Convection-Enhanced Delivery in the Treatment of Epilepsy

Abstract

Summary: Convection-enhanced delivery (CED) is a novel drug-delivery technique that uses positive hydrostatic pressure to deliver a fluid containing a therapeutic substance by bulk flow directly into the interstitial space within a localized region of the brain parenchyma. CED circumvents the blood-brain barrier and provides a wider, more homogenous distribution than bolus deposition (focal injection) or other diffusion-based delivery approaches. A potential use of CED is for the local delivery of antiseizure agents, which would provide an epilepsy treatment approach that avoids the systemic toxicities of orally administered antiepileptic drugs and bystander effects on nonepileptic brain regions. Recent studies have demonstrated that brief CED infusions of nondiffusible peptides that inhibit the release of excitatory neurotransmitters, including -conotoxins and botulinum neurotoxins, can produce long-lasting (weeks to months) seizure protection in the rat amygdala-kindling model. Seizure protection is obtainable without detectable neurological or behavioral side effects. Although conventional diffusible antiepileptic drugs do confer seizure protection when administered locally by CED, the effect is transitory. CED is a potential approach for seizure protection that could represent an alternative to resective surgery in the treatment of focal epilepsies that are resistant to orally-administered antiepileptic drugs. The prolonged duration of action of nondiffusible toxins would allow seizure protection to be maintained chronically with infrequent reinfusions.

Long-Lasting Attenuation of Amygdala-Kindled Seizures after Convection-Enhanced Delivery of Botulinum Neurotoxins A and B into the Amygdala in Rats

“…CED has an advantage over other brain delivery methods in that the distribution of the therapeutic agent within a brain volume can be restricted (Rogawski, 2009). At the same time, CED permits uniform delivery within the target zone; however, leakage can occur.…”

“…In the present study, we sought to assess the potential of locally delivered botulinum neurotoxins to confer seizure protection in the amygdala kindling model, an experimental paradigm that allows assessment of the duration of toxin action for weeks to months. We administered the toxins using convection-enhanced delivery (CED), which provides a larger and more homogeneous distribution than conventional bolus injection and does not damage the surrounding tissue (Gasior et al, 2007;Rogawski, 2009). …”

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…Drug therapy using direct CED in brain been reported for treating glioma [7] and epilepsy [8]. CED-based in vitro, ex vivo and in vivo animal models have led to active genetherapy trials for treating Parkinson disease (PD)and are supported by histological studies on disease pathology [9].Use of MRI navigation in some clinical trials, helps accurately targeting and providing real time monitoring of viral vector delivery (rCED).…”

The Epilepsy Spectrum: Targeting Future Research Challenges

“…In the future, cell transplants that generate endogenous neurotransmitters and neuromodulators may have a role in epilepsy. Convection-enhanced delivery is a novel drugdelivery technique that uses positive hydrostatic pressure to deliver a fluid containing a therapeutic substance by bulk flow directly into the interstitial space within a localized region of the brain, circumventing the BBB and providing a wide and homogenous distribution of the drug (Rogawski 2009). Gene therapy may be useful in local drug delivery with the use of adenovirus, adenoassociated virus, herpesvirus, or other delivery vectors to induce brain cells to produce local modulatory substances (Boison 2007).…”