Sunday, December 1, 2019

Perampanel with a focus on myoclonic epilepsy

Canafoglia L, Barbella G, Ferlazzo E, Striano P, Magaudda A, d'Orsi G, Martino T, Avolio C, Aguglia U, Sueri C, Giuliano L, Sofia V, Zibordi F, Ragona F, Freri E, Costa C, Nardi Cesarini E, Fanella M, Rossi Sebastiano D, Riguzzi P, Gambardella A, Di Bonaventura C, Michelucci R, Granata T, Bisulli F, Licchetta L, Tinuper P, Beccaria F, Visani E, Franceschetti S. An Italian multicentre study of perampanel in progressive myoclonus epilepsies. Epilepsy Res. 2019 Oct;156:106191. doi: 10.1016/j.eplepsyres.2019.106191. Epub 2019 Aug 16.

Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales. Forty-nine patients aged 36.6 ± 15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2-12 mg (5.3 ± 2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4-6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy. Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the 'Action myoclonus' section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness. PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.

Hu SC, Hung KL, Chen HJ, Lee WT. Seizure remission and improvement of neurological function in sialidosis with perampanel therapy. Epilepsy Behav Case Rep. 2018 Mar 12;10:32-34.

A 15-year-old boy experienced myoclonic seizures for 3 years. He initially had occasional myoclonus, gradually progressive ataxia, tremors, and psychomotor and speech regression developed. Eventually, he exhibited nearly continuous myoclonus. He received treatment of sodium valproate, levetiracetam, clobazam, and phenobarbital, without efficacy. A ketogenic diet also proved ineffective. Adjunctive therapy with 4 mg/day of perampanel was started and was gradually titrated to 10 mg/day. The remission of myoclonic seizures was achieved within one month. The patient's neurological and cognitive functions improved to a certain degree during the following 20 months. Sialidosis was confirmed by the mutations of NEU1 gene.

Ikemoto S, Hamano SI, 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. Seizure. 2019 Nov 5;73:75-78. doi: 10.1016/j.seizure.2019.10.023. [Epub ahead of print]

Perampanel (PER) is a selective, non-competitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor. In Japan, PER is approved for patients with epilepsy who are at least 12 years old for the adjunctive treatment of primary generalised tonic-clonic seizures and partial-onset seizures (with or without secondary generalization). We surveyed the efficacy, adverse effects, and serum concentrations of PER, focusing especially on patients younger than 12 years of age.

We retrospectively surveyed the clinical information of patients treated with PER and assessed the efficacy at 6 months after treatment initiation. We compared efficacy, adverse effects, and serum concentration in patients younger or older than 12 years of age. Responders were defined as those who experienced a ≥50% seizure reduction.

Eighty-four patients were enrolled. The average age of the younger group was 7.1 ± 3.3 (standard deviation) years compared to 16.4 ± 3.7 years in the older group. The responder rate was 42.9% (36/84). The responder rate did not differ between the two age groups (<12 years, 20/44, 45.4%; >12 years, 16/40, 40.0%; p = 0.78). The younger age group had a significantly lower concentration-to-dose (CD) ratio than the older age group (<12 years, 1849.8 ± 2209.3; >12 years, 3076.3 ± 3352.2, p = 0.02). Treatment-emergent adverse events (TEAEs) were observed in 22.6% (19/84) of patients, with the most common being somnolence (8/84, 9.5%).

PER may be an alternative to treat seizures in paediatric drug-resistant epilepsy. Serum concentrations of PER might be lower in patients younger than 12 years than in older patients.

1 comment:

  1. Enoch C.T. So, Chloe M. Mak, Grace S.F. Ng, Kwing Wan Tsui, Kam Hung Ma, and Wai Lan Yeung. Reduction in Myoclonus and Ataxia Following the Use of Perampanel in Patient With Sialidosis Type 1 Pediatric Neurology, in press

    Sialidosis is a rare autosomal recessive disorder under the umbrella of lysosomal storage diseases. The gene mutation of NEU1 in chromosome 6 results in lysosomal neuraminidase deficiency. The milder type, type 1 or the normosomatic type, has a late onset in childhood or adolescence and presents with a triad of bilateral macular cherry red spot, ataxia, and myoclonus. We hereby present a case of type 1 sialidosis with reduced myoclonus, ataxia, and improved activities of daily living after addition of perampanel….

    This boy had experienced numerous neurological symptoms by the time he presented to us at age 17 years. Born at term, he first noted hand tremor and clumsiness at age 10 years; this was followed by progressive incoordination of the legs and frequent falls at age 12 years. Over the next few years, he experienced blurred vision, nocturnal jerky movements of his arms, and subsequently, an afebrile generalized tonic-clonic convulsion at age 16 years...

    Electroencephalography was abnormal, with polyspike and wave discharges associated with his jerking movements suggestive of myoclonic seizures…

    He was treated with levetiracetam with no additional benefit with doses beyond 15 mg/kg/day. Levetiracetam reduced the witnessed nocturnal myoclonus, and he did not expereince recurrent generalized convulsions. However, his general condition and function deteriorated over the next few months, highlighted by his frequent falls and his need for assistance in daily activities including meals, bathing, walking, teeth cleansing, and defecation.

    In view of his condition, perampanel 2 mg per day was added and improvements were noted in three days. He was able to walk the entire ward length independently with reduced ataxic gait. His hand tremor diminished, as evidenced by the more legible archimedean spiral drawing and handwriting. On three-month follow-up with the daily dose of 4 mg perampanel, he has not experienced further falls, although he still needed external support when walking outside. Activities of daily living were otherwise independent. Cerebellar signs remained but were less prominent. No behavioral changes or suicidal ideation were reported. He is currently on perampanel 6 mg/day.