Next, we have Dr. David Argersinger, Trial of Convection-Enhanced Delivery of Mucemol in Patients with Medically Intractable Epilepsy. Thank you for the introduction. Thanks for having me here today. My name is Davis Argersinger. I'm a post-baccalaureate research assistant in the Surgical Neurology Branch at the NIH, and I'm here to present on convection-enhanced delivery of mucemol in patients with drug-resistant epilepsy. This research was funded by the Intramural Research Program at the NIH. So, minimally invasive therapies for drug-resistant epilepsy have been advocated, and one such therapy is convection-enhanced delivery, a minimally invasive method for infusion of pharmacological agents into the extracellular space of the brain. And for this study, we sought to investigate the role of mucemol, a potent and selective GABA-A receptor agonist, the role of its treatment in treating drug-resistant epilepsy. Its role in neuronal suppression has previously been investigated in animal studies, and in a past clinical trial, it was safely delivered to the brains of humans with movement disorders. It has not, however, been delivered to the brains of humans using convection-enhanced delivery. As I mentioned, convection-enhanced delivery is a selective neuropharmacological treatment modality. It's minimally invasive, provides an opportunity to bypass the blood-brain barrier and thus avoid side effects associated with systemic therapies for epilepsy. It's focally suppressive, meaning in our study, the selective inhibitory effects of mucemol were limited to our target structures, and it's also been studied extensively in non-human primates at the NIH. However, as I mentioned, this study is the initial introduction of mucemol into the human brain by convection-enhanced delivery. So given all that, our objective was to investigate the safety and effectiveness in suppressing seizures of intracerebral mucemol infusion into the epileptic focus of patients with drug-resistant epilepsy. Our outcomes included seizure frequency, changes in epileptiform discharge activity, and changes in beta frequencies. Here's our study design. Seizure foci of our patients were localized using video EEG and electrocorticography before placement of the depth electrode catheter. Depth electrode catheter EEG recording took place for five days before the intracerebral infusion studies, which occurred over two days. Following the infusion studies, patients underwent standard surgical procedure for their respective epilepsy diagnoses, and after the standard surgical procedure, patients were followed for two years. In total, we enrolled three patients to be eligible for participation among other criteria. Patients must have had persistent, drug-resistant, simple or complex partial seizures occurring at least twice per month. Our first patient was a 44-year-old woman with a 10-year history of left index finger twitching, which progressively worsened over time to include her entire hand and arm. Our second patient was a 26-year-old male whose seizures began at age three. He experienced three to four seizures per month since that time before enrolling in the study. And our third patient was a 34-year-old man whose first seizure occurred at age 23. He had complex partial and generalized seizures over the next 11 years. Again, across all three patients, symptoms did not adequately improve with AEDs. So all three patients underwent convection-enhanced delivery for 12 to 24 continuous hours of an artificial CSF vehicle and one or two milliliters of mucemol into the seizure focus using a crossover design. A modified depth electrode catheter was used for all infusions shown here. There's a central lumen that was used for infusion of fluids and here the electrodes can be seen. The same catheter design was used by Dr. Dennis Spencer and colleagues at Yale in previous microdialysis studies. So for all patients, AEDs were slowly withdrawn leading up to the infusion periods to evoke seizure activity and then they were resumed after infusion completion. As you can see here in patient three, the dose was escalated after the first two had tolerated their dose as well. The study team was masked the identity of the infusate. However, mucemol was purposely infused after vehicle and all infusions in order to avoid any carryover effects of mucemol remaining in the lumen used for infusions. Here's imaging for patient one again. Here's the design of the depth electrode catheter. Here we can see the white arrow pointing to cortical laminar sclerosis and the right precentral gyrus. This patient was diagnosed with epilepsy of partialis continua. Interoperatively, methyl methacrylate was used to anchor the depth electrode catheter to nylon screws that were implanted. And then here MRI was used to confirm placement of the depth electrode catheter in this case in the right motor cortex. For patient two, pre-study imaging confirmed diagnosis of mesiotemporal sclerosis shown here in A and B. Operations took place in the interoperative MRI suite with Lexel frame and surface coils. This is just an example of the interoperative placement of the depth electrode catheter. And here in images F through H, MP-RAGE imaging was used to confirm the precise placement of the tip of the depth electrode catheter medial to the temporal horn and shown here inferior to the lateral ventricle. Here's T2 axial imaging. This was after depth electrode placement but before the infusions began. Here's during vehicle infusion, during mucemal infusion and 24 hours post-infusion. The main takeaway from this slide was that infusion of our fluids was difficult to visualize, suggesting that future trials should use a surrogate tracer to better visualize distribution of infused fluid. On to patient three, pre-study imaging was inconclusive of lesions that would evoke drug-resistant epilepsy. And again, MP-RAGE imaging was used to confirm precise placement of the depth electrode catheter. And then again, T2 imaging during the infusions. The white arrow here shows the depth electrode component of the depth electrode catheter. And again, surrogate tracer would be advised in future trials to better visualize fluid distribution. So under the result, seizure frequency was reduced in patient one during mucemal infusion but unchanged in patients two and three. Patient one had six seizures on average per day during the pre-infusion recording period. Four during the vehicle infusion and no seizures during mucemal infusion. Patient two did not have seizures during vehicle or mucemal infusion. And patient three had two seizures during both the vehicle infusion and mucemal infusion. Slightly above average and slightly due to the fact that AEDs, as I said, were withdrawn throughout the infusion period. The EEG recordings, here's a sample EEG for patient one. And A, before mucemal infusion, B, during, and C, after. So epileptiform discharge frequency improved in patient one during mucemal infusion. She had periods of up to 15 seconds with no epileptiform discharges during mucemal infusion compared to discharges that were seen every one to three seconds during the pre-infusion recording period. Patients two and three, both infrequent epileptiform activity with no appreciable change in discharge frequency was seen before, during, or after infusion periods. And across all patients, all three patients, upon power spectral analysis, mean beta frequencies did not vary significantly in any of the three patients. After standard surgery outcome, patient one experienced a notable reduction in seizure frequency. She underwent multiple sub-peel transactions as her seizure focus was located in the eloquent cortex. Patients two and three were seizure-free during the two-year follow-up period after anterior temporal lobectomy. So in conclusion, convection-enhanced delivery of mucemal into the epileptic focus of patients with drug-resistant epilepsy did not damage adjacent brain parachroma or adversely affect seizure surgery outcome. This first-in-human study was safe across all trials and effective in one of three patients at reducing seizure frequency during mucemal infusion. And as I mentioned, a surrogate tracer should be used to track infusion distribution within the epileptic focus and surrounding structures in future clinical trials using convection-enhanced delivery. I'd like to thank everyone at the NIH for their help with this project, and thank you especially Dr. John Heiss. Thank you very much. Any questions? Yes, Dr. Salas. Yes, I'm surprised that didn't work for two patients. And one of the drawbacks of this convection technology in general is what you showed in your MRI scan. This is the backtrack of everything you inject in the brain. The least pathway is always the pathway you already made in the brain. Can you comment on that? Is that anything that you have been thinking to solve this problem? Is the result, I won't say poor result, the failure to control epilepsy in the two last cases the fact that all the emotional came back and you really didn't infuse where the focus of epilepsy was? Yes, we weren't entirely sure if that was in fact backtracking or if it was some type of edema from the placement of the catheter. In previous animal studies performed by members in the surgical neurology branch, that was an early problem, especially non-human primates. And I know they took measures to modify catheters that were used and step cannulas and two-step cannulas and trying to come up with a design that had worked, and I think they had gained valuable results in their primate studies. But going forward, that's a design that we'd want to evaluate in future human trials, especially if we're using a similar catheter design. So that's a great question. Thank you. Thanks. APPLAUSE

convection-enhanced delivery

mucemol

drug-resistant epilepsy

seizure frequency

surrogate tracer