Parametric subtracted post-ictal diffusion tensor imaging for guiding direct neurostimulation therapy.

Parametric subtracted post-ictal diffusion tensor imaging (pspiDTI) is a novel imaging technique developed at our center to visualize transient, patient-specific, ictal-associated water diffusion abnormalities in hippocampal-associated axonal tissue. PspiDTI can elucidate putative connectivity patterns, tracing ictal propagation following a partial-onset seizure without generalization secondarily. PspiDTI compares two DTI volumes acquired during the early post-ictal period (<4 hr), and baseline inter-ictal interval (>24 hr post-seizure). This technique performs a voxel-wise parametric test to identify statistically significant transient ictal-associated changes in water diffusivity involving white matter (WM). Our technique was applied to six patients with refractory partial-onset epilepsy who were candidates for direct cortical responsive neurostimulation (RNS) therapy. Global and region-specific fractional anisotropy decreases, relative to baseline, were detected in all patients with a 17.01% (p < .01) relative mean decrement, while trace increases were found in 6/6 (100%) patients with a 13.30% (p < .01) relative global mean increment. Changes in diffusivity were anatomically compared with transient hyper-perfusion as detected by subtracted ictal SPECT co-registered to MRI (SISCOM). In 5/6 (83.33%) patients, alterations in WM diffusivity were detected adjacent to the SISCOM signal localized predominantly in gray matter. In 4/6 patients, post-implant RNS electrocorticography revealed early ictal propagation between implanted RNS depth leads guided by pspiDTI, hence validating concordant abnormal diffusivity regions detected by our technique. PspiDTI can complement the conventional pre-surgical evaluation to provide additional crucial information regarding WM ictal-propagation pathways between predominantly gray matter ictal-onset zones. When incorporated into a multi-modality pre-surgical workflow, pspiDTI can aid in defining critical nodes between ictogenic regions. This information can be used to strategically implant a limited set of two RNS depth leads for maximizing the extent to which direct cortical RNS can modulate a potentially extensive epileptogenic network.

On-demand pulsatile intracerebral delivery of carisbamate with closed-loop direct neurostimulation therapy in an electrically induced self-sustained focal-onset epilepsy rat model.

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 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.

Epilepsy surgery and vagal nerve stimulation: what all neurologists should know.

Epilepsy surgery treatment should be considered as standard of care for all patients with medically intractable partial-onset epilepsy who are found to be good surgical candidates based on their presurgical evaluation. Delaying surgical treatment continues to be a problem among neurologists. The early recognition of pharmacoresistance and patients' referral for presurgical evaluation can shorten the time to identify potential surgical candidates. A successful early surgery can be expected to significantly improve these patients' quality of life, not only because of a seizure-free state but also by improving psychiatric comorbidities. Vagal nerve stimulation (VNS) is currently the only FDA-approved neurostimulation treatment strategy for patients who are not considered candidates for epilepsy surgery. VNS has been shown to decrease seizure frequency by approximately 50% in 30 to 40% of implanted patients. The future of epilepsy surgery and neurostimulation for those individuals with medically intractable partial-onset epilepsy shows great promise.