SUMMARYPurpose: To determine whether muscimol delivered epidurally or into the subarachnoid space can prevent and/or terminate acetylcholine (Ach)-induced focal neocortical seizures at concentrations not affecting behavior and background electroencephalography (EEG) activity. Methods: Rats (n = 12) and squirrel monkeys (n = 3) were chronically implanted with an epidural or subarachnoid drug delivery device, respectively, over the right frontal/parietal cortex, with adjacent EEG electrodes. Recordings were performed in behaving rats and chaired monkeys. Via the implants, either a control solution (artificial cerebrospinal fluid, ACSF) or muscimol (0.25-12.5 mm) was delivered locally as a ''pretreatment,'' followed by the similar delivery of a seizure-inducing concentration of Ach. In five additional rats, the quantities of food-pellets consumed during epidural ACSF and muscimol (2.5 mm) exposures were measured. In a last group of four rats, muscimol (0.8-2.5 mm) was delivered epidurally during the ongoing, Achinduced EEG seizure. Results: In contrast to ACSF pretreatments, epidural muscimol pretreatment in rats completely prevented the seizures at and above 2.5 mm. In the monkeys, subarachnoid muscimol pretreatments at 2.5 mm completely prevented the focal-seizure-inducing effect of Ach, whereas similar deliveries of ACSF did not affect the seizures. Furthermore, 2.5 mm epidural muscimol left the eating behavior of rats intact and caused only slight changes in the EEG power spectra. Finally, muscimol delivery during Ach-induced EEG seizures terminated the seizure activity within 1-3 min. Conclusions: The results of this study suggest that muscimol is a viable candidate for the transmeningeal pharmacotherapy of intractable focal epilepsy.

In 2008, a group of clinicians, scientists, engineers, and industry representatives met to discuss advances in the application of engineering technologies to the diagnosis and treatment of patients with epilepsy. The presentations also provided a guide for further technological development, specifically in the evaluation of patients for epilepsy surgery, seizure onset detection and seizure prediction, intracranial treatment systems, and extracranial treatment systems. This article summarizes the discussions and demonstrates that cross-disciplinary interactions can catalyze collaborations between physicians and engineers to address and solve many of the pressing unmet needs in epilepsy.

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Long-term, periodic, transmeningeal muscimol delivery with the SPD is essentially a safe procedure. If further improved and successfully adapted for use in humans, the SPD can be used for the treatment of intractable focal neocortical epilepsy affecting approximately 150,000 patients in the US.

Intracranial pharmacotherapy is a novel strategy to treat drug refractory, localization-related epilepsies not amenable to resective surgery. The common feature of the method is the use of some type of antiepileptic drug (AED) delivery device placed inside the cranium to prevent or stop focal seizures. This distinguishes it from other nonconventional methods, such as intrathecal pharmacotherapy, electrical neurostimulation, gene therapy, cell transplantation, and local cooling. AED-delivery systems comprise drug releasing polymers and neuroprosthetic devices that can deliver AEDs into the brain via intraparenchymal, ventricular, or transmeningeal routes. One such device is the subdural Hybrid Neuroprosthesis (HNP), designed to deliver AEDs, such as muscimol, into the subdural/subarachnoid space overlaying neocortical epileptogenic zones, with electrophysiological feedback from the treated tissue. The idea of intracranial pharmacotherapy and HNP treatment for epilepsy originated from multiple sources, including the advent of implanted medical devices, safety data for intracranial electrodes and catheters, evidence for the seizure-controlling efficacy of intracerebral AEDs, and further understanding of the pathophysiology of focal epilepsy. Successful introduction of intracranial pharmacotherapy into clinical practice depends on how the intertwined scientific, engineering, clinical, neurosurgical and regulatory challenges will be met to produce an effective and commercially viable device.