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 29À234 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 mg per ml (range 20À120 mg per ml), with corresponding serum levels of 4À14 mg 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 11.5À15 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.

Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

“…CED is a drug-delivery technique that uses hydrostatic pressure to deliver a drug-containing fluid by bulk flow directly into the interstitial space within a localized brain region, thus achieving a wider distribution than conventional infusion [112]. Furthermore, recently, Cook et al [117] reported that chronic i.c.v. administration of the ASD valproate is safe and effective in subjects with medically refractory epilepsy over many months.…”

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

“…Active pressure microinfusion pumps are advantageous in this respect. A recent clinical study successfully utilized a subcutaneously implanted microinfusion pump connected to a catheter system for long-term infusion of the broad-spectrum ASD valproic acid (valproate) into the ventricle of patients with sysDRE [62]. From the ventricles, the drug is distributed to the epileptic network within the brain parenchyma also via passive diffusion.…”

“…Although invasive techniques are associated with several risks of complications such as mechanical device failure, catheter obstruction, catheter misplacement, infection, rejection, CSF leak, and the need for refill [49,62], highly promising results emerged from studying the concept of intracranial drug delivery in epilepsies. Nevertheless, to avoid the risk of surgical complications associated with intracranial drug delivery, it is important to consider alternative, less invasive routes of ASD administration in sysDRE.…”

“…A first-in-man clinical study recently investigated chronic (several months), continuous unilateral icv infusion of valproate in patients suffering from drug-resistant focal seizures with or without secondary generalization [62]. Valproate is generally considered well-tolerated, and hepatotoxicity is rare, but its teratogenicity limits its chronic use in pregnant women, and other systemic adverse effects are frequently described.…”

“…Valproate is generally considered well-tolerated, and hepatotoxicity is rare, but its teratogenicity limits its chronic use in pregnant women, and other systemic adverse effects are frequently described. The study focused on dose-finding, pharmacokinetics, and safety of this approach [62]. Five TLE patients in which systemic valproate was ineffective were included in this study and were implanted sc with a pump connected to a catheter system.…”