Abstracts

Rationale: Temporal Lobe Epilepsy (TLE) is the most common partial-onset epilepsy and often refractory to antiepileptic drugs. Convection-enhanced delivery (CED), a method of targeted drug delivery, has been proposed as a novel epilepsy treatment due to reduced systemic toxicity and potential to deliver therapeutic agents that cannot be administered orally. However, local drug delivery must be monitored to ensure sufficient targeting, and supplemented with detailed characterization of the underlying neuroarchitecture governing infusate distribution. Since previous reports have shown distributions within the hippocampus are influenced by its underlying structure, it is reasonable to expect variability of infusate distribution in structurally injured hippocampi. Therefore, CED was implemented to study extracellular transport in a pre-clinical rodent model of chronic limbic epilepsy. Using CED, MR imaging, and histology, we investigated the pattern of distribution of a contrast agent and the controlling factors of its spread in the hippocampus of rats that have undergone electrically-induced self-sustaining status epilepticus (SSSE), an unremitting seizure known to cause neuronal damage and edema in the hippocampus and associated structures. Methods: Male Sprague-Dawley rats were surgically implanted with a cannula guide into the dorsal hippocampus and with electrodes into the ventral hippocampus, then stimulated to undergo SSSE. 24 hours later, MR imaging was performed in vivo in an 11.1T magnet system. High-resolution T1 and T2-weighted images were acquired prior to infusion to generate baseline contrast enhancement images (T1) and to visualize morphological changes (T2). Animals were then infused at a rate of 0.3 l/min with 5 l of MR contrast agent, albumin labeled gadolinium-DTPA chelate (Gd-albumin) that was tagged with Evans blue dye. Immediately following infusion, high resolution T1 imaging was repeated to visualize distribution profiles of the contrast agent. Perfusion-fixation was performed for histological assessment. Fluorojade C, Cresyl violet, GFAP, IBA-1, and CD-68 staining was used to visualize neuronal degeneration, cell swelling, astrocytic response, microglial activation, and macrophage proliferation resulting from SSSE.Results: An episode of SSSE resulted in structural changes within hippocampal and parahippocampal structures at 24 hours post-SSSE, as evidenced by T2-weighted images and verified in histological preparations. Infusions of Gd-albumin into injured hippocampi resulted in larger volume distribution (V_d) profiles that correlated with increased injury severity. Among measured stimulation parameters such as electrical stimulation intensity and duration, only the time required to return to baseline EEG was correlated with V_d.Conclusions: This is the first study to monitor CED in an animal model of epilepsy with MR and histology. Our results demonstrate CED can reliably deliver infusate throughout the hippocampus, but injury may result in acute changes in hippocampal structure that in turn are factors that influence distribution volume.