8 years the school children, how do PER side effects, commonly observed sleepiness, drowsiness, or sedation (4) affect the daily routine of children including studies, co-curricular activities, and social skills, and what could be done to help children with DS cope up with it.

Furthermore, it has to be stated whether altering the dosage has a profound impact on the patient’s health of their age or their gender although it is mentioned that younger age groups have a higher efficacy with PER (1). Also, the various side effects of PER are mentioned, but it needs to be discussed what impact varying dosages provided to different patients concerning its adjustments would have on any changes in the side effects. Various side effects from using PER were observed, remarkably, possessing suicidal thoughts, and in two cases, attempts at taking life were noted, this tendency was overpowered due to withdrawal of the drug however even though the patients had a history of psychiatric disorder it is not clear how to deal with patients having such dangerous side effects and if the withdrawal of PER is the only way of avoidance then how to continue the treatment for DS (5). Moreover, there is no mention of life expectancy in patients with DS and whether PER plays any role in improving it as there have been common cases of premature mortality in DS patients due to sudden unexpected death in epilepsy (SUDEP) and status epilepticus (6). On top of that, patients with DS are said to have neurodevelopmental delays, such as hypotonia around 1 year of age, ataxia, dysautonomia, unsteady gait, and poor fine motor abilities. The article does not mention if PER has any positive influence in correcting such disabilities (6).

The points taken into consideration highlight the need to further study the pathophysiology of PER to increase its efficacy so that it may help result in a further decrease in intractable epilepsy and neuropsychological symptom progression in children. The writers did a remarkable job of defining that PER compared to when used as an antiepileptic in adults is a lot beneficial in treating resistant refractory seizures. However, it has to be highlighted, and needs further studies on what measures could be taken to increase the PER efficacy and decrease its adverse effects.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was a standard submission to Translational Pediatrics. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-401/coif). The authors have no conflicts of interest to declare.

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References

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