Perspectives: Developing a hybrid neuroprosthesis for epilepsy treatment

An ambitious program to develop a novel intracranial therapeutic device for the treatment of epilepsies that are both drug-resistant and unsuited for surgery is underway at The Epilepsy Center, New York University. The device, US Patent No. 6,497,699, is named the “Hybrid Neuroprosthesis”, or HNP. As the name implies, the invention is a hybrid of electrophysiological and pharmacological components that serves to correct abnormal neural functions, and, like other prostheses, it is fully implanted in the body.

The basic idea behind the development of the HNP is that since many forms of epileptic seizures originate in well-defined epileptogenic zones in brain, the optimal way to treat these seizures is to get access to the very sites of these epileptogenic zones and treat them locally.

There is a significant advantage to this strategy: It makes surgical tissue removal unnecessary and it allows the exposure of the epileptogenic zones to appropriately high concentrations of antiepileptic drugs without inducing side-effects from the drugs going through other parts of the brain or through the body.

Our goal is to translate this HNP strategy into a medical implant that:

• Records electrophysiological activity in the epileptogenic zones,
• Recognizes abnormal electrophysiological signals prior to an imminent clinical seizure, and
• Prevents the development of this seizure by delivering antiepileptic drugs into the epileptogenic zones.

Preclinical trials

Since the announcement of this research program, our research team has made significant progress in the preclinical work that should precede the actual clinical trials.

First, we refined the animal model that serves to test the function of the HNP before the clinical trials. Some key data were published in 2004, in the journal Epilepsia (vol. 45; Suppl.7; pages 212-213). This animal model, employing monkeys, is necessary, as neither computer models nor tissue cultures or slice preparations are able to simulate the complex interactions between an epileptogenic zone and an implanted HNP.

Second, to extract as much information from these demanding animal experiments as possible, we collected new data for demonstrating that localized antiepileptic drug deliveries in the primate brain do produce antiepileptic effects, and that the intracranial catheters for such drug deliveries cause no apparent behavioral abnormalities or harmful tissue damage.

Third, we modified our original HNP software, named “SeizureGuard”, for recognizing abnormal, epileptiform EEG signals in the mentioned monkey model of epilepsy.

HNP software development

We have made progress in developing a second version of this software, which can recognize abnormal epileptiform EEG signals in epileptic patients prior to clinical seizures. This software development effort uses electrophysiological data collected with our Nicolet EEG systems at Tisch Hospital. A unique feature of the SeizureGuard software is that it uses relatively simple calculations, and, as a consequence, it can run on processors that do not consume much electricity. For fully implanted devices, such as the HNP, this will be an important advantage. Furthermore, our most recent laboratory studies have revealed that seizures can be better predicted if EEG recordings are complemented with neuronal action potential recordings from the epileptogenic zone. We are in the process of modifying the SeizureGuard software accordingly and testing the ability of the HNP to deliver antiepileptic drugs in response to the signs of an imminent seizure

HNP drug delivery unit development

Our collaboration with Lenox Laser (Glen Arm, Maryland) led to a $369,890 grant from the National Institutes of Health. While the primary aim of this project is to develop a method for delivering and sampling proteins in brain, it has also helped us to improve the drug delivery catheter of the HNP. This improved catheter will allow the delivery of antiepileptic drugs via laser-made, microscopic perforations, filtering out the surrounding brain cells and thus eliminating the possibility of catheter-clogging.

A milestone was reached by completing the development of the first prototype of the minipump that will mediate the drug deliveries into the epileptogenic zones. This cylindrical, miniature peristaltic pump, weighing less than 15 grams and having a diameter of as small as 15 mm, can be periodically refilled through the skin and is also able to periodically deliver a second drug solution to prevent unwanted tissue reactions in the HNP-treated area. Importantly, the design of this minipump allows its continuous control by the SeizureGuard software. As a consequence, the minipump will be able to deliver drugs into the brain only when necessary,for the duration of the electrophysiological signs of an imminent epileptic seizure to prevent the seizure itself.

While the HNP is designed to treat both cortical and subcortical epileptic areas, we have been concentrating our efforts to first develop the version that specifically treats cortically originating seizures. Over the past year, we have finalized studies in lab rats, proving the ability of subdurally delivered antiepileptic drugs to diffuse into the underlying seizure focus and prevent focal seizure. Some of these studies were published in Epilepsia (vol. 47; pages 1792-1802) and Brain Research (vol.1188, pages 228-232). Building on these results, we have been able to demonstrate for the first time that subdural drug deliveries can eliminate focal epileptiform spikes in epilepsy patients (publication in press in Epilepsy Research).

We are beginning the next phase of these studies with four objectives. These are: (1) to complete the SeizureGuard software, (2) to identify the optimal antiepileptic drug solution in rats, (3) to implant the prototypes of the device in monkeys, and (d) to expand on the "human proof of concept" in clinical studies. This project can have a great impact on therapy for epilepsy and other neurological disorders such as stroke, Alzheimer's and Parkinson's disease.

Nandor Ludvig, MD, PhD, is the Principal Investigator on this project. Orrin Devinsky, MD, Co-Founder of the Epilepsy Therapy Project is Director of the Comprehensive Epilepsy Center at NYU and Ruben I. Kuzniecky, MD, are co-investigators on this project.

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