Dataset Information

Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: A first-in-man study.

ABSTRACT: Background:A clinical feasibility study was undertaken at a single center of long-term intra-cerebroventricular drug delivery of the anti-seizure medication valproic acid, into the cerebrospinal fluid (CSF) in order to treat drug resistant focal seizures, using an implantable infusion system. The primary objective was to establish the dose range of VPA administered in this manner. Secondarily, safety, pharmacokinetics (PK) and a preliminary estimate of effectiveness were evaluated. Methods:In this single arm study, five adult subjects, with 29-234 focal onset seizures per month from a seizure focus involving the mesial temporal lobe were implanted with the system (clinicaltrials.gov identifier NCT02899611). Oral valproic acid (VPA) had previously been ineffective in all subjects. Post-surgery, pharmacokinetic studies of CSF infused VPA were performed. Valproic acid doses were increased stepwise in a standardised protocol. Findings:The procedure and implantation were well-tolerated by all subjects. Four subjects responded with > 50% seizure reduction at the highest tested dose of 160 mg/day. Two subjects experienced extended periods of complete seizure freedom. All five subjects reported significant quality of life improvement. No clinical dose limiting side effects were encountered and there was no evidence of local periventricular toxicity in three subjects who were evaluated with imaging (T2 MRI). Side effects included nausea and appetite loss but were not dose-limiting. Mean CSF valproic acid levels were 45 ?g per ml (range 20-120 ?g per ml), with corresponding serum levels of 4-14 ?g per ml. Subjects have received therapy for up to 2.5 years in total . The efficacy analysis presented focuses on the period of time with the current pump with a mean 12.5 months, range 11.5-15 months. Pump failure requiring reimplantation was a significant initial issue in all subjects but resolved with use of pumps suitably compatible with long-term exposure to valproic acid. Interpretation:The study demonstrated that chronic intraventricular administration of valproic acid is safe and effective in subjects with medically refractory epilepsy over many months. The procedure for implanting the infusion system is safe and well-tolerated. High CSF levels are achieved with corresponding low serum levels and this therapy is shown to be effective despite unsuccessful earlier use of oral valproate preparations. Drug side effects were minimal. Funding:The study was funded by Cerebral Therapeutics Inc., Suite 137 12635 East Montview Blvd Aurora CO 80045.

SUBMITTER: Cook M

PROVIDER: S-EPMC7205744 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: A first-in-man study.

Cook Mark M Murphy Michael M Bulluss Kristian K D'Souza Wendyl W Plummer Chris C Priest Emma E Williams Catherine C Sharan Ashwini A Fisher Robert R Pincus Sharon S Distad Eric E Anchordoquy Tom T Abrams Dan D

EClinicalMedicine 20200503

<h4>Background</h4>A clinical feasibility study was undertaken at a single center of long-term intra-cerebroventricular drug delivery of the anti-seizure medication valproic acid, into the cerebrospinal fluid (CSF) in order to treat drug resistant focal seizures, using an implantable infusion system. The primary objective was to establish the dose range of VPA administered in this manner. Secondarily, safety, pharmacokinetics (PK) and a preliminary estimate of effectiveness were evaluated.<h4>Me ...[more]

PMID: 32395709

Similar Datasets

Project description:OBJECTIVE:Closed-loop implantable neural stimulators are an exciting treatment option for patients with medically refractory epilepsy, with a number of new devices in or nearing clinical trials. These devices must accurately detect a variety of seizure types in order to reliably deliver therapeutic stimulation. While effective, broadly-applicable seizure detection algorithms have recently been published, these methods are too computationally intensive to be directly deployed in an implantable device. We demonstrate a strategy that couples devices to cloud computing resources in order to implement complex seizure detection methods on an implantable device platform. APPROACH:We use a sensitive gating algorithm capable of running on-board a device to identify potential seizure epochs and transmit these epochs to a cloud-based analysis platform. A precise seizure detection algorithm is then applied to the candidate epochs, leveraging cloud computing resources for accurate seizure event detection. This seizure detection strategy was developed and tested on eleven human implanted device recordings generated using the NeuroVista Seizure Advisory System. MAIN RESULTS:The gating algorithm achieved high-sensitivity detection using a small feature set as input to a linear classifier, compatible with the computational capability of next-generation implantable devices. The cloud-based precision algorithm successfully identified all seizures transmitted by the gating algorithm while significantly reducing the false positive rate. Across all subjects, this joint approach detected 99% of seizures with a false positive rate of 0.03?h-1. SIGNIFICANCE:We present a novel framework for implementing computationally intensive algorithms on human data recorded from an implanted device. By using telemetry to intelligently access cloud-based computational resources, the next generation of neuro-implantable devices will leverage sophisticated algorithms with potential to greatly improve device performance and patient outcomes.

Dataset Information

Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: A first-in-man study.

Publications

Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: A first-in-man study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets