Low dose perampanel added to levetiracetam (Keppra)

Experience of Low Dose Perampanel to Add-on in Glioma Patients with Levetiracetam-uncontrollable Epilepsy

Abstract

After introduction of levetiracetam (LEV), treatment of seizures in patients with malignant brain tumors has prominently improved. On the other hand, we still experience some cases with LEV-uncontrollable epilepsy. Perampanel (PER) is a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoaxazolepropionate acid receptor antagonist that has recently been approved for treating focal epilepsy as a secondary drug of choice. Available literature reporting PER medication in patients with gliomas is still sparse. Here, we report our initial experience with glioma patients and report efficacy of adding low dose 2-4 mg PER to LEV in patients whose seizure were uncontrollable with LEV monotherapy. Clinical outcome data of 18 consecutive patients were reviewed. This included nine males and nine females aged 24-76 years (median, 48.5 years), treated for glioma between June 2009 to December 2018. We added PER to patients with LEV-uncontrollable epilepsy. Adverse effects, irritability occurred in two patients, but continuous administration was possible in all cases. Though epileptic seizures occurred in four cases receiving 2 mg PER, 17 cases achieved seizure freedom by dose increments; final dose, 2-4 mg PER added to LEV 500-3000 mg. Our study revealed anti-epileptic efficacy of low dose PER 2-4 mg as first add-on therapy to LEV in glioma patients who have failed or intolerable to LEV monotherapy. Low dose PER added on to LEV may have favorable efficacy with tolerable adverse effects in glioma patients with LEV-uncontrollable epilepsy.

https://www.ncbi.nlm.nih.gov/pubmed/31748440

Repurposing perampanel (glutamate receptor blocker)?

About a week ago there was a major study published in the journal Nature called "Glutamatergic synaptic input to glioma cells drives brain tumour progression".

https://www.ncbi.nlm.nih.gov/pubmed/31534219

I've uploaded the full study to the Pathology folder in the Brain Tumor Library.

The study discovers a communication network between neurons and glioma cells, with certain effects (including tumor invasiveness) mediated by AMPA type glutamate receptors. Furthermore, these effects were blocked in vitro by the approved AMPA glutamate receptor antagonists, perampanel.

Perampanel was approved in 2012 for  partial seizures and generalized tonic-clonic seizures for people older than 12 years, so could also have anti-seizure effects in addition to potential anti-tumor effects.

The relevant discussion from the Nature paper is as follows:
The selective non-competitive AMPAR antagonist perampanel is an approved antiepileptic drug shown to have potential antitumour effects in patients with glioma and warrants further investigation. Chronic administration of perampanel to xenografted mice decreased the proliferation of GB cells as determined by in vivo imaging of tumour regions over time (Fig. 5j, k, Extended Data Fig. 9a) independently of cell-autonomous effects as determined by an in vitro proliferation assay (Extended Data Fig. 9b).

This is not the first paper to discuss perampanel effects on glioma and/or seizure control for glioma patients. For example:

AMPA receptor antagonist perampanel affects glioblastoma cell growth and glutamate release in vitro
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211644

Adjunctive perampanel for glioma-associated epilepsy.
https://www.ncbi.nlm.nih.gov/pubmed/30377587

Perampanel for uncontrollable seizures and tumor volume reduction

New study:  Seizures and Tumor Progression in Glioma Patients with Uncontrollable Epilepsy Treated with Perampanel.

https://www.ncbi.nlm.nih.gov/pubmed/29970574  (abstract only)

http://sci-hub.tw/10.21873/anticanres.12737  (PDF download from sci-hub)


"Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free"

"Tumor volume and peritumoral edema within 6 months were volumetrically analyzed by MRI-FLAIR images, and the volume changes were evaluated. The tumor volume decreased in eight of 9 patients during 6 months by FLAIR image (Figure 2) and increased in one (Case 9) of 9 patients"


See also

Seizure response to perampanel in drug-resistant epilepsy with gliomas: early observations

https://www.ncbi.nlm.nih.gov/pubmed/28492978