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On-Demand Pulsatile Intracerebral Delivery of Carisbamate with Closed LABORATORY INVESTIGATION J Neurosurg 122:1283–1292, 2015 On-demand pulsatile intracerebral delivery of carisbamate with closed-loop direct neurostimulation therapy in an electrically induced self-sustained focal-onset epilepsy rat model Erwin Z. Mangubat, MD, MPH,1 Robert G. Kellogg, MD,1 Timothy J. Harris Jr.,2 and Marvin A. Rossi, MD, PhD2 Departments of 1Neurosurgery and 2Neurological Sciences, Rush University Medical Center, Chicago, Illinois OBJECT The authors evaluated the preclinical feasibility of acutely stabilizing an active bihemispheric limbic epileptic circuit using closed-loop direct neurostimulation therapy in tandem with “on-demand’” convection-enhanced intracere- bral delivery of the antiepileptic drug (AED) carisbamate. A rat model of electrically induced self-sustained focal-onset epilepsy was employed. METHODS A 16-contact depth-recording microelectrode was implanted bilaterally in the dentate gyrus (DG) of the hip- pocampus of Fischer 344 rats. The right microelectrode array included an integrated microcatheter for drug delivery at the distal tip. Bihemispheric spontaneous self-sustained limbic status epilepticus (SSLSE) was induced in freely moving rats using a 90-minute stimulation paradigm delivered to the right medial perforant white matter pathway. Immediately following SSLSE induction, closed-loop right PP stimulation therapy concurrent with on-demand nanoboluses of the AED [14C]-carisbamate (n = 4), or on-demand [14C]-carisbamate alone (n = 4), was introduced for a mean of 10 hours. In addition, 2 reference groups received either closed-loop stimulation therapy alone (n = 4) or stimulation therapy with saline vehicle only (n = 4). All animals were sacrificed after completing the specified therapy regimen. In situ [14C]-autora- diography was used to determine AED distribution. RESULTS Closed-loop direct stimulation therapy delivered unilaterally in the right PP aborted ictal runs detected in either ipsi- or contralateral hippocampi. Freely moving rats receiving closed-loop direct stimulation therapy with on- demand intracerebral carisbamate delivery experienced a significant reduction in seizure frequency (p < 0.001) and minimized seizure frequency variability during the final 50% of the therapy/recording session compared with closed-loop stimulation therapy alone. CONCLUSIONS Unilateral closed-loop direct stimulation therapy delivered to afferent hippocampal white matter path- ways concurrent with on-demand ipsilateral intracerebral delivery of nano-bolused carisbamate can rapidly decrease the frequency of electrographic seizures in an active bihemispheric epileptic network. Additionally, direct pulsatile delivery of carisbamate can stabilize seizure frequency variability compared with direct stimulation therapy alone. http://thejns.org/doi/abs/10.3171/2015.1.JNS14946 KEY WORDS deep brain stimulation; convection enhanced drug delivery; microfluidic electrode; white matter; NeuroPace; epilepsy; responsive neurostimulation; neuromodulation ESPITE treatment with antiepileptic medications, togenic source or focus is present within a subset of these approximately 30% of patients with epilepsy con- patients, and this group is likely to respond to time-tested tinue to experience seizures.5 Pharmacological re- resective surgery. Unfortunately, the remaining pharmaco- Dsistance in focal-onset epilepsy is defined as the failure of resistant patient population will not meet criteria for resec- at least 2 appropriate antiepileptic drugs (AEDs) at maxi- tive surgery. Such patients possess one or more epilepto- mally tolerated doses, with a low probability of becoming genic sources involving eloquent cortex or have elusive seizure free with additional AEDs.13 A localizable epilep- foci or epileptic networks. ABBREVIATIONS AD = afterdischarge; AED = antiepileptic drug; BBB= blood-brain barrier; CED = convection-enhanced delivery; CHS = continuous hippocampal stimula- tion; DG = dentate gyrus; ECOG = electrocorticography; PP = perforant pathway; SSLSE = self-sustained limbic status epilepticus; TTL = transistor-transistor logic. SUBMITTED May 12, 2014. ACCEPTED January 5, 2015. INCLUDE WHEN CITING Published online February 27, 2015; DOI: 10.3171/2015.1.JNS14946. DISCLOSURE This study was supported by an investigator-initiated research grant from Ortho-McNeil Janssen Scientific Affairs, LLC. ©AANS, 2015 J Neurosurg Volume 122 • June 2015 1283 Unauthenticated | Downloaded 10/09/21 12:36 AM UTC E. Z. Mangubat et al. The underlying mechanisms of pharmaco-resistant epi- the Rush University Institutional Animal Care and Use lepsy are multifactorial.18,34 A major factor that limits sys- Committee. All animals were individually housed and ac- temic administration of AEDs is the unwanted side effects climated for at least 10 days upon arrival from the Harlan of the therapeutic agent on brain systems not involved in colony. They were kept under environmentally controlled the epileptogenic process. In focal-onset epilepsies, side ef- conditions (12-hour light/dark cycle at 20°C–23°C) and fects and systemic toxicities can be minimized or avoided 50% relative humidity with ad libitum Wayne food pellets by restricting delivery of the therapeutic agent to a limited and water. region of brain.27 Convection-enhanced delivery (CED) has shown some promise for treating certain neurological dis- Surgery eases by circumventing the blood-brain barrier (BBB) and, Preoperatively, each animal was anesthetized with in- therefore, bypassing BBB-associated AED transporters 34 traperitoneal pentobarbital (50 mg/kg). Hair was removed that can contribute to pharmacoresistance. CED’s abil- from the rat’s head with an electric shaver. The skin was ity to deliver therapeutics directly to the central nervous prepared with a 1% tincture of iodine and chlorhexidine- system parenchyma provides a potential approach for more 3,8,26 based scrub product. A customized 16-contact microelec- effectively treating refractory focal-onset epilepsies. trode probe with an integrated 0.25-mm-inner-diameter In recent years, implantable direct brain stimulation stainless steel catheter (NeuroNexus Technologies) (Fig. therapy has gained momentum for the treatment of phar- 1) was implanted in the right hippocampal dentate gyrus maco-resistant epilepsy. The Responsive Neurostimulation (DG) (1.4 mm lateral to bregma, depth 4.2 mm from corti- System (RNS, NeuroPace, Inc.) is a closed-loop implant- cal surface).30 A 16-contact microelectrode without fluidic able direct neuromodulation technology recently approved capabilities (NeuroNexus Technologies) was implanted by the FDA as an adjunctive therapy in individuals who in the left DG. Due to limited recording instrumentation have pharmaco-resistant focal-onset epilepsy with up to capabilities, only 8 contacts were used on each side. A 2 epileptogenic sources. Efficacy of the NeuroPace RNS twisted pair of Teflon-coated stainless steel bipolar stimu- capitalizes on a closed-loop approach where direct stimu- lating electrode wires was positioned in the right middle lation is delivered to an epileptogenic source upon detec- perforant pathway (PP) (8 mm posterior and 2 mm lateral tion of an evolving electrographic seizure with the goal to bregma). The PP in the rat demonstrates well-developed of inhibiting its development and propagation. A recent axonal afferents to the hippocampal formation.1 These pivotal, randomized controlled trial evaluating the effi- inputs are particularly robust in the DG. The stimulat- cacy of the NeuroPace RNS has demonstrated a statisti- ing electrode was stereotactically lowered to a depth that, cally significant reduction in seizures in the stimulation upon stimulation, would result in a characteristic evoked arm compared with the sham phase.25 As a result, the FDA potential from each contact in the dentate gyri bilaterally. Neurological Devices Panel unanimously recommended Additionally, final implant depth coordinates of the DG the approval of the NeuroPace RNS in February 2103. The microelectrodes were guided by evoking neuroanatomi- system received final FDA approval in late 2013. cally specific electrophysiological signatures via the right This study examines the feasibility of augmenting ter- PP stimulating electrode. Specifically, evoked waveforms mination of the seizure onset in a rat model of focal-onset consisting of an excitatory postsynaptic potential and su- epilepsy through a combination of responsive direct brain stimulation and on-demand nano-volume bolused intrace- rebral CED of a novel AED, carisbamate (RWJ 333369, Ortho-McNeil Janssen; now known as YKP509, SK Bio- pharmaceuticals). Carisbamate has previously been proven to be an effective AED in animal models of focal-onset ep- ilepsy and infantile spasms.14,29,38 Unlike established AEDs (carbamazepine, phenytoin, lamotrigine, and topiramate), carisbamate demonstrates activity in the lamotrigine-resis- tant amygdala kindled rat.14 Carisbamate’s efficacy against recurrent spontaneous seizures in the kainate poststatus epilepticus model7 and the GAERS model of spike-wave epilepsy has been previously proven.2 This study uses the electrically induced self-sustained limbic status epilepticus (SSLSE) epilepsy model in rats modified from Lothman et al.19 and Mazarati et al.22 Methods Animals FIG. 1. Photograph of the drug delivery, stimulation, and recording de- vice used in this study (upper) and schematic diagram of the electrode Twenty-eight Fischer 344 male rats (weight 275–355 array showing the position of the 16 stimulating/recording
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