On-demand pulsatile intracerebral delivery of carisbamate with closed-loop direct neurostimulation therapy in an electrically induced self-sustained focal-onset epilepsy rat model.
OBJECTIVE
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 intracerebral 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 hippocampus 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 [(14)C]-carisbamate (n = 4), or on-demand [(14)C]-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 [(14)C]-autoradiography 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 ondemand 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 pathways 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.
Departments of 1Neurosurgery and.
Erwin Z
EZ
Mangubat
Departments of 1Neurosurgery and.
Robert G
RG
Kellogg
2Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
Timothy J
TJ
Harris
2Neurological Sciences, Rush University Medical Center, Chicago, Illinois.
Marvin A
MA
Rossi
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000627:therapeutic use; D002219:Carbamates / Q000008:administration & dosage* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004599:Electric Stimulation Therapy; D004828:Epilepsies, Partial / Q000188:drug therapy / Q000628:therapy*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D016896:Treatment Outcome
D000927:Anticonvulsants; D002219:Carbamates; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol
AD = after-discharge; AED = antiepileptic drug; BBB = blood-brain barrier; CED = convection-enhanced delivery; CHS = continuous hippocampal stimulation; DG = dentate gyrus; ECOG = electrocorticography; NeuroPace; PP = perforant pathway; SSLSE = self-sustained limbic status epilepticus; TTL = transistor-transistor logic; convection enhanced drug delivery; deep brain stimulation; epilepsy; microfluidic electrode; neuromodulation; responsive neurostimulation; white matter